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Organometallic Chemistry Research Perspectives 1st
Edition Richard P. Irwin Digital Instant Download
Author(s): Richard P. Irwin
ISBN(s): 9781606928745, 1606928740
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Year: 2008
Language: english
ORGANOMETALLIC CHEMISTRY
RESEARCH PERSPECTIVES
ORGANOMETALLIC CHEMISTRY
RESEARCH PERSPECTIVES
RICHARD P. IRWIN
EDITOR
Nova Science Publishers, Inc.

New York
Copyright © 2007 by Nova Science Publishers, Inc.
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LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA

Organometallic chemistry research perspectives / Richard P. Irwin, editor.
p. cm.
Includes index.
ISBN-13: 978-1-60692-874-5
1. Organometallic chemistry--Research. I. Irwin, Richard P.
QD411.O665 2006
547'.05--dc22
2007019178
Published by Nova Science Publishers, Inc. New York

CONTENTS
Preface vii
Chapter 1 Polyhedral Boron Hydrides in Use:
Current Status and Perspectives 1
Igor B. Sivaev and Vladimir I. Bregadze
Chapter 2 Hydrosilylation of CH2=CH- Groups Immobilized
on the Interlayer Surface of an Ion-Exchangeable
Layered Perovskite with Hydorochlorosilanes
and Oligosiloxanes 61
Seiichi Tahara, Kazuyoshi Ohta, Satoru Yoshioka,
Yosuke Takeda, Yuko Uchimaru
and Yoshiyuki Sugahara
Chapter 3 Use of Electrochemistry and Palladium Catalysts
for an Efficient Synthesis of Carbonyl Compounds 83
Isabella Chiarotto
Chapter 4 Mixed Transition Metal Acetylides with Different Metals
Connected by Carbon-Rich Bridging Units: On the Way
to Heteromultimetallic Organometallics 99
Heinrich Lang and Alexander Jakob
Chapter 5 Recent Advances in Organometallic Materials
Derived from Ferrocenylacetylide 165
Wai-Yeung Wong
Chapter 6 The Bio-Organometallic Chemistry of [2Fe2S] Models
Related to Iron Hydrogenase Active Site 197
Xiaojun Peng and Jun Hou
Chapter 7 Recent Advances in Organotin(IV) Complexes
Containing Sn-S Bonds 221
Abbas Tarassoli and Tahereh Sedaghat
vi Contents
Chapter 8 Organometallic Complexes of Rhodium(I), Iridium(I)

and Ruthenium(II) Containing Hemilabile Functionalized
Phosphine-Chalcogen Donor Ligands : Synthesis,
Reactivities and Applications 249
Dipak Kumar Dutta
Chapter 9 Electronic Properties of Transition Metal Carbene and
Silylene Complexes - A Quantum Chemical Study at
Selected Model Complexes 289
Uwe Böhme
Index 299
PREFACE
Organometallic chemistry is based on the reactions and use of a class of compounds (R-
M) that contain a covalent bond between carbon and metal. They are prepared either by direct
reaction of the metal with an organic compound or by replacement of a metal from another
organometallic substance. Research in organometallic chemistry is also conducted in the areas
of cluster synthesis, main-group derivatives in unusual oxidation states, organometallic
polymers, unstable organometallic compounds and intermediates in matrices, structure
determination of organometallic compounds in the solid state [X-ray diffraction] and gaseous
states [electron diffraction], and mechanisms of reactions of transient silylenes and related
species. In addition to the traditional metals and semimetals, elements such as selenium,
lithium and magnesium are considered to form organometallic compounds, e.g.
organomagnesium compounds MeMgI, iodo(methyl)magnesium and diethylmagnesium
which are Grignard reagents an organo-lithium compound BuLi butyllithium; Organometallic
compounds often find practical uses as catalysts, in the processing of petroleum products and
in the production of organic polymers. This book presents leading-edge new research in the
field.
Chapter 1 - This review is designed to highlight the current status and perspectives of
application of polyhedral boron compounds and their metal complexes. The main attention is
paid to application of polyhedral boron hydrides in medicine including boron neutron capture
therapy for cancer, radionuclide diagnostics and therapy, as well as antitumor activity of some
metal derivatives of carboranes. Boron neutron capture therapy - a binary cancer treatment
based upon the interaction of two relatively harmless species, a 10B nucleus and a thermal
neutron, which results in the formation of the highly energetic 4He and 7Li as products. These
fission products have an effective range of ~10 μm in tissue, thus, effectively limiting the
extent of cellular damage to approximately one cell diameter. Therefore, the selective
concentration of boron compounds within the tumor cells, followed by their capturing of
thermal neutrons, should result in localized destruction of the malignant cells in the presence
of the normal cells. Another possible medical application of polyhedral boron hydrides is
radionuclide diagnostics and therapy of cancer, where these compounds can be used for
attachment of radionuclide labels to various cancer-targeting biomolecules. Other fields of
potential application of polyhedral boron hydrides and their metal complexes are synthesis of
new materials (liquid crystals, NLO materials, magnets, semiconductors, etc.), radionuclide
extraction from nuclear wastes, ion-selective electrodes, production of thermally stable
viii Richard P. Irwin
polymers and high burning composite propellants, development of new catalysts for organic
synthesis.
Chapter 2 - Novel preparation of inorganic-organic hybrids using ion-exchangeable
layered perovskites via hydrosilylation has been explored. CH2=CH- groups were
immobilized on the interlayer surface through an alcohol-exchange-type reaction between an
n-propoxy derivative of HLaNb2O7·xH2O (HLaNb) with 4-penten-1-ol or 9-decen-1-ol to
form a CH2=CH(CH2)nO-derivative of HLaNb (n = 3 or 8), and hydrosilylation of the
CH2=CH- groups of the CH2=CH(CH2)nO- groups with SiH groups in hydrochlorosilanes,
hydride-terminated polydimethylsiloxane (H-PDMS) or octahydridosilsesquioxane (OHSQ)
was conducted subsequently. When the CH2=CH(CH2)3O-derivative of HLaNb was reacted
with dichloromethylsilane, trichlorosilane or H-PDMS, X-ray diffraction (XRD) patterns,
infrared (IR) adsorption, and 13C and 29Si CP/MAS nuclear magnetic resonance (NMR)
spectra showed the occurrence of hydrosilylation in the interlayer space. Although the XRD
pattern of the product of the reaction between the CH2=CH(CH2)8O-derivative of HLaNb and
OHSQ showed no notable increase in interlayer distance, the IR and 13C and 29Si CP/MAS
NMR spectra suggested the occurrence of hydrosilylation. The occurrence of hydrosilylation
between the CH2=CH- groups and OHSQ in the interlayer space was also indicated by a
comparison of the pyrolysis behavior of the product of the reaction between the
CH2=CH(CH2)8O-derivative of HLaNb and OHSQ with those of pyrolyzed HLaNb and the
pyrolyzed CH2=CH(CH2)8O-derivative of HLaNb. These results clearly demonstrate that
hydrosilylation in the interlayer space is a potential new method for preparing various organic
derivatives of ion-exchangeable layered perovskites.
Chapter 3 - The great utility of carbonylic compounds as starting materials is well known;
the importance of the carbonyl group derives from its reactivity, being susceptible to
nucleophilic attack at carbon and eletrophilic attack at oxygen. Transition metals can be used
as reagents and catalysts to bring carbon monoxide into many organic compounds. Among
transition metals, used in organic synthesis, palladium complexes offer versatile and very
useful synthetic methods for carbonylation reaction and, generally, for carbon-carbon bond
formation.
A lot of investigations aimed at the use of electrochemistry as a selective and
environment friendly tool in organic synthesis, have allowed to develop a new methodology
for palladium(II) catalyst recycling by means of its anodic oxidation at a graphite electrode in
the absence of any other co-catalyst or stoichimetric oxidant. This methodology was applied
to the synthesis of carbonyl compounds such as methyl acetylencarboxylates, starting from
alkynes, oxazolidin-2-ones, in very good yields, starting from 2-amino-1-alkanols, and N,N'-
disubstituted ureas starting from amines, in an very efficient synthesis.
The advantage of the anodic recycling at a graphite electrode of Pd(II) is that it proceeds
efficiently under atmospheric pressure of carbon monoxide, avoids the use of copper or halide
ions and high pressure of O2 gas which also implies the formation of water and causes
undesired side reactions.
Chapter 4 - The chemistry of mono- and bis(alkynyl) transition metal complexes,
modified ferrocenes, functionalized alkynyls, diaminoaryl NCN pincer molecules (NCN =
[C6H2(CH2NMe2-2,6)2]-), and 1,4- and 1,3,5-substituted benzene derivatives towards diverse
metal fragments will be discussed and serves to understand the manifold and sometimes
unexpected reaction behavior of such species. Interesting novel (hetero)bi- to undecametallic
compounds with often uncommon structural motifs are formed in which the respective
Preface ix
transition metal building blocks are connected by carbon-rich π-conjugated organic and/or
inorganic bridging units. The reactions based on the modular molecular “Tinkertoys”
approach depend upon the steric and electronic properties of the metal centers and ligands
involved, which also will be discussed. The electrochemical behavior of such 1-dimensional
molecular wire molecules, coordination polymers, star-like structured and dendritic oriented
transition metal systems, respectively, is presented as well.
Chapter 5 - There is a flurry of interest in the research community in the development of
carbon-rich bi- or multi-metallic assemblies containing π-conjugated chains. It has been
demonstrated that molecular wires comprising mixed-valence bimetallic fragments or remote
redox-active organometallic building blocks linked by all-carbon chains could be used in
molecular electronics, optoelectronic devices and chemical sensing appliances. In recent
years, the author has been engaged in the chemistry and material properties of oligoacetylenic
ferrocenyl complexes and their organometallic derivatives by virtue of their potential in
various areas of materials science. The synthesis, characterization, crystal structures, optical
spectroscopy and electrochemistry of a series of homometallic and heterometallic alkynyl
complexes end-capped with ferrocenyl entities which contain conjugated organic bridges will
be presented. The electronic and redox properties will be examined as a function of the chain
length and nature of the spacer group and the data are compared with the results obtained
from theoretical computational studies.
Chapter 6 - Hydrogenases are enzymes that catalyze the reversible uptake/evolution
hydrogen. The X-ray single crystal structure determinations have shown that the active site of
iron hydrogenase features the organometallic community of [2Fe2S] compounds. Small
molecular synthetic models, which structurally mimic the [2Fe2S] centre, serve as important
probes of structure and chemistry at the active site of Fe-only hydrogenase. The azadithiolate-
bridged diiron compounds that have been developed as structural model systems for Fe-only
hydrogenase are reviewed in this article. The functionalized diiron complexes which show
some ability to generate hydrogen are surveyed, with emphasis on the synthesis and the
electrocatalytic properties. The electrocatalytic properties of all complexes investigated by
cyclic voltammetry in the presence and absence of acid are described. In addition, the
application of electrochemical and IR spectroelectrochemical (SEC) techniques to the
elucidation of the details of the electrocatalytic proton reduction is described. The functional
mechanistic proposals are discussed from these work.
Chapter 7 - In view of widespread industrial and biomedical applications of
organotin(IV) compounds containing Sn-S bond, the synthesis, spectroscopic characterization
and X-ray strucrural studies of some novel organotin complexes with 2-amino-1-
cyclopentene-1-carbodithioic acid (ACDA) and its N-alkyl derivatives (RACDA) are
investigated and reviewed. The presence of competing reactive center in these
aminodithiocarboxylato ligands and the remarkable diversity in structure of organotin
dithiolates lead to the interest in the study of such sulfur-nitrogen containing ligands. X-ray
crystallographic studies of these organotin complexes show the bonding take place through
the dithioate moiety and reveal a variety of coordination geometry around the Sn atom. These
studies also show that an intramolecular hydrogen bond is formed between NH proton of
amine group and one of sulfur atoms from dithiolate moiety. In ACDA complexes the
neighboring molecules are oriented in such a way that an intermolecular hydrogen bond is
also formed between another NH proton and one sulfur atom of the neighboring molecule, so
that this sulfur atom is involved in one intra- and one inter-molecular hydrogen bonding. In
x Richard P. Irwin
this chapter the reaction of ACDA and RACDA (R= Et, Bu and Bz) with di- and tri-organotin
chlorides will be discussed and the characterization of complexes will be investigated in
solution and in solid state by spectroscopic methods and X-ray crystallography.
Chapter 8 - Organometallic complexes of rhodium, iridium and ruthenium have gained
much importance because of their novelty, reactivity and applications in diverse fields. Some
important examples of applications of such metal complexes as commercial homogeneous
catalysts are : L-DOPA synthesis(Rhodium(I)-chiral catalyst); Monsanto / B. P. Chemicals
process for carbonylation of methanol to acetic acid (Rhodium(I) catalyst) and the process
called ‘Cativa’ (Iridium(I) catalyst with Ru-complex activator). Neutral and cationic
rhodium(I), iridium(I) and ruthenium(II) complexes of functionalized phosphine-chalcogen
donors P-X (X = O, S, Se) ligands are of much interest in recent time because of expected
novel structures and stereo-chemical control in catalytic applications in various important
organic synthesis. Different types of P-X ligands like R2P-(CH2)n-COOX´, X´ = H / alkyl, n =
1-3; R2P-(CH2)nXR, R = alkyl/aryl; Ph2PC6H4COOMe; mono-, di- and tri-chalcogen
functionalized poly-phosphines such as Ph2P(CH2)nP(X)Ph2, (n =1-4),
MeC(CH2PPh2)2(CH2P(X)Ph2) and other ligands CO, COD (1,5-cyclooctadiene) etc. form
interesting metal complexes. Rhodium(I) carbonyl complexes containing bidentate chelating
ligand such as diphenylphosphinomethane oxide / sulphide / selenide have shown interesting
structural features. The chelated complex of the type [Rh(CO)Cl(2-Ph2PC6H4COOMe)] has
been synthesized and the X-ray structure indicates a long range intramolecular ‘Secondary’
Rh…O interactions (Rh – O distance 3.18 Å). The effect of chain length of the bifunctional
i.e. `Soft and Hard' donors chelating ligands of tertiary phosphines with functional carboxylic
acid or ester, or unequal softness of the chelating donors i.e. tertiary phosphines
functionalised with sulfur or selenium donors having aliphatic and aromatic backbones on the
‘Hemilability' of the metal - O / S / Se bonds are discussed. In chelate metal complexes
containing hemilabile ligands like P-X, the labile M-X bonds cleave and provide a vacant
potential coordination site for reversible binding of substrates to metal centre by dynamic
chelating ability i.e. by ‘Opening and Closing’ mechanism. The steric effect, electronic effect
and kinetics of oxidative addition (OA) reactions of the complexes with different
electrophiles like CH3I, C2H5I, C6H5CH2Cl etc. are discussed. The activation of small
molecules like CO, CH3I, I2, etc. by the metal complexes and evaluation as catalysts
precursors for carbonylation of alcohol are also discussed. The catalytic activities of suitable
metal complexes are reported for carbonylation, hydrogenation and hydroformylation of
important substrates for potential industrial organic compounds. The metal complexes of
types [Rh(CO)2Cl(P~O)] and [Rh(CO)Cl(P~O)2]; show high catalytic carbonylation reactions
of methanol to acetic acid / ester with high Turn Over Number(TON) of about 1500. The
metal complexes and the products were characterized mainly by Infrared, UV-Visible
spectroscopy, NMR studies, X-ray crystallography and GCMS technique.
Chapter 9 - Common features and principal differences between carbene and silylene
complexes of early and late transition metals are analyzed from a quantum chemical point of
view. Cp2Ti=EH2 and (OC)4Fe=EH2 with E= C, Si were chosen as representative examples
for that purpose. The nature of the transition metal carbon and silicon bond was analyzed with
CDA, NBO and the EHT-method. The distinctive properties of transition metal silylene
complexes are caused by two main reasons: the silylene substituent acts mainly as σ-donor,
and there is very weak π-bonding in silylene complexes.
In: Organometallic Chemistry Research Perspectives ISBN: 978-1-60021-780-7
Editor: R. P. Irwin, pp. 1-59 © 2007 Nova Science Publishers, Inc.
Chapter 1
POLYHEDRAL BORON HYDRIDES IN USE:

CURRENT STATUS AND PERSPECTIVES
Igor B. Sivaev and Vladimir I. Bregadze

A.N.Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, Moscow, Russia
ABSTRACT
This review is designed to highlight the current status and perspectives of application
of polyhedral boron compounds and their metal complexes. The main attention is paid to
application of polyhedral boron hydrides in medicine including boron neutron capture
therapy for cancer, radionuclide diagnostics and therapy, as well as antitumor activity of
some metal derivatives of carboranes. Boron neutron capture therapy - a binary cancer
treatment based upon the interaction of two relatively harmless species, a 10B nucleus and
a thermal neutron, which results in the formation of the highly energetic 4He and 7Li as
products. These fission products have an effective range of ~10 μm in tissue, thus,
effectively limiting the extent of cellular damage to approximately one cell diameter.
Therefore, the selective concentration of boron compounds within the tumor cells,
followed by their capturing of thermal neutrons, should result in localized destruction of
the malignant cells in the presence of the normal cells. Another possible medical
application of polyhedral boron hydrides is radionuclide diagnostics and therapy of
cancer, where these compounds can be used for attachment of radionuclide labels to
various cancer-targeting biomolecules. Other fields of potential application of polyhedral
boron hydrides and their metal complexes are synthesis of new materials (liquid crystals,
NLO materials, magnets, semiconductors, etc.), radionuclide extraction from nuclear
wastes, ion-selective electrodes, production of thermally stable polymers and high
burning composite propellants, development of new catalysts for organic synthesis.
1. INTRODUCTION
After the discovery of the first boranes by Alfred Stock in 1912 [1], these compounds
were considered for a long time as academic curiosities. The boom in borane chemistry
2 Igor B. Sivaev and Vladimir I. Bregadze
started at the end of 1940’s when some of them (B5H9 and B10H14) were believed to be most
powerful rocket fuels superior to the available hydrocarbon fuels.
The US Army launched Project HERMES in the late 1940’s, in 1952 the US Navy
Bureau of Aeronautics started Project ZIP, and in 1956 the US Air Force sponsored Project
HEF (High Energy Fuels). Many gifted scientists and engineers were mobilized for these
projects, all working under a veil of secrecy. At least five boron fuel production plants were
built in the USA and one plant was built in the USSR. In 1955 the US government launched a
major project to build a boron-fuel-powered long-range strategic bomber called the Valkyrie
XB-70A (“Boron Bomber”). Two of these magnificent jet aircraft were eventually built. One
XB-70A was destroyed in a mid-air collision with a fighter jet over California's Mojave
Desert, but the remaining bomber is on display at the Wright Patterson Air Force Base in
Ohio, USA. Although they never flew solely on boron fuel, their construction led to
technological advancements in the design of high speed aircraft. In fact, the XB-70A served
as a model for the design of the Concorde supersonic jet.
Ultimately, the era of boron fuels came to a close. By the end of the 1950s, new
generations of jet engines and new fuels involving liquid hydrogen and hydrazine made boron
fuels obsolete. Technical problems with boron fuels - including byproducts that decreased
engine function and high fuel consumption rates - had proved too hard to overcome. In 1959,
the US military cancelled the boron fuels program, having invested the equivalent in modern
currency rates of more than one billion dollars. Documents concerning the boron fuel projects
were declassified some later and the public could finally see the monumental scale of these
efforts [2].
2. MAIN TYPES OF POLYHERAL BORON HYDRIDES.

SYNTHESIS AND PROPERTIES
One of the most important and exciting events in the chemistry of the XX century was the
discovery of polyhedral boron hydrides at the end of 1950-s. Polyhedral boron hydrides are
characterized by electron-deficient bonding, meaning that there are too few valence electrons
for bonding to be described exclusively in terms of two-centered two-electron bonds. One
characteristic of electron-deficient structures is the aggregation of atoms to form unusual
three-centered two-electron bonds, which typically results in formation of trigonal boron
faces and hypercoordination [3]. In contrast to the known boron hydrides, the polyhedral
boron hydrides were shown to be exceptionally stable. Investigation of the properties of these
compounds led to the conclusion that these compounds have aromatic properties [4]. It was
the first example of non-planar three-dimensional aromatic compounds and resulted to
development of concept of three-dimensional aromaticity that is generally accepted at the
present time [5].
The closo-decaborate anion [B10H10]2- (Figure 1) is the first known representative of
family of the closo-polyhedral boron hydrides. Its synthesis was first reported by Hawthorne
and Pitochelli in 1959 [6]. The classical method of synthesis of the closo-decaborate anion is
based on the reaction of decaborane(14) B10H14 and triethylamine in boiling toluene resulting
in the desired product in 92% yield [7]. The other method is based on the solid state pyrolysis
of tetraethylammonium tetrahydroborate (Et4N)BH4 and gives the target product in the yield
Polyhedral Boron Hydrides in Use: Current Status and Perspectives 3
up to 80 % [8,9]. Synthesis of numerous derivatives of the closo-decaborate anion has been

developed [4,10-19].
2- 2- - -
Co
[B10H10]2- [B12H12]2- [CB11H12]-
[3,3'-Co(C2B9H11)2]-
BH
CH
[1,2-C2B10H12] [1,7-C2B10H12] [1,12-C2B10H12]
Figure 1. Main types of stable polyhedral boron hydrides.
The closo-dodecaborate anion [B12H12]2- (Figure 1) was first prepared by Hawthorne and
Pitochelli in 1960 as a side-product of the reaction of 2-iododecaborane and triethylamine
[20]. This synthesis was the brilliant verification of the results of quantum-chemical
calculations performed by Longuet-Higgins and Roberts, who predicted in 1955 that the
icosahedral boron hydride system would be stable only as the [B12H12]2- dianion [21]. A few
years later several high-yield methods of its synthesis were proposed by different research
groups [22-26]. At present there are several preparative methods for synthesis of the
[B12H12]2- anion. Some of them are based on decaborane. Thus, pyrolysis of decaborane with
triethylamine-borane Et3N·BH3 at 190 oC in ultrasene gives the desired product in 92 % yield
[23,24,27]. Another widely used in laboratory practice method is reaction of decaborane with
NaBH4 in refluxing diglyme giving the target product in 91% yield [25,28]. Other methods
are based on commercial bulk chemicals and avoid highly toxic and expensive decaborane.
Thus, pyrolysis of Na[B3H8] generated in situ by oxidation NaBH4 with iodine in diglyme
gives the desired product in the yield up to 90 % [29]. The solid-state synthesis from
potassium tetrafluoroborate KBF4 and calcium hydride CaH2 results in the target product in
more than 90% yield [30]. Another method includes use widely available boron materials,
such as boric acid and sodium borates in combination with various reducing agents [31].
Further development of this approach can give the [B12H12]2- anion in large amounts at a
reasonable price.
The B-H bonds in the closo-dodecaborate anion have a hydridic character and amenable
to attack by electrophilic reagents resulting in substitution of hydrogen atoms. There are two
distinct mechanisms for substitution in polyhedral boron hydrides, ordinary aromatic
electrophilic substitution and electrophile-induced nucleophilic substitution (EINS). The last
one includes abstraction of a hydride anion from a BH vertex under electrophilic attack (or by
Lewis acid) followed by attack of the “boronium ylide” formed with nucleophile [32].
Synthesis and chemical properties of the closo-dodecaborate anion and its derivatives have
been reviewed recently [33,34], some more recent reports are included [35-41].
The carba-closo-dodecaborate anion [CB11H12]- (Figure 1) was first prepared by Knowth
in 1967 in the multi-step synthesis starting from decaborane and sodium cyanide [42,43]. A
safer and more convenient modification of the synthesis was proposed later by Hermanek’s
group [44]. In an important recent advance, the two-step synthesis of the [CB11H12]- anion
from decaborane by Brellochs reaction with formaldehyde followed by insertion of two BH
vertices gives the desired product in yield up to 65 % [45]. Using substituted benzaldehydes
instead of formaldehyde at the first stage, the corresponding C-phenyl derivatives can be
prepared [46,47]. An alternative approach of the [CB11H12]- anion synthesis is the carbon
vertex insertion into the 11-vertex nido-precursor Na[B11H14] that is accessible in 50 % yield
in one-step reaction from NaBH4 and BF3·OEt2. The reaction of [B11H14]- with chloroform
under basic conditions results in the desired product in 20-25 % yield [48]. In the similar way,
the substituted C-phenyl derivatives can be prepared by the reaction of the [B11H14]- anion
with substituted benzyl chlorides [49].
The C-H bond in the [CB11H12]- anion is weakly acidic and can be deprotonated by strong
bases, whereas the B-H bonds have hydridic character and are amenable to attack by
electrophilic reagents. Synthesis and chemical properties of the carba-closo-dodecaborate
anion and its derivatives have been reviewed very recently [50].
The synthesis of ortho-carborane (1,2-dicarba-closo-dodecaborane 1,2-C2B10H12, figure
1) and some its C-substituted derivatives were first reported in 1963 independently by
chemists from the USSR and USA [51-54]. ortho-Carboranes are prepared by the reaction of
acetylenes (including both mono and disubstituted alkynes) with B10H12L2 generated in situ
from decaborane B10H14 and a weak Lewis base (L =/MeCN, R2S, R3N). The reaction can be
performed in the presence of a wide range of functional groups except the ones containing
acidic hydrogen atoms (acids, alcohols, amines, etc.). These functionalities must be protected
prior to conversion of an alkyne to a carborane. The meta- and para-carboranes (1,7- and
1,12-C2B10H12, Figure 1) are prepared by thermal isomerization of ortho-carborane. At 400-
500 oC ortho-carborane converts to the meta-isomer, which in turn rearranges to the para-
isomer between 600-700 oC [55].
The CH groups in the carboranes are weakly acidic and can be readily deprotonated by
strong bases (n-BuLi, NaNH2, etc.) generating carboranyl anions (or organometallic
derivatives CM) that are sufficiently nucleophilic to react with a wide range of electrophiles
including alkyl halides, carbon dioxide, aldehydes, acid chlorides [55-57]. In contrast, the
boron vertices can be derivatized using reactive electrophilic reagents [56-58].
One of the boron atoms adjacent to the both carbon atoms of ortho-carborane 1,2-
C2B10H12 and its derivatives can be removed using alkoxide bases [55], amines [59], or
fluoride ion [60] to generate 7,8-dicarba-nido-undecaborate anion [7,8-C2B9H12]- or its
derivatives. The [7,8-C2B9H12]- anion contains a bridging hydrogen atom which can be
readily removed with base to yield the dicarbollide dianion [7,8-C2B9H11]2-. The dicarbollide
dianion is formally isolobal to cyclopentadienide and has therefore been used to prepare a
wide range of organometallic complexes, including a carborane analogue of ferrocene, first
reported by Hawthorne and coworkers [61]. The cobalt bis(1,2-dicarbollide) anion [3,3’-
Co(1,2-C2B9H11)2]- (Figure 1), one of the very first metallacarboranes synthesized [62], is,
probably, the most studied and the most used at present time metallacarborane [63-72].
All the polyhedral boron hydrides described above are available from commercial
sources. It should be noted, however, that the polyhedron boron hydrides, especially those
produced from decaborane, are very expensive and find practical applications only in some
exclusive areas where no alternative exists. On the other hand, a revival in industrial
production of boron cluster compounds and their price reducing can be expected only after
the development of some important applications for these species.
Since the first review on potential applications of polyhedral boron hydrides published by
Plešek fifteen years ago [73] apparent progress in this fields has been demonstrated and in
this article we will make emphasis on the directions that have received the most development
since that time.
3. APPLICATION OF POLYHEDRAL BORON HYDRIDES

The era of boron chemistry aimed at advanced jet and rocket propulsion systems ended in
the early 1960s, however, the interest in the polyhedral boron hydrides as high energy density
materials still persists and some salts of the closo-decaborate and the closo-dodecaborate
anions were proposed as components of components of high burning composite propellants
[74]. However, the main interest in application of the polyhedral boron hydrides is connected
with medicine [57,75] and traditionally centered on their use in boron neutron capture therapy
for cancer [76,77].
3.1. Boron Neutron Capture Therapy
3.1.1. General Principles

Boron neutron capture therapy (BNCT) for cancer is a binary method for the treatment of
cancer, which is based on the nuclear reaction of two essentially nontoxic species,
nonradioactive 10B and low-energy thermal neutrons. The neutron capture reaction by 10B
produces an α-particle 4He2+ and 7Li3+ ion together with 2.4 MeV of kinetic energy and a 480
keV photon. These high-linear-energy transfer ions dissipate their kinetic energy before
traveling one cell diameter (5-9 µm) in biological tissues, ensuring their potential for precise
cell-killing. Therefore, high accumulation and selective delivery of boron into the tumor
tissue are the most important requirements to achieve efficient neutron capture therapy of
cancer. There are three most important requirements for development of boron compounds:
(1) achieving minimal tumor concentrations in the range of 20-35 µg of 10B per gram of
tumor tissue; (2) selective delivery of boronated compounds to tumor cells, while at the same
time, the boron concentration in the cells of surrounding normal tissue should be kept low to
minimize the damage to normal tissue; (3) sufficiently low toxicity [78,79]. Ideally, only
tumor cells will be destroyed without damage to healthy tissues in the irradiated bulk. The
absence of an adverse effect on the surrounding healthy tissues is attributed to the fact that the
thermal neutron capture cross-sections of elements involved in tissues are 4-7 orders of
magnitude smaller than that of the 10B isotope (table 1).
Table 1. Thermal neutron capture cross-sections of isotopes characterized

by the largest capture cross-sections and cross-sections of isotopes
of some physiologically important elements
Isotope Capture Isotope Capture cross- Average content

cross-section section (barn) in tissues
(barn)
10
B 3.8 x 103 1
H 0.33 (10.0 %)
113
Cd 2.0 x 104 12
С 3.4 x 10-3 (18.0 %)
149
Sm 4.2 x 104 14
N 1.8 (3.0 %)
151
Eu 5.8 x 103 16
O 1.8 x 10-4 (65.0 %)
155
Gd 6.1 x 104 31
P 0.18 (1.16 %)
157
Gd 2.6 x 105 32
S 0.53 (0.20 %)
Despite the fact that the thermal neutron capture cross-section of the 10B isotope is
smaller (see table 1) than those of some other elements (113Cd, 149Sm, 151Eu, 155Gd, or 157Gd),
at present the 10B isotope is virtually an alternativeless element for neutron capture therapy
for cancer because it readily forms stable covalent compounds. Moreover, the use of boron
clusters containing ten or more boron atoms per molecule “increases” the neutron capture
cross-section by an order of magnitude considering a boron cluster as a structure element
alternative to a single metal atom. At the same time, the synthesis of stable in vivo complexes
of cadmium and f-elements capable of undergoing modifications is quite an intractable
problem presently. Only 157Gd complexes currently have potential use in nuclear capture
therapy [80].
The only two BNCT agents currently used for clinical trials are L-p-dihydroxy-
borylphenylalanine (BPA), a boronated aminoacid analogue, and disodium
mercaptoundecahydro-closo-dodecaborate Na2B12H11SH (BSH), both are the so-called
‘second generation’ BNCT drugs (Figure 2).
NH2
COOH SH 2 -
2Na+
B
HO OH BH (B)
L-para-boronophenylalanine sodium mercapto-closo-dodecaborate

(BPA) (BSH)
Figure 2. Clinically used BNCT agents.

Both these drugs are very far from ideal. Therefore, many different types of boron
containing compounds have been designed and synthesized for testing as BNCT drugs over
the past 30 years. In order to fulfill the requirements for the BNCT agents, these new
compounds should consist of a boron-containing part connected via a hydrolytically stable
linkage to a tumor-targeting part responsible for delivering of a boron fragment to the tumor
cell and its retention there (Figure 3).
Figure 3. Principal scheme of BNCT agent.
The BNCT agents currently under investigation are the ‘third generation’ boron carriers
and can be classified either according to their chemical structure and compound category,
their high molecular weight or their biological target recognition properties.
3.1.2. Low Molecular Weight Boron Compounds

Synthesis of low molecular weight boron compounds is in a focus of attention of many
groups of chemists. The most widespread chemical effort has been related to the design and
synthesis of boron-containing cellular building blocks. The rationale for their synthesis is
that, in contrast with normal cells, tumor cells have an elevated requirement for certain
constituents necessary for cell replication (nucleic acid precursors, amino acids,
carbohydrates, etc.).
Nucleotides and Nucleosides

Boron-containing nucleosides are good candidates for BNCT. The rationale for their
synthesis was suggested to be hypothetical incorporation of boron-containing nucleoside
triphosphates into DNA reducing effectively minimal therapeutic concentration to 20-35 µg
10
B/g [79,81-84]. More recently, it was recognized that active triphosphates, due to their
cytotoxicity, are responsible for the most of the severe toxic side-effects in antimetabolite
chemotherapy. Triphosphates of boron-containing nucleoside prodrugs could exert a similar
toxicity profile without neutron radiation when administered systemically at high doses, and it
is uncertain if this toxicity can be tolerated [85].
At present, however, boron-containing nucleosides are still considered as promising
candidates for BNCT because of their potential to be retained in rapidly dividing tumor cells
after 5’-monophosphorylation by phosphorylating enzymes, thymidine kinase 1 and
deoxycytidine kinase. Thymidine kinase 1 is pyrimidine specific, phosphorylating thymidine
and 2’-deoxyuridine, whereas deoxycytidine kinase has a broad substrate specificity,
phosphorylating 2’-deoxycytidine, 2’-deoxyadenosine, and 2’-deoxyguanosine. Cellular
efflux of such 5’-monophosphates would be retarded due to the negatively charged phosphate
moiety. Design strategy for BNCT nucleoside prodrugs should focus on structures which
enter tumor cells either by passive diffusion or via nucleoside membrane transporter and are
selectively trapped intracellularly as anabolically and catabolically stable non-toxic 5’-

monophosphates and/or 5’-diphosphates [85].
Syntheses and results of biological studies of carborane-containing nucleosides have been
reviewed several times during the last 10 years [81-85]. Based on the results of phosphoryl
transfer assays of a few series of carborane-containing nucleosides, three-dimensional
quantitative structure-activity relationship has been developed [86]. Structures of some
carborane-containing nucleosides synthesized are presented in Figure 4.
NH2
O
N
HN N
N N
O N
HO HO
O O
OH O O
O O
S
HN HN
O N O N
HO HO
O O
OH OH
O O
H
O X
N N NH3+
n
N O N O
HO HO
O O
n=1-4 X = (CH2)n
n=2-6
OH OH X = (CH2)2O(CH2)2
Figure 4. Structures of some carborane-containing nucleosides.
Synthesis and biological evaluation of the first cobalt bis(dicarbollide) analogues of

thymidine have been reported recently by Lesnikowski et al. [70,87,88] (Figure 5).
-
O
O O
2
Co
Co
Co O
N N 2
Co
Co
Co
N O N O
HO HO
O O
OH OH
Figure 5. Structures of cobalt bis(dicarbollide) based nucleosides.
Aminoacids
The interest in the development of carborane-containing amino acids arose soon after the
first carboranes were synthesized and o-carboranylalanine was one of the earliest described
carborane-based analogues of biomolecules. It was first synthesized as the racemic mixture
independently by Brattsev [89] and Zakharkin [90]. Subsequently, other methods of its
synthesis in high yield [91-93] as well as the stereoselective synthesis of the L-isomer [94]
have been proposed. More recently several more useful stereoselective syntheses of the L-
and D-isomers have been developed [95-97]. At present time, a number of various carborane-
containing amino acids are synthesized including the p-carborane analog of tyrosine [98],
carborane derivatives of 1-amino-cyclobutanecarboxylic acid [99-102], and β-carboranyl-α-
trifluoromethyl-α-aminoacid [103,104] (Figure 6). Synthesis and use of carborane-containing
aminoacids have been reviewed very recently [105].
COOH COOH COOH
NH2 NH 2 NH 2
HO
OH
HO COOH COOH
NH2 NH2
O
COOH
OH OH
NH2
O
CF3
COOH CH2 CH 2 C COOH
HO NH 2
OH OH
NH 2
OH
Figure 6. Structures of some carborane-containing aminoacids.

Due to the hydrophobicity of carborane, most carborane-containing amino acids are not
soluble in water. In order to increase solubility, some hydrophilic substituents were
introduced or the carborane was transformed to the nido-form. Several amino acids based on
anionic boron hydrides [78,106] and metallacarboranes [67] have been prepared (Figure 7).
H COOH - -
NH2
Co
(OCH 2CH 2)2CHCOOH
O COOH 2-
NH3+
NH2
Figure 7. Structures of anionic boron-containing aminoacids.
Besides numerous polyhedral boron hydride based α-aminoacids, a few compounds with
carborane cage incorporated between amino and carboxylic groups were reported [107,108].
Carbohydrates
Synthesis of the first carborane-containing carbohydrates was described more than 25
years ago as a way to compensate for the hydrophobicity of the carborane cage and to
enhance the water solubility of carborane biomolecules [109-112]. The concept still persists
[102,113-115], however nowadays much more attention is paid to using carbohydrates as
tumor-targeting agents. This form of biomolecular recognition involves binding of a
carbohydrate to a lectin receptor. Endogenous lectins are found on surfaces of many normal
and malignant cells and involved in various biological functions, acting as specific receptors
and/or mediating endocytosis of specific glycoconjugates. Because lectins recognize and bind
to the terminal (non-reducing) sugar residues of oligosaccharides, endocytosis is relatively
uninfluenced by the size or composition of the aglycon. This feature has stimulated interest in
carbohydrate-mediated delivery (glycotargeting) of various compounds (including drugs and
polynucleotides) to cells expressing the corresponding lectins [116]. Transformation of a
normal cell to a tumor cell often results in the change of lectin composition of the cell surface
and is usually accompanied by over-expression of the certain lectins. Attachment of boron
moiety to an oligosaccharide ligand of the lectin will lead to the preparation of boron-
containing neoglycoconjugates, which can be used for targeted delivery of boron to the tumor
tissues. Recently, syntheses of various boron-containing conjugates have been reported by
several research groups [40, 117-129]. Some examples of lactose conjugates with various
polyhedral boron hydrides are presented in Figure 8.
OAc OAc
O OAc
AcO
O O O
OAc AcO
O NH
OAc NH
OH OH
O OH
HO
O O O
OH -
HO H
O
OH NH
OH OH
O OH
HO
O O O 2-
OH HO
O
OH NH O
Figure 8. Structures of some boron-containing lactoses.
Porphyrins and Phthalocyanines

Porphyrins and phthalocyanines have been observed by nearly a century to accumulate
selectively in a variety of tumors [130]. Photodynamic therapy (PDT) has become a clinically
established bimodal cancer therapy whereby superficial tumors loaded with a photosensitizing
porphyrin or related macrocycle are irradiated with red laser light to form an excited triplet
state which reacts with molecular oxygen and other substrates to generate highly cytotoxic
species (e.g. single oxygen, superoxide anion, hydroxyl radicals) that cause irreversible
destruction of tumor cells [131]. Although only two porphyrins Photofrin® and VisudyneTM
have been approved by the U.S. Food and Drug Administration many others are currently
being evaluated in animal models for the treatment of certain cancers and other diseases.
In the past two decades boron-containing porphyrins have been investigated as possible
BNCT agents and BNCT/PDT dual sensitizers in preclinical studies. Two approaches have
been used for the synthesis of these compounds - condensation of boron-containing building
blocks, on the one hand, and attachment of boron cages to natural or synthetic porphyrins and
phthalocyanines, on the other hand. The first carborane-containing porphyrins were reported
by Haushalter and Rudolph in 1978 [132,133] and this field is under extensive development
[131, 134-136]. The most of the prepared carborane-containing porphyrins are based on the
meso-tetraphenylporphyrin skeleton and contain from one to eight closo- or nido-carborane
cages (Figure 9). Beside carborane-based porphyrins, syntheses of meso-
tetraarylporphyphyrins containing cobalt bis(dicarbollide) [71,72,137], closo-dodecaborate
[138] and carba-closo-dodecaborate [139] moieties were reported (figure 9).
R Me
R= R=
NH N
HN
R R
N HN O
R Me
R= O - R= O 2- R= O 2-
NH2 S O
- -
R= R=
Co Co
O(CH2CH2O)2 N+ (CH2CH2O)2
Figure 9. Structures of some boron-containing porphyrins.
A number of carboranyl porphyrins have been obtained on the basis of the natural
porphyrins derivatives such as deuteroporphyrin IX and hematoporphyrin IX and two of
them, VCDP and BOPP (Figure 10), have been extensively studied in animals. BOPP was
reported to have a tumor-normal brain ratio from 13:1 to 400:1 for different glioma models
[140,141]. High boron levels in tumor (> 60 µg 10B/g tumor) were achieved in these animal
studies. However, data obtained from a human Phase I clinical trial showed that BOPP does
not deliver therapeutic concentrations of boron to the tumors of glioblastoma patients, and
dose escalation is prevented by the toxicity of this compound. Nevertheless, BOPP has shown
promise as an effective PDT photosensitizer [142-145].
More recently, syntheses of closo-dodecaborate derivatives of naturally occurring
porphyrin systems pyropheophorbide a [146] and bacteriochlorin p [147] have been reported.
Syntheses and results of biological studies of boron-containing porphyrins have been
reviewed several times during the last 5 years [131,134-136] and some more recent
publications include [137-139,147-150].
-
K+
O O
H O
- O
K+ O
H
O
NH N NH N
O O
N HN N HN
O O O
O
OH HO OH HO
VCDP BOPP
Figure 10. Structures of some carborane-containing porphyrins.
Synthesis of boron hydride based phthalocyanines has received much less development.
After the first paper reviewed this field [134], only four reports have been published during
the last 5 years [151-154] (Figure 11).
R O O R
N N
N M N
N N
N
R O O R
O O
R = -CH2 , -NH C , -O CCH2
Figure 11. Structures of some boron-containing phthalocyanines.
DNA Binders
Another group of low molecular weight boron compounds received great attention for the
last years is DNA binders. BNCT agents that target DNA are attractive because, as mentioned
previously, the amount of boron required for successful therapy is reduced if the 10B is
deposited in proximity to the DNA. Acridine dyes have been shown to stain the nuclei of
many different cell types and therefore have the potential of being boron delivery agents to
tumor cells. A series of carborane containing analogues of DNA intercalating compounds,
acridine and phenanthridine, were prepared by Sjöberg et al. [155-158] (Figure 12) and
analyzed in cultured human malignant glioma spheroids. These compounds, however, were
found to be not specific to cancer cells, thus to gain tumor specificity, the proposed strategy is
to prepare conjugates with tumor targeting agents (vide infra).
NH2*HCl
HO N *HCl
N HN*HCl
NH2*HCl
N N
*HCl
H2N NH2 H2N NH2
N+ AcO- N+ AcO-
Figure 12. Structures of some carborane-containing acridines and phenanthridines.
Recently a series of Pt-based DNA metallointercalators with carborane-containing

ligands have been synthesized and found to have significant anti-cancer activity (see below).
Related to the intercalators are DNA grove binders. The initial focus was to use
bibenzimidazole compounds related to Hoechst 33258, a compound that has been shown to
target the minor groove of DNA with a great deal of specificity. A series of carborane
analogues of Hoechst 33258 was synthesized and their DNA binding capacity was evaluated
[159,160] (Figure 13).
Polyamines, such as putrescine, spermidine, and spermine, are important biochemical
constituents that are essential for cell growth and differentiation. Elevated concentrations of
these substances were found in rapidly proliferating tumor cells whose polyamine transport
system is upregulated. These structures, under physiological conditions, exist as cationic
moieties and bind very tightly to DNA via electrostatic interactions. A series of carboranyl
derivatives of spermidine and spermine were synthesized [155,161-164] (figure 14). These
compounds demonstrate rather high cellular uptake in vitro but, at the same time, high
cellular and in vivo toxicity [163,164].
N
OH
N NH
NH
N N
Hoechst 33258
N NH
NH
N N
N
O
N NH
NH
N N
Figure 13. Structures of some carborane-containing analogues of Hoechst 33258.
NH2
NH2 H2N N
H2N N
*3HCl
*4HCl
OH
NH2
OH
NH NH
NH N
*4HCl
OH
OH
Figure 14. Structures of some carborane-containing polyamines.

There are many synthesized and partially evaluated boron-containing low molecular
weight compounds which do not fall into any of the above classifications [57,79]. However,
there is at least one factor that unifies practically all low molecular weight boron compounds:
they have not reached the stage of being evaluated clinically. Many have been screened in cell
culture: some using purified enzymes to determine their metabolism; other have been
evaluated in rodents with a variety of subcutaneously transplanted animal and human tumors;
and fewer have been screened against these same tumors that were implanted intracranially;
and many and many compounds have been synthesized but have not been evaluated at all.
Based on the data available, how does one decide to eliminate or further evaluate a
compound, since additional studies are both costly and time-consuming? The key question in
BNCT agent development is assessing the usefulness of enzymatic, cell culture, and animal
studies in determination of clinical potential of the compounds. Another question is, how do
these newer agents compare with those two compounds that are now being used clinically?
Probably, we are very close to synthesis of a compound that could work in BNCT much
better than BSH and BPA or, perhaps, someone already has synthesized such compound and
put it on a laboratory shelf. It should be noted here that some boron compounds
demonstrating high cellular uptake but being not specific to cancer cells or/and high in vivo
toxicity could be used in BNCT as conjugates with tumor targeting agents, e.g. targeted
liposomes [79,165].
3.1.3. High Molecular Weight Boron Delivery Agents

High molecular weigh delivery agents usually contain a boron cluster linked through a
hydrolytically stable bond to a tumor-targeting moiety, such as monoclonal antibodies
(mAbs) or low molecular weight receptor targeting ligands. Examples of these include
epidermal growth factor (EGF) or the mAb cetuximab (IMC-C225) to target the EGF receptor
or its mutant isoform EGFRvIII, which are over-expressed in a variety of malignant tumors
[165].
The use of antibodies to deliver boron to tumor cells was suggested in the 1960s. The
initial investigation of boron-conjugation chemistry with model protein substrates such as
bovine serum albumin and human γ-globulin was initiated nearly simultaneously in several
laboratories in the 1970s. The studies focused on the type of boron compounds that were to be
used, the linkages that would be required, and the effect of such covalent attachment and its
boron moiety on the physiochemical properties of the conjugate formed. The results of these
early studies were surveyed in Hawthorne’s review [78]. However, some fundamental
strategic problems arose soon after the first boron-containing conjugates were obtained. It
was estimated that the boronated antibody molecule must contain 103 10B atoms (approx. 100
boron cages) to provide the necessary therapeutic boron concentration in tumor [166]. The
question is: could that number of boron cages introduced to the antibody molecule with
retention of its conformational and targeting specificity? It was demonstrated that the
introduction of approx. 1300 10B atoms per molecule of 17-1A Mab monoclonal antibody
using N-succinimidyl 3-(2-undecahydro-closo-dodecaboranyldithio) propionate
[B12H11SS(CH2)2COO(N(CO)2(CH2)2)]2- resulted in 90 % loss of its immunoreactivity [167].
This result indicates that attaching 100 functional groups on the antibody molecule apparently
results in the loss of its targeting specificity. It means that the minimum modification of the
antibody molecule is needed for retention of its immunoreactivity. Thus, there emerged two
requirements in order to prepare boron-containing antibodies for BNCT: 1) synthesis of a
boronated macromolecules containing up to 100 boron cages, and 2) development linkage

technology to attach such structures to antibodies.
The initial approach included the use of a preformed macromolecule containing a large
number of functional groups to which the boron polyhedron could be covalently attached. The
first macromolecule that has been used as a platform for delivery of boron compounds was
polylysine, a polymer having multiple reactive amino groups. The protein-binding polyhedral
boron derivative, isocyanato-closo-dodecaborate [B12H11NCO]2-, was linked to polylysine and
subsequently to the anti-B16 melanoma mAb IB16-6 [168]. The bioconjugate had an average
of 2700 boron atoms per molecule and retained 58 % of the native antibody
immunoreactivity. Other bioconjugates prepared by this method had more 1000 boron atoms
per molecule of antibody and retained 40-90 % of the immunoreactivity. Using site-specific
linkage of boronated polylysine to the carbohydrate moieties of anti-TSH antibody resulted in
a bioconjugate that had approx. 6000 boron atoms with retention of its immunoreactivity
[169]. One of the limitations of this approach is that the polymer itself is not a discrete and
homogeneous entity and that heterogeneity is markedly increased following boronation since
the number of boron groups attached to each polymeric molecule could vary.
Dendrimers are one of the most attractive polymers that have been used as boron carriers
due to their well-defined structure and large number of reactive terminal groups. Initially,
second- and fourth-generation polyamidoamino (PAMAM) dendrimers, which have 12 and
48 reactive terminal amino groups, respectively, were reacted with the isocyanato derivative
of closo-decaborate anion [Me3NB10H8NCO]-. The boronated dendrimer then was linked to
mAb IB16-6 directed against the murine B16 melanoma [170,171]. More recently, the fifth-
generation PAMAM dendrimers was boronated with the same polyhedral borane anion and
linked to the anti-EGFR mAb cutuximab or the EGFRvIII specific mAb L8A4. The resulting
bioconjugate contained ~ 1100 boron atoms per molecule and was found to retain the native
antibody immunoreactivity [172,173].
Besides monoclonal antibodies, boronated PAMAM dendrimers can be targeted to tumor
using epidermal growth factors [174,175], vascular endothelial growth factor [176], and folic
acid, vitamin that is transported into cells via folate receptor mediated endocytosis [177].
Synthesis of a few other boronated dendrimers that potentially could be used as boron
delivery agents for BNCT were described recently [178,179].
Another type of polymers that could be used as boron carriers are dextranes, glucose
polymers that consist mainly of a linear α-1,6-glucosidic linkage with some degree of
branching via a 1,3-linkage. Several examples of [B12H11SH]2- coupling to modified dextran
derivatives were described [180-184].
Two different approaches to tumor targeting of boronated polymers using streptavidin-
biotin strategy [185] and bispecific antibodies [171,186] were considered in earlier review
[79].
One of the observed differences between tumor cells and their normal counterparts is the
rate of metabolism of low-density lipoproteins (LDLs). The LDL vesicle comprises a
phospholipids/cholesterol shell with a diameter of approximately 15-20 nm, filled with
cholesteryl and glyceryl esters of long-chain alkyl carboxylic acids. This difference is based
on the increased need that tumor cells possess for cholesterol in order to facilitate new
membrane formation. The overexpression of the LDL receptors on the tumor cell membrane
is responsible for its LDL accretion. This provides a basis for cellular differentiation and the
targeting of tumor cells with boron if cholesteryl esters of the LDL core are replaced with a
boron species that would simulate cholesterol in its physiochemical properties.
This concept was proposed by Kahl at the beginning of 1990s. The initial compounds
synthesized were esters of carborane carboxylic acid with various fatty acid alcohols [187].
Later some other derivatives of cholesterol were synthesized [188-193]. More recently LDLs
were proposed as tumor delivery agents for carborane-containing porphyrins [194].
While LDLs are natural lipoproteins with a proclivity for those tumor cells in which the
receptors for these vesicles are overexpressed, liposomes can be considered as related
synthetic vesicles. The liposomes consist of a phospholipids bilayer that forms a spherical
shell surrounding an aqueous core. Modification of the liposomal surgace by PEGylation or
attachment of antibodies or receptor ligands will increase their circulation time and improve
their selective targeting. Design strategies for boron-containing liposomes for BNCT centered
on both non-targeted and tumor-targeted formulations [165]. The latter includes liposomes
conjugated to transferrin [195-197], EGF [198-201], antibodies [202], vascular endothelial
growth factor [203], α(v)-integrin specific arginine-glycine-aspartate peptides [204], and folic
acid [205-208].
Most liposomes designed for BNCT contained hydrophilic low molecular weight boron
agents, which presumably localized in the aqueous core of the liposomes during preparation.
These boron agents include BSH [196,209-211] and BPA [212,213], anionic polyhedral
boron hydrides with or without simple substitution patterns [206-208,214-218], carborane-
containing amines [219], polyamines [206], acridines [198-202], porphyrins [220],
carbohydrates [221], and nucleosides [222].
Phospholipids are common lipid bilayer components of liposomes and they have been
proven to be effective anchors for boron compounds in the form of single- [205,223] or dual-
chain nido-carborane [197,224,225] or closo-dodecaborate [41] phospholipid mimetics.
Cholesterol is another major component of the mammalian cell membrane and most
liposomal formulations. Therefore, the development of carborane-containing derivatives of
cholesterol [188-193] is potentially an effective approach for delivery of boron to cancer cells
via both liposomes and LDL. More recently, a novel strategy for the design and synthesis of
carboranyl cholesterol mimics has been proposed. In this mimics, both the B and the C rings
of cholesterol were replaced with a carborane cluster (Figure 15). The novel carboranyl
cholesterol mimics are excellent lipid bilayer components for construction of nontargeted and
receptor-targeted boronated liposomes for BNCT of cancer [203].
3.1.3. Second Component: Neutron Sources

Neutron sources for BNCT are currently limited to nuclear reactors and several reactors
with very good neutron beam quality have been developed and currently are being used
clinically [226]. The advantage of a reactor is that the neutrons from reactors are relatively
cheap, if capital costs are discounted. The disadvantages of reactors are that the capital costs
are very high and reactors are too complicated for an ordinary clinic to operate, so these
clinics cannot afford to build and maintain a small nuclear reactor to use as a neutron source.
O C D
O A B
HO
O
5
HO
O
4 HO
Figure 15. Structures of some carborane-containing analogues of cholesterol.
Another approach is to use accelerators and accelerator-based neutron sources are being
developed in several countries [227-229]. Accelerators offer a number of potential advantages
over reactor-based neutron sources for clinical applications. First, accelerators can be easily
turned off when the neutron field is no longer required. This, and the fact that neutrons are not
produced via a critical assembly of fissile material, means that licensing and regulations
associated with maintaining the neutron source are substantially simplified. Second, the
variety of neutron-producing reactions that are accessible to accelerators, allows for a number
of neutron energy source spectra to be produced. Consequently, for some accelerator types, a
number of clinically useful epithermal neutron fields can be produced by the same
accelerator, and the neutron flux energy spectrum of the field can be tailored to the spatial
characteristics of a particular patient’s tumor. Third, the capital expenses of an accelerator-
based BNCT system will be substantially lower than those associated with installation of a
reactor system in or near a hospital. And finally, accelerators have been prominent features of
radiotherapy departments in hospitals for years; clinicians have a longstanding and
comfortable experience with such devices for patient irradiation. It is likely that accelerator
hardware for BNCT irradiations could be sited within an existing radiotherapy room with the
addition of extra shielding [227].
3.1.4. Clinical Status of BNCT

Although the clinical potential of BNCT was recognized in the 1930s, the clinical trials
were carried out up to recently only in two countries, in USA (1954-1961, 1994-present) and
Japan (1968-present). The BNCT geography has expanded sharply for the last 10 years when
the clinical trials started in European Union (at Petten, 1997), Finland (1999), Sweden (2001-
2004), Czech Republic (2001), and Argentina (2003). Significant growth and wider
development of the clinical trials could be expected with further development of accelerator-
based neutron sources that can be incorporated into medical surroundings and with
development of a new generation of BNCT agents.
High-grade gliomas, and specifically glioblastoma multiforme, that are still extremely
resistant to all current forms of therapy, including surgery, chemotherapy, radiotherapy,
immunotherapy, and gene therapy, are the main subject of BNCT. Melanomas, which cannot
be treated by either surgical excision or stereotactic radiosurgery, are other candidates for the
BNCT treatment. The use of BNCT for treatment of the head and neck recurrent tumors
(squamous cell carcinomas, sarcomas, parotid tumor) and adenocarcinoma of the colon that
had metastasized to the liver have been reported recently [77].
3.2. Boron Neutron Capture Synovectomy
Rheumatoid arthritis is an autoimmune disease characterized by recurrent swollen,

inflamed and painful joints. It afflicts 1–2 % of the US population. Since the cause of
rheumatoid arthritis is unknown, patients are treated symptomatically. Anti-inflammatory
drugs are effective in approximately 90% of all patients. In the remaining 10% patients, the
inflammation in one or more joints will not respond to drugs and a more severe approach is
taken. In the USA, the only option is surgical synovectomy, a costly and painful procedure
followed by extensive physical therapy and rehabilitation. Symptomatic relief lasts roughly
2–5 years since the cause of rheumatoid arthritis has not been addressed. Radionuclide
synovectomy using beta-particle emitters injected directly into the joint is routinely used in
Europe and elsewhere and gives about the same symptomatic relief, for the same fraction of
patients, for the same length of time, as surgery. Radionuclide synovectomy is less costly,
less painful and requires no rehabilitation time relative to surgery. It is, however, not
approved for routine clinical use in the USA due to concerns regarding healthy tissue
irradiation caused by leakage of the β-emitter away from the joint.
Boron Neutron Capture Synovectomy (BNCS) was proposed as a way to carry out
radiation synovectomy without the concern regarding leakage of a radioactive substance. A
10
B- labeled compound injected into the joint space would be followed by local irradiation
with a beam of low-energy neutrons. The experimental parameters required for the successful
implementation of BNCS as a treatment modality for rheumatoid arthritis [230,231]. The
boron neutron capture reaction could be used to selectively ablate arthritic tissue, without
causing damage to other tissue and/organs so long as highly selective and efficient boron
delivery vehicles could be developed [232,233].
3.3. Polyhedral Boron Hydrides in Radionuclide Diagnostics

and Therapy [75]
Initially, labeling polyhedral boranes with radionuclides was performed with the aim to
study biodistribution and pharmacokinetics of boron compounds for BNCT [234]. For in vivo
imaging of boron compounds, radiolabeled derivatives are of particular interest since their
biodistribution can be easily monitored by using single-photon emission computed
tomography (SPECT) and positron emission tomography (PET), depending on the
radionuclide employed. In many cases, radiolabeling gives detailed information about boron
pharmacokinetics that can be used to generate improved patient treatment protocols, for
example by providing information about the required dosage of tumor-seeking boron
conjugates, and optimal treatment time.
Another important field is use of boron clusters as pendant groups for attachment of
radionuclides to tumor-seeking biomolecules for targeted radionuclide therapy. The principle
of this mode of treatment is based on selective delivery of radionuclide to cancer cells. Due to
very high cytotoxicity of radionuclides, the use of highly tumor-specific transport system is
required. The targeting vectors used in radionuclide diagnostics and therapy are of protein
nature. These may be monoclonal antibodies directed toward tumor-specific antigens or
regulatory peptides binding to receptors overexpressed on or by malignant cells. The
important advantage of targeted radionuclide therapy over boron neutron capture therapy is
that the therapeutic concentration of radionuclides in tumor are, as a rule, a few order of
magnitude less than the therapeutic concentration required for BNCT. As a consequence, the
less modification of the tumor-seeking molecule is required, which prevents loss of tumor
specificity. The same tumor-seeking compounds may also be used for detection and
characterization of tumors.
3.3.1. Polyhedral Boron Hydrides as Carriers of Radiohalogen Label

The most common procedures employed for radiolabeling proteins are
radiohalogenations and labeling with radioactive metal ions. Halogen radioisotopes are
especially attractive since they share many chemical properties and possess a variety of half-
lives and decay modes (table 2), which enables optimization of half-life and emitted radiation,
depending on the biomedical problem to be solved. Radiohalogens used in nuclear medicine
today fall into two main categories, those useful in imaging applications and those useful in
therapy applications [235].
Table 2. Radiohalogens used in imaging and therapy
Nuclide Half-life Mode of decay Possible application

18
F 1.8 h β+ PET Imaging
75
Br 1.6 h β+ PET Imaging
76
Br 16 h β+ PET Imaging
77
Br 2.4 days electron capture SPECT Imaging
80m
Br 4.4 h Auger e- Therapy
82
Br 35.3 h β- Therapy
123
I 13.2 h electron capture SPECT Imaging
124
I 4.2 days β+ PET Imaging
125
I 59.4 days electron capture Therapy
131
I 8.0 days β- Therapy
211
At 7.2 h Α Therapy
Today, nuclear medicine imaging is carried out with highly sophisticated SPECT
instruments available in most hospitals worldwide. Another imaging modality, PET, is being
used clinically, but is not as widely available. The radioactive decay property that allows the
use of radionuclides for imaging in emission of photons with sufficient energy to detect in a
device external to the body. Radionuclides that are useful for SPECT imaging emit photons in
high abundance and have sufficient energy (>100 keV) to escape the body and be detected. In
PET imaging, positrons emitted by the radionuclide interact with electrons in an annihilation
process to produce two coincident 511 keV photons, which are detected simultaneously in a
detector ring. An important characteristic is the energy of the emitted positron. The higher its
energy, the further a positron will travel before the annihilation occurs. A longer distance of
positron travel in tissue results in an overall loss of spatial resolution. Another important
characteristic is the abundance of the positron emissions since a low abundance requires more
radioactivity to be administrated.
123
I is a commercially available SPECT isotope that has very favorable SPECT imaging
properties (159 keV) and a reasonable half-life (13.2 h). This isotope is widely used in
nuclear medicine and can be shipped around the world. 77Br is a single photon and positron
emitter with a 57 h half-life. However, its limited availability and two higher energy gamma
rays, as well as low percent positron emission (1%), make it less desirable as a SPECT or
PET isotope.
From a purely physical point of view, 18F has the most favorable nuclear properties for
imaging with PET. The half-life (110 min), high percentage of β+ emission (97%), and
relatively low positron energy (0.635 MeV) make it the ideal PET halogen for high-resolution
images. However, radiofluorination reactions of polyhedral boron hydrides have not yet been
reported. 75Br is a potential PET imaging isotope with a reasonable half-life (97 min).
However, compared to 18F, it suffers from a higher positron energy (1.74 MeV), a 71%
positron emission and second high energy gamma, all of which contribute to its overall poorer
resolution for imaging. 76Br is a possible radionuclide for PET studies. This nuclide has a
half-life of 16.2 h and emits 54% positrons per decay, properties that are well suited for
labeling. 124I is a positron-emitting radionuclide that has gained considerable interest recently.
The interest comes from the fact that it has a relatively long half-life (4.2 d) and both imaging
(PET) and therapeutic properties. However, the emission properties of this radionuclide are
far from ideal.
Radiohalogens used for therapy applications have particle emissions such that they
provide more or higher quality interaction (ionization) in biological tissues than the
radionuclides used in imaging. In principle, any radiohalogen that emits an electron (β-, β+, or
Auger electron) or α-particle (4He nucleus) might be used for therapy.
The most commonly used radiohalogen for therapy is 131I. The factors that have made
this radionuclide widely used are its availability and reasonably long half-life (8.0 d). This has
made it relatively inexpensive and readily transported to clinical sites. The β-particle
emissions of 131I travel a few mm in tissue. This distance is important in tumors as the β-
particle travels well beyond the cell it is attached to or internalized in, providing a radiation
field effect. It is useful for solid tumors where penetration of the carrier molecule is difficult,
or targeted receptors are not available on all cells. Unfortunately, 131I does not have optimal
properties as its decay produces high energy photons. These photons are problematic as they
make it difficult to conduct labeling at the required high levels and can cause the patient to be
isolated to minimize the radiation exposure to health care professionals and family members.
On the other hand, the photons do allow imaging of the distribution of radioiodine within a
patient by SPECT. It is important to be able to evaluate the distribution of radionuclide in a
patient and to estimate the radiation dose to the target and not-target tissues. This provides
information regarding the biological effect on normal tissues and the potential for an effective
therapy of the tumor.
Another radiohalogen nuclide of interest for therapy is 125I. The particle emitted in
radioactive decay of 125I, that makes it of particular interest, is an Auger electron. The Auger
electrons deposit there energy in a very short distance (e.g. a few Å), which makes it high
linear energy transfer (LET). While this short distance requires the Auger electron emitting
radiohalogen to be internalized and localized in a specific location (i.e. associated with double
strand DNA) to provide an effective therapy, it causes little damage to non-target tissues.
Although 125I is readily available, it is not an ideal radionuclide for therapy as it has a
relatively long half-life (59.4 d), so other Auger electron-emitting radiohalogens are of
interest. The SPECT imaging radionuclide 123I has Auger electron emissions and a much
shorter half-life; few studies have been performed with this radionuclide to determine its
effectiveness in therapy.
211
At is another radiohalogen of interest for therapy. Although the half-life of 211At is
relatively short (7.2 h), it is the only α-emitting radiohalogen nuclide that is considered
acceptable for use in humans. In contrast to β-particle emission, the α-particles emitted by
211
At decay have a range of 50-70 mm due to their much higher interaction with tissue. This
high LET makes 211At particularly attractive for therapy of metastatic cancer or in
applications where single cells are targeted. While it is estimated to take several hundred (e.g.
> 400) β-particle emitting radionuclides on a single cell to kill that cell due to the fact that
most of the particles’ energy is deposited outside of the cell, it is estimated that only a few
(e.g. 1-14) associated α-particle emitting radionuclides can kill a cell. The closer the 211At
atom decays to the nucleus, the fewer atoms are required to kill the cell, making internalizing
targeting agents particularly attractive.
Thus, specific targeting of halogen radionuclides is a promising approach to improved
diagnosis and treatment of tumors. A problem in using radiohalogens for labeling of tumor-
targeting proteins and peptides is that the commonly used radiohalogenation methods provide
labels, which, after internalization and lysosomal digestion, rapidly “leak” from malignant
cells as radiohalogenated degradation products. The main reason for such leakage is free
diffusion of the radiometabolites through lysosomal and cellular membranes [236].
Dehalogenases and peptidases have been considered as enzyme systems responsible for the
dehalogenation of radiohalogenated proteins in vivo. This results in increased accumulation of
the radioiodide in the thyroid, whereas the radiobromide anion is not excreted but remains
distributed in the extracellular space, decreasing the contrast of the image. If the
radiometabolite cannot penetrate the cellular membrane, it will be trapped intracellularly until
its excretion by exocytosis. Since exocytosis is relatively slow in comparison with diffusion,
the cellular retention and, consequently, the tumor accumulation of radionuclide are
improved. This resulted in a new concept in which the cellular retention can be improved by
placing radiohalogen label on a structure that cannot penetrate the cellular membrane and
remain trapped inside the cell.
The polyhedral borane anions were found to be reasonable linkers for attachment of
radiohalogens to tumor-targeting proteins and peptides. For such applications, the following
features of these compounds are important: 1) the high strength of the boron-halogen bonds
(higher than in their carbon-halogen counterparts); 2) the absence of enzymatic systems for
cleavage of the boron-halogen bond due to the very exogenous nature of such compounds and
3) the negative charges of polyhedral borane anions which may improve intracellular
retention of bound radiohalogens without elevated uptake in kidneys.
Radionuclide targeting using polyhedral borane anions as pendant groups can in many
cases utilize compounds which have been developed for use as boron carriers in BNCT.
Functional groups which enable boron hydride coupling with tumor-seeking molecules are
amino acids (–CH(NH2)COOH), amines (–NH2), acids (–COOH), isocyanates (–NCO), and
isothiocyanates (–NCS). A number of derivatives containing these functionalities were
prepared and described above.
One example is a p-isothiocyanatophenyl derivative of nido-carborane [7-(4-SCNC6H4)-
7,8-C2B9H11]- synthesized earlier for coupling with anticarcinoembryonic antigen IgG for
BNCT [237]. This compound was labeled with the positron-emitting nuclide 76Br and coupled
to anti-HER2 antibody trastuzumab used for therapy of breast cancer. The label was found to
be stable in vitro under physiological and denaturing conditions, and retention of
immunoreactivity of trastuzumab after labeling was demonstrated in a cell binding test
(Figure 16) [238].
N=C=S
- N=C=S
-
H 1.) 76Br- H
Chloramine-T 76Br
(pH 7.2)
2.) Na2S2O5
Mab NH2
(pH 9.3) S -
NH C NH Mab
H
76Br
Figure 16. Labelling of antibodies with 76Br-brominated [7-(4-SCNC6H4)-7,8-C2B9H11] -.
Similarly, the isothiocyanate derivative of the closo-dodecaborate anion

[B12H11NH2CH2C6H4-4-NCS]- prepared previously for a BNCT project [239] was used for
radiolabeling of proteins. This compound was labeled with the Auger electron-emitting
nuclide 125I and coupled to anti-HER2/neu humanized antibody trastuzumab [240] (Figure
17). The study of the biodistribution of a radioconjugate prepared in mice revealed decreased
radioactivity uptake in thyroid in comparison with the directly radiolabeled antibody.
Effective targeting of a head and neck squamous cell carcinoma xenograft model using
chimeric monoclonal antibody cMAb U36 radioiodinated with closo-dodecaborate linker was
demonstrated [241,242]. The labeling of the isothiocyanate derivative with 76Br followed by
coupling to anti-HER2/neu humanized antibody trastuzumab was also described (Figure 17)
[243]. At the same time, the use of the isocyanate derivative for labeling low-molecular
weight Affibody ZHER2:342 was found to be non-effective [244].
-
N=C=S
NH2
1.) 125I-/76Br- 2.) Na2S2O5

Chloramine-T
(pH 7.2)
-
N=C=S
NH2
125I/76Br
Mab NH2
pH = 9.0
S -
NH C NH Mab
NH2
125I/76Br
Figure 17. Labelling of antibodies with 125I-iodinated and 76Br-brominated [B12H11NH2CH2C6H4-4-NCS]-.

131
I-labeling of protein conjugates with isothiocyanate derivatives of the 7,8-dicarba-
nido-undecaborate and closo-decaborate anions have reported (Figure 18) [245].
O - O 2-
H
NH N=C=S NH
N=C=S
Figure 18. Anionic boron hydride isothiocyanates.

nido-Carborane derivatives were also suggested as pendant groups for direct iodination of
proteins that either lack tyrosine residues or in which the tyrosine residues are buried inside
the protein structure [246].
Polysaccharides are known to be not degradable by proteolytic enzymes in lysosomes and
do not diffuse through cellular membranes. Thus, attached to an internalizing targeting
protein, such polysaccharide linkers will remain intracellularly after protein degradation. The
stability of the nido-carborane-dextran conjugate labeled with 125I was evaluated in rat liver
homogenates to be higher than one of labeled albumin (Figure 19) [247].
H -
NH2
1.) dextran CHO 2.) NaBH3CN
H -
NH CH2 dextran
125I-
Chloramine-T
(IodoGen)
H -
125
I NH CH2 dextran
Figure 19. Labelling of dextran with 125I-iodinated [7-(3-NH2CH2CH2CH2)-7,8-C2B9H11]-.
A radiolabeled borane-dextrane conjugate was prepared by coupling mercapto-closo-

dodecaborate [B12H11SH]2- with allyl-functionalized dextran followed by radioiodination
[248] (Figure 20).
2- dextran O 2-
CH=CH2
SH S O dextran
Na2S2O8
125 -
I
Chloramine-T
2-
S O dextran
125
I
Figure 20. Labelling of dextrane with 125I-iodinated [B12H11SH]2-.
Another approach termed “pretargeting”, employs biotin (vitamin H) derivatives to

deliver therapeutic radionuclides to cancer cells in vivo. In the pretargeting approach, a
monoclonal antibody-streptavidin conjugate (mAb-SAv) is injected and allowed to bind
antigens on cancer cells. After a period of time sufficient for adequate tumor targeting (e.g. 24
h), a clearing agent is used to remove excess mAb-ASv conjugate from blood. After an
appropriate time (e.g. 1-3 h), the radiolabeled biotin derivative is administered such that it can
bind with the pretargeted mAb-SAv on cancer cells due to the extraordinarily high biotin-
streptavidin affinity. At present, a number of boron-containing derivatives of biotin were
synthesized and radioiodinated and their biodistribution studied [249-251] (Figure 21).
The use of polyhedral borane anions as pendant groups for attachment of the α-emitting
radionuclide 211At to tumor-seeking biomolecules is of special interest. The problem is that
direct oxidative astatine labeling of proteins gives a very weak astatine-protein bond, which
prohibits its application in targeted radionuclide therapy. This problem may be circumvented
by astatine labeling of N-succinimidyl 3-(tributylstannyl) benzoate or N-succinimidyl 5-
(tributylstannyl)pyridine-3-carboxylate, followed by conjugation to the targeting protein.
However, all in vivo distribution studies performed so far indicate a release of astatine from
the targeting conjugate. Study of the nido-carborane conjugates with tumorbinding protein
human epidermal growth factor hEGF revealed higher labeling yield (70%) than that obtained
by indirect labeling using N-succinimidyl astatobenzoate whereas in vitro stability is close to
stability hEGF labeled with astatobenzoate (Figure 22) [252,253].
Wilbur and coworkers concentrating on the use of nido-carborane derivatives for
astatination of biotin found that nido-carborane can be directly labeled in 70-80% yield and
the biotin derivatives containing astatinated nido-carborane moieties are more stable to in vivo
deastatination than aryl astatine derivatives; however, the astatinated nido-carborane
derivatives undergo some deastatination [249,250,254].
HN NH
O H H
-
H O NH NH
131
I NH O S
2
O O
HN NH
HO O
O S O H H
-
H
125
I NH NH NH NH S
O
O NH N
HN NH
HO O
O S O H H
-
H
125
I NH NH NH NH S
HN NH
HO O
O O H H
-
H
125
I NH NH S
HN NH
O 2- H H
131
I O NH NH
NH O S
2
O O
O O
Figure 21. Radioiodinated boron-containing derivatives of biotin.
O
O
H - NH hEGF
N
211
NH S
At
O NH2+Cl
Figure 22. Labelling of hEGF with astatinated nido-carborane.

3.3.2. Polyhedral Boron Hydrides as Chelators for Radiometals

An alternative approach involves the radiolabeling of proteins that have been covalently
modified with metalchelating groups. The ligand systems used for metal complexation
include derivatives of EDTA, DTPA, DOTA, TETA, NOTA, etc. It is essential for effective
imaging that the radioactive metal ions remain complexed by the protein-chelator conjugate.
A particular concern in this regard is the competition for metal binding from serum
transferrin, which is known to remove metal ions from chelates in vivo. Of utmost importance
is the magnitude of the radionuclide-chelator dissociation rate, which must be minimal. Most
desired would be an especially robust chelation system that is promptly excreted along with
tightly-held radiometal even if the antibody or the chelate-antibody linker molecule suffered
catabolic degradation. One possible solution to this problem was proposed using an
extraordinarily stable metallacarborane clusters readily prepared in aqueous solution and
bearing organic substituents for conjugation purposes. A pendant arm, such as a carboxylate
functional group, can be used to form an amide linkage with biomolecules via established
peptide coupling methodology [234].
99m
Tc is one of the most widely used radionuclides for nuclear medicine imaging. This is
due to the favorable properties of this isotope: the emission of a 140 keV γ-ray with an
abundance of 89% and a half-life of 6.0 h [255-257]. The nido-carborane cage has been
proposed as pendant group for labeling proteins with 99mTc. The high-yield preparative
methods of synthesis of [3,3,3-(CO)3-3,1,2-MC2B9H11]- and [1-HOOCCH2CH2-3,3,3-(CO)3-
3,1,2-MC2B9H10]- (M = Re, 99Tc) were developed [258] (Figure 23). More recently, the
radiolabeling of the nido-carborane derivatives with 99mTc in water under weakly basic
conditions was described (Figure) [259-261].
C
O O
C C
99m
H COOH - Tc COOH -
99m +
[ Tc(CO)3(H2O)3]
o
KF, H2O, 85 C
Figure 23. Synthesis of 99mTc-labeled metallacarborane.
High stability of the radiometallacarborane obtained was demonstrated by its incubation

with a 1000-fold excess of cysteine or histidine in phosphate buffered saline (pH 7.2) at 37oC
for 24 h [259].
3.4. Boron Clusters as X-Ray Contrast Agents
Another possibility of medical application of the polyhedral boron hydrides is X-ray

contrasting imaging. Highly iodinated molecules have application in medicine as X-ray
contrast agents due to the opacity of the iodine atoms to low energy X-rays [262]. Even with
the recent phenomenal growth of MRI and ultrasound procedures, X-ray imaging studies
remain the workhorse of modern radiology (currently 75-80% of all diagnostic imaging
procedures are X-ray related). Today, iodinated X-ray contrast agents are used in about 20
million procedures annually in the United States, mainly in computed tomography and
angiographic applications. The U.S. market for X-ray contrast media has grown from $ 103
million in 1985 to more than $ 550 million in 1997, and approximately $ 1 billion today with
a worldwide market worth $3.2 billion.
Current X-ray contrast agents are principally composed of substituted iodinated benzene
compounds and their dimers. Most of the iodinated benzene derivatives have three iodine
atoms substituted in an alternating fashion with other substituents that are designed to
increase water solubility and decrease in vivo toxicity. Although the current radiographic
contrast media have been optimized over many years of development, improvements are still
being sought. One of the methods of improving contrast agents is to increase the iodine
content in the molecules. An increase in the percentage of molecular weight due to iodine in a
contrast agent from 28.7 to 37.5 % is known to double the contrast of the radiographic image
at selected X-ray energies. This fact suggests that chemical moieties other than benzene rings,
which can be more highly iodinated, might present new alternatives for contrast agents. The
anionic polyhedral boron hydrides could can be easily halogenated and have the potential for
incorporation of a large number of iodine atoms per molecule (molecules containing 65-85
wt. % of iodine can be obtained) [263-265].
3.5. Carboranes as Pharmacophores
The exceptional hydrophobic character and the spherical geometry of the carboranes
[266,267] might allow them to work effectively as hydrophobic pharmacophores. This
approach was first applied when phenylalanine and tyrosine residues in various bioactive
peptides and polypeptides were replaced with the o-carborane cluster [91,94,268,269]. Later
synthesis of carborane analogue of the anti-estrogen tamoxifen containing the carborane
fragment in place of the A ring phenyl group was reported [270].
Endo et al. proposed to use carboranes as the cores from which to construct a series of
potent estrogen receptor agonists [271-275] and antagonists [275-277]. The rationale behind
the design of the agonists was that hydrophobic carborane cluster could be used in place of
the C and D rings of 17β-estradiol, which play an important role in the binding of the steroid
to the estrogen receptors through hydrophobic interactions. Good binding to the receptors and
estrogenic activity requires the appropriate hydrophobic group be located adjacent to a
phenolic ring, in addition to the having an appropriately positioned H-bonding substituent. As
a result, a series of carborane derivatives containing phenolic substituents were prepared. The
position of the phenolic OH group, the nature of the substituents off the remaining carborane
CH group, and the choice of carborane isomer were all varied to obtain structure-activity
relationships. One of the carborane compounds prepared was found to be ten times more
active than 17β-estradiol in a luciferase reporter gene assay (Figure 24).
Figure 24. Molecular structures of 17β-estradiol and its p-carborane analogue.-
Consequently, Endo et al. prepared and screened a series of carborane-based retinoic acid
receptor agonists [278-280] and antagonists [281,282] having both amide and amine cores,
containing carborane substituents at the 3 and 4 positions of the central aryl group. More
recently, syntheses of novel carboranyl testosterone (Figure 25) [283-285] and cholesterol
(Figure 15) [203] mimics were reported.
OH
OH
Testosterone N
OH OH
N
O O
Figure 25. Structures of some carborane-based analogues of testosterone.
3.6. Carborane-Based Antitumour Agents
3.6.1. Platinum(II) Complexes with Carborane-Containing Ligands

The clinical utility of platinum anticancer agents is well proved. One leading anticancer
agent, cisplatin, is useful in treating some human cancers but is limited by both its side-affects
and the ability of some cancer cells to acquire a resistance to the drug [286]. Therefore, it is
desirable to develop a new platinum-based anticancer drug with broader spectrum of activity,
improved clinical efficacy and reduced toxicity, better than cisplatin.
As it was mentioned above, a series of platinum(II) complexes containing carborane-

based ligands were prepared as DNA metallointercalators for BNCT [287-292] by Rendina et
al. (Figure 26). Some of them were found to have rather high anti-cancer in vitro activity
against L1210 murine leukaemia cell line and its cisplatin-resistant variant (L1210/DDP) as
well as against 2008 human ovarian cancer cell line and its cisplatin-resistant variant
(2008/C13) (table 3).
+ +
OTf-
N N
N Pt S OTf-
S Pt N
+ N N
CH2 N
OTf-
S Pt N
N
1 2
+
Cl NH3 -
OTf
H2N Pt Cl H2N Pt Cl
NH3 NH3
+
NH3 NH3 -
OTf
H2N Pt Cl H2N Pt Cl
Cl NH3
3 4
Figure 26. Structures of some platinum(II) complexes with carborane-containing Ligands.
Table 3. IC50 (µM) values for some platinum(II) carborane complexes

against selected tumor cell lines
Compound L1210 L1210/DDP 2008 2008/C13

1 1.6 0.9 1.7 2.1
2 0.9 0.8 - -
3 2.0 2.5 13 13
4 1.1 1.4 5.5 5.6
Cisplatin 0.5 6.9 0.6 10
The relative cytotoxicities of the Pt(II) carborane complexes are similar in both the
cisplatin-sensitive and cisplatin-resistant cell lines. This clearly indicates that the mechanism
of cytotoxicity of the Pt(II) carborane complexes is not affected by the cisplatin resistance
mechanism(s). Preliminary in vitro DNA-binding experiments indicate that the complexes are
capable of targeting plasmid DNA.
Several other potentially DNA-intercalating carborane-based platinum(II) complexes
were prepared [293-295], however no data on their biological activity were reported.
3.6.2. Organotin Derivatives of Carboranes

Antitumor in vitro activiry of many organotin derivatives have been well documented
[296-298]. A number of organotin derivatives of carboranes were synthesized and antitumor
activity of some of them was determined (Figure 27) [299-303].
O O
O O
Cl
Sn N Sn N
Sn
Cl
O O
O O
1 2 3
Figure 27. Structures of someorganotin derivatives of carboranes.
Table 4. IC50 (ng/ml) values for some organotin carboranes

against selected tumor cell lines
Compound 1 2 3 4 cisplatin Doxorubicin

MCF-7 5 10 11 44 800 1200
WiDr 31 102 45 37 8 20
The compounds studied were shown to be somewhat less active than doxorubicin and
more active than cisplatin, suggesting that the carborane derivatives have intermediate anti-
cancer activity.
3.7. Weakly Coordinating Anions
There is considerable interest to weakly coordinating anions for numerous applications.

Probably, the most appreciated is the need for inert counterions in the preparation of
extremely reactive cations, especially strong Brønsted acids, and cationic catalysts.
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His own life would be far more worthy of salvation from the
impending doom than that of Demarzule. From the first moment
that he had conceived the repository and presented the idea to
Demarzule, Toshmere had planned that it would hold not Demarzule,
but Toshmere himself.
There was only one way to go ahead with such a gigantic project,
however, and that was letting Demarzule believe that it would be for
him. Since it could not be prepared in secret, Demarzule would have
to assent to the construction. He would do that if he thought it were
for himself. The idea would appeal to his egotistical mind; the
thought of his own personality spanning the eons, while all the
civilization he knew decayed and was swept away, would delight
him.
"The revival," said Demarzule. "Let me see how life is to be brought
back."
Toshmere swung another projector into line above the bowl and
snapped another switch. Invisible rays suddenly bathed the mass of
shapeless protoplasm within the bowl. As they watched, it quivered
and flowed, swiftly changing shapes, and growth and life took
possession of it.
The ruler of the Sirenians watched the reformation of the animal in

the bowl. Limbs and torso formed in shadowy gray outline, then
abruptly solidified and the animal leaped up, alive and startled.
Even Demarzule was somewhat taken aback by the seeming miracle.
"It is swift," he remarked. "The specimen is unharmed?"
"Completely," said Toshmere. "The process is not so rapid after a
long period of time has elapsed. The level of life is very low, but
never will it completely disappear. The lower it is, however, the
longer it takes for restoration. After many hundred ela, it might
require as much as a tor-ela."
"But it would be sure to succeed regardless?"
Toshmere nodded.
The hundred ships of the Sirenian bore on their steady course with
the enemy constantly gaining even though Galaxies away. At last the
lookout spotted a likely System in which the fifth planet showed
signs of habitability. Demarzule ordered preparations be made for a
halt.
The planet they found was inhabited by the remnants of a dying
civilization that had retro-graded almost to its infancy. The
opposition offered was quickly disposed of and the Sirenian refugees
began the frantic and hopeless task of constructing defenses against
the coming of the overwhelming force of the Dragbora, defenses
they knew were as penetrable as air to the new, fearful weapon
strength of the enemy.
But while gigantic screen generators were swiftly reared against the
sky and beam emplacements were dug, the best and wisest of the
scientists were busy preparing the repository for the Hetrarra,
Demarzule.
The huge, crystal-like container, which would be rendered
impervious to all known forces except the key frequency whose
formula was inscribed upon the outside, was to be lowered
thousands of feet into the great ore beds of the planet, in the hope
of avoiding the final blast that would shear the planet.
Two men would go into that repository, but only one would survive
the eons.
Toshmere was the only one completely acquainted with the entire
process so that it would be necessary for him to direct the operation
of the instruments. But Toshmere knew that Demarzule had no
intention of allowing him to leave the repository with knowledge of
its secrets—any more than Toshmere intended that Demarzule
should be the one to benefit by those secrets.
For three tor-ela the Sirenians worked frantically, putting up their
mighty defense works, and then their lookout posted a hundred
thousand light years out in space announced the arrival of the
terrible Dragboran fleet—just before a tongue of light from that fleet
lashed out at him and swept him into the eternities.
Toshmere approached Demarzule in his headquarters as the word

came. "There is not much time left, Hetrarra. The repository is
ready."
Demarzule looked out upon the sprawling works and great machines
so pitifully huddled together on an alien planet. This was all that
remained of the vast empire which he had dreamed of extending to
the limits of space itself, the empire over which he was to have been
supreme Hetrarra. And in a short moment this remnant would be
wiped out under the devastating supremacy of the now mightier
Dragbora.
He looked at Toshmere hesitantly. In the face of certain death the
old, lean, sinewy scientist showed nothing but calm. The Hetrarra
took one final glance at the remnants of his Sirenian Empire and
nodded.
"I am ready," he said.
They went out to the entrance to the shaft leading toward the heart
of the planet. The shaft had been built with the knowledge of only a
few Sirenians and none of them were aware of its purpose, thinking
rather that it was a means of defense.
Nobody saw the Hetrarra and the genius Toshmere enter the
elevator that carried them forever into the depths below the surface
of the planet.
Underwood and Illia came to the end of the page and Underwood
swore softly as he thumbed through the few remaining sheets.
There was no more about the ancient Demarzule and Toshmere.
The writer of the history had apparently been one of the Sirenian
scientists, a confidant and friend of Toshmere who had been close to
him in those last days. He had been one of the few to witness the
descent of the two into the depths of the planet, but he knew
nothing of what happened when they reached the bottom and
sealed the repository.
He did not know which one had survived in that mighty struggle that
must have taken place below.
And shortly no one of the Sirenians cared what the fate of their
deserting Hetrarra might have been, for the great Dragboran fleet
was upon them. With the mighty, unknown weapon that struck
terror to the mightiest of Sirenia, they sped out of space and swiftly
nullified the Sirenian defenses. It was a carnage that was frightful
even to the Sirenians, so schooled in the methods of shedding blood.
Their defenses might not have existed for all the effect they had on
their enemy. At first one by one, and then by tens, the operators
were touched by death and their machines turned to molten ruin.
At last, when only incandescent metal and sprawling dead lay of the
Sirenian fleet, the enemy ships withdrew, and the handful of
survivors dared hope that there might be escape for them.
But there was none. As the fleet withdrew beyond their vision, a
single small ship appeared in the heavens and they screamed with
the knowledge of what it was. But they were dead long before the
planet exploded into its component fragments which hurtled in all
directions into space.
Underwood put the manuscript down, his mind reluctant to close the
scene of vast and terrible battle that had occurred so long ago. It
had answered some of the problems raised by asteroidal archeology.
It explained the utter lack of relationship between Stroid III, which
was the language of the Sirenians, and Stroid I and II, which were
undoubtedly native to the vanished planet.
But this snatch of history prepared by the unknown scientist
companion of Toshmere raised the greatest enigma of all.
Illia's eyes looked up into Underwood's. "Who could have won?" she
said. "If it was Toshmere, the alien will be all that we hoped he
would be. If it is Demarzule, then Terry is right—he should be
destroyed."
Underwood glanced out toward the nutrient bath where the alien
slept, where the shadowy outlines of a faintly human figure already
appeared in the misty depths of the nutrient solution.
"It's got to be Toshmere," he said, and hoped he was right.
CHAPTER SEVEN
The viewing balcony above the floor of the museum hall was
completed and the disciples of the Great One began to flow through
in a never-ending stream. To Underwood, it was a sickening,
revolting sight. As he watched the faces of those who came and
worshipped at the shrine, he saw them transformed, as if they had
seen some great vision. They came with burdens of care lining their
faces—all ages, young and old—and they left with shining eyes and
uplifted faces. There were even sick and crippled who came and left
crutches, eyeglasses and trusses.
Twice a day, William B. Hennessey stood upon the balcony and
uttered a prayer to the Great One, and the stream of fanatic
worshipers stopped and bowed down.
One of Underwood's biologists, Craven, was so fascinated by the
exhibition of mass hysteria that he asked for permission to make a
study of it.
Underwood forced the spectacle out of his mind. He knew he
couldn't endure staying there at the museum if he allowed his mind
to dwell upon the decadence of mankind.
The mass of protoplasm in the nutrient bath was becoming more
and more a typical mammalian embryo, anthropomorphic in most
respects, but with differences that Illia and Underwood could not
assign to the natural development of the creature, or to the unusual
circumstances of its revival, because there was no standard with
which to compare it.
Then, one day near the end of the fourth month, Underwood
received an urgent call from Phyfe.
"Come over at once!" he said. "We've found the answer in the
repository. We know who the Great One is."
"Who?"
"I want you to see for yourself."
Underwood swore as Phyfe cut off. He turned his observations over
to the operator on duty and left the building. The lexicography and
philography sections of the institute were in an old sprawling block
across the city by the spaceport; the semantics section was also
housed there. The repository had been taken there for continued
examination.
Dreyer and Phyfe met him. The old archeologist was trembling with
excitement. "I've found the mummy!" he said.
"What mummy?"
"The mummy of the one in the repository who was killed by the
successful one."
"Who was it?"
"You'll see. He left a record for the discoverers of the repository."
They went into the enclosure that had been built to house the alien
structure. Inside, the repository looked many times the size it had
appeared in space. Underwood followed them into the familiar
passages. They went down into the main chamber which had held
the protoplasm of the Great One. Then Underwood observed an
opening leading lower down.
"You found a way into the rest of the repository?"
"Yes, and how unfortunate we were not to have found our way into
that portion first. But come."
Phyfe disappeared through the narrow opening and they passed
three levels filled with unknown artifacts. Then at last they came to
the smallest chamber formed by the curve of the outside hull. It was
too small for them to stand upright and filled rapidly with Dreyer's
cigar smoke.
"There it is, right where we found it," said Phyfe.
Underwood looked at the thing without recognition. It appeared as if
a rather huge, dried-up bat had been carelessly tossed into the
corner of the chamber.
"Completely dessicated," said Phyfe. "He didn't stay here long
enough between his death and the destruction of the planet for
decay to set in. He simply dried up as the molecules of water were
frozen and dispersed. I wish there were some way the biologists
could find to restore him. He's so shapeless it's difficult to tell what
he looked like."
"But who is he?"
"Here is the record he left. Apparently they had some kind of small
electric tool they carried with them to write on metallic surfaces.
How they read them is a mystery because we have to have a mass
of equipment as big as this chamber to decipher the stuff. Here are
photographs of his message that we have rendered visible."
Underwood took the sheaf of photographs. They showed the walls of
the chamber including the dried mummy lying inert where it had
fallen in pain and death. But standing out in sharp white characters
was a lengthy inscription written by the ancient creature of eons
ago.
"Can you read it?" asked Phyfe.
Underwood scanned the characters and nodded slowly. He had not
been able to keep up on the language as Phyfe had, but he could
read it now with fair facility.
The first part of the message was a brief reiteration of the history of
the ill-fated refugees that he already knew, but then he came to a
fresh portion.
"Demarzule has slain me!" the message read.
The words were like pellets of ice suddenly shot with bullet speed
into his face. He looked up at the impassive faces of the other two
men and read there the decision they had made.
Then, slowly, his eyes lowered to the sheet again and he went on
deliberately with the reading.
"I have attempted to get to the main chamber and destroy the
transformation equipment, but I cannot. Demarzule has learned how
to operate the equipment. Though there is nothing creative in him,
and all his aims are of conquest and destruction, he still has the
command of vast stores of Sirenian science.
"I am not a warrior or clever in the ways of fighting. It was not
difficult for Demarzule to best me. I die soon, therefore it is for you
who may read this in the ages to come. This is my message to you,
my warning: Destroy the contents of the protoplasm chamber
without mercy. Demarzule is there and he will be the scourge of any
civilization in which he arises. He dreams of conquest and he will not
rest until he is master of the Universe. He has destroyed galaxies; he
will destroy others if he lives again. Kill him! Erase all knowledge of
the dreadful Sirenian Empire from your memory!
"Should you be tempted to restore the Hetrarra and believe your
science a match for ours, remember that the knowledge required to
enter this repository is only the minimum. It is the lowest common
denominator of our civilization. Therefore, kill—"
The record ended with the last scrawled admonition of the ancient
scientist, Toshmere.
For long moments, the chamber of the repository was silent. Phyfe
made no comment as Underwood finished. He saw the tensing of
the physicist's jaw and the staring fixation of his eyes, as if he would
penetrate the ages with his naked vision and try to picture the dying
scientist scrawling his message on the walls of the death chamber.
Then Phyfe said at last, "We can't risk the revival of Demarzule now,
Del. Think what it would mean to turn loose a mentality having
command of such a superior science."
"We're not exactly planning to turn him loose," said Underwood
defensively. "We'll still have control when he revives. He can be kept
in suitable confinement—and finally disposed of, if necessary. It
seems worth it if we could tap the science he knows."
"Are you forgetting that we do not have control of him in any sense
of the word? The Disciples have. We're under direction of the
Institute, which can be wiped out in an instant by the Science
Committee. They, in turn, are mere puppets of the Disciples who
hold the voting power. When Demarzule revives, he'll have a ready
made following who'll regard him not only as Emperor, but as god. I
tell you we have no alternative but destruction."
Underwood's jaws tightened further. Within his grasp was a science

that might represent thousands of years of normal development of
the Solar system. He could not give up a gift such as the Sirenian
culture offered.
Then his eyes found those of Dreyer, who had said nothing, who sat
on his heels placidly in his haze of smoke. And there he read the
irrevocable answer.
"All right," he said. "You win—you and old Toshmere. Let's get inside
to a phone and I'll give the word to turn the radiation off."
Swiftly now they clambered up the stairs as if to escape some foul
tomb of the long-dead. They hurried into the building and into the
office of Phyfe. There Underwood called Illia.
She answered instantly, as if she had been waiting for his message,
fearfully and without hope.
"It's Demarzule, the conqueror," he said. "Turn off the radiation and
drain the tank. We'll stand the consequences of that, but we dare
not go on with the restoration."
Illia bit her lip and nodded. "It might have been Earth's great
chance," she said, and there was something like a sob in her voice.
"I'll turn it off at once."
Phyfe said, "Know what, Underwood? There's going to be trouble
over this. I think I'll ask for a transfer back to the expedition. Would
you like to come along with us?"
"I suppose so, but I'm afraid the Scientific Committee won't let us
get away that easily. You and I are through for the rest of our lives.
Didn't you think of that, Phyfe? We'll be lucky if we don't have to
spend the rest of our lives in prison. But, Dreyer, you don't need to
be caught in this. Get away before they come for us."
"I hadn't considered it that way," said Phyfe, "but I suppose you're
right. The Disciples won't be likely to let us get away this easy, will
they?"
Before Dreyer could speak, a call came through on the office
interphone. Phyfe switched on and the frantic face of Esmond, one
of the junior archeologists, appeared.
"Phyfe!" the man exclaimed. "I don't know what it is all about, but
the police are on the way down to your office. They have warrants
for the arrest of you and Dr. Underwood!"
Phyfe nodded. "Thanks, Esmond. I'll see that there's no trouble for
you because of this. I appreciate it. They didn't lose any time, did
they?" he said to Underwood. "But as long as Demarzule has been
destroyed, we've accomplished what we've tried to do."
"Wait a minute!" said Underwood. "Do we know that Demarzule has
been destroyed? Something must have gone wrong; the police came
too quickly."
"Look!" Shaken out of his customary calm, Dreyer was pointing
through the window across the city.
There, where they knew the Carlson to be, was a great shining
bubble of light.
"A force shell!" Underwood exclaimed. "How—?"
"They have evidently been prepared for a long time," said Dreyer.
Underwood tried the phone again and called for Illia, but there was
no response from inside the shell of impenetrable energy. A moment
of terrible fear caught Underwood up in its turbulence. What of Illia?
Was she all right?
"Whatever the answer," Phyfe exclaimed, "it's a ten to one shot that
Demarzule is not destroyed. In which case we'd better not be
taken!"
"What can we do? They'll have the building surrounded. There'll be
no chance of getting out."
"This is an old building. There are rooms and sub-basements that
few know about, and the staff are all scientists. They'll be loyal.
Come on!"
"No, wait," said Underwood. "Nothing can be gained by my hiding in
this rabbit warren underneath the city. There is only one chance of
destroying Demarzule, and that is my getting back to the museum
and doing it personally."
"You're crazy! The Disciples will never let you back in there. Come
on, man, we're wasting time!"
"You two go on and hide, Phyfe. I'll try to lay the blame on you and
a group of scientists, and swear my own innocence. It's the only way
to get access to Demarzule. Get going. Wait—have you got a
burner?"
"In the drawer there. We'd better take it."
Underwood yanked open the drawer and found the weapon. Then
he held the muzzle a short distance from his upper arm and fired.
His face twisted involuntarily with pain and Phyfe stared in
amazement. "What for?" the archeologist demanded.
Underwood tossed him the weapon as the room filled with the
stench of his burned flesh. "You shot me when I refused to order the
radiation off. It's a thin story and if they won't believe it I'll be a
goner. But if we don't risk it, Demarzule will be the next ruler of
Earth."
Dreyer nodded. "It's a chance. You'd better take it. Good luck."
A sudden commotion down the hall outside the door warned of the
approach of the arresting officers. Phyfe gave a last despairing
glance at Underwood, who was clutching the painful burn on his
arm. The archeologist turned and darted swiftly through a door at
the rear of the office, followed by Dreyer.
Almost instantly the main door was flung wide and two heavily
armed officers burst into the room. Their impulsive charge was
halted as they stared at the groaning physicist.
"Get help," Underwood said desperately. "I've got to get to the
museum. It may not be too late if Dr. Morov turned the beam off.
Phyfe forced me to order it stopped. Scientists don't want the Great
One revived. He shot me when I refused. Would have killed me if—"
Underwood sagged forward over the desk and fainted from the pain
he could no longer endure.
CHAPTER EIGHT
The beefy Committee Chairman regarded Underwood in the crowded
hearing room with the self-righteous, detached anger of one who
represents approximately a million voters. He told Underwood, "The
reprieve you have been granted is not given because your crime is
considered any less grievous. Because your act threatened a
possession of this government which may potentially change the
entire life of Earth for the better, your crime is deemed punishable
by death.
"However, you are the only man capable of directing the project.
Therefore, your sentence is commuted and will be resolved if you
successfully conclude the project of restoring the Great One. Only by
so doing may you prove your innocence. If an accident brings
failure, three separate committees of competent scientists will bring
a verdict that will determine whether you shall live."
"And what of Dr. Illia Morov?"
"Her sentence is life imprisonment for her attempt to destroy the
Great One."
"She obeyed my orders given under duress, as I have explained. I
cannot be responsible for the successful restoration if I am to be
denied competent assistance. Her knowledge is absolutely essential
to the success of the work."
The chairman frowned. "The civil courts have exercised judgment. It
may be possible for her to be bound over to us as you were, but her
sentence cannot be commuted except by special appeal and retrial.
We will see what can be done in the matter."
Underwood choked back the blast he would like to have hurled, his
denunciation of everything that symbolized the rotten culture into
which he had been driven by accident of birth. He dared hope only
that Illia would be granted leniency, that somehow they could think
of a way to destroy the alien.
He had forced his mind shut against all possibilities of antagonism

between the culture of Sirenia and that of Earth. Now he was aware
of the full potentialities of a mind like Demarzule's, armed with
Sirenian super-science, loose among Earthmen, and he was
motivated by an urge to destroy that was as great as his former
desire to save and restore. Earth was in bad enough shape without a
Demarzule.
For himself and for Illia he almost dared hope that they might find
escape from the wrath of the Disciples—perhaps to the Venusian
colonies—for there was nothing left for them upon Earth.
The Chairman added with deadly significance, "Just to make sure
that no risk is being taken with the Great One, you will be constantly
attended by an armed guard. You will carefully explain every move
before you make it—otherwise you may not be alive to make it."
That was all then. Underwood was led out under heavy guard
between the rows of watchers, most of whom were Disciples. He
could almost feel the doubt and hate directed toward him.
When he returned to the museum, guards of the Disciples stood
everywhere. The scientists worked with blank, expressionless faces—
and guns at their backs.
Craven, the biologist who had made detailed studies of the Disciples,
glanced up from his desk uncertainly as Underwood walked in. He
had been placed in charge temporarily during the absence of Illia
and Underwood.
"I'm sorry about—everything, Del. Especially about Dr. Morov. When
I saw her turning off the radiation I knew that something was
wrong, but when she said that word had come from you to do it, I
knew it was time for us to take over. I'm glad that they found you
were not in sympathy with the scientists who wanted the Great One
destroyed."
His words refused to fall into place in Underwood's mind so that they
made sense. But after a moment it came—though there were
personal guards attached to every other scientist in the place, there
was none standing watch over Craven. So Craven was one of them,
a Disciple. And if Craven, why not others?
But the biologist had been studying the Disciples from a scientific
standpoint. Had he succumbed in spite of that or because of it?
It was a problem beyond Underwood's grasp. He evaded a reply
with: "How is everything going? Is the cell division increasing?
Intensities of radiation and nutrient solution being stepped up
according to our plans?"
Craven nodded. "As far as I can tell, the Great One is developing
properly. You'll want to make a complete check, of course. The daily
reports are ready for your inspection."
Underwood grunted and left, followed by the silent, ever-present
guard. He went out to the test board where the trio of technicians
kept constant watch on the processes. Everything was functioning
according to instructions in the repository—instructions prepared by
Toshmere.
Everywhere were the guards, and up on the balcony were the
unending streams of Disciples of the Great One. It was like a
nightmare to Underwood. How had control of the project slipped
away? It had happened so rapidly and insidiously that he had not
been aware. But that was not it; the truth was that he had never
had control. From the moment that the scientists brought the
protoplasm of Demarzule to Earth and revealed the story of their
find, it had been inevitable.
Inevitable, Underwood thought, and the greatest semantic blunder
ever made. It might have been a good thing if it had been Toshmere
instead of Demarzule. The world had had no leaders for a century
except the bungling, vote-buying politicians. Toshmere might have
led them back to a semblance of strength and initiative, but what
would the conqueror and destroyer, Demarzule, do?
The following day, Illia returned. Underwood was shocked by her

appearance. She had dreamed of a new and saner world to be
brought by the alien out of space, just as Underwood had dreamed
of a new world of science to be revealed. And now their dreams had
turned into a monster.
The worst of their meeting was that there was nothing they could
say to each other. Illia came into the tiny world of nightmare under
the force shell in the custody of guards, and one remained
constantly by her side as she resumed her duties. Likewise,
Underwood's own guard never left him. Underwood had to maintain
his pretense of innocence before them.
"It was Phyfe and Dreyer," he said to Illia. "I'm glad you didn't
succeed in destroying Demarzule."
She hesitated an instant, then nodded with understanding. "I didn't
know what you were doing, but I supposed there was some reason.
I didn't suspect their evil plot."
And that was all. There was nothing more they could say. Nothing of
her despair at her white-faced, lusterless appearance. Nothing of her
lost dream.
The mass grew and took shape. Limbs and head and torso were
distinctly formed and losing their fearsome, embryonic cast. The
creature would be of adult form and shape, Underwood saw, and
would not represent a return to infancy. It was fully eight feet tall
and was humanoid to the extent of having four limbs and head and
torso, but the X-rays showed radical differences in bone and joint
structure. One cranial and two abdominal organs were completely
unfamiliar and could be identified by none of the biologists on the
project.
For a time Underwood nursed the hope that these structural
differences might make it impossible for Demarzule to survive on
Earth. But the further the lungs developed, the more evident it
became that the Sirenian would adapt to the atmosphere. As to
food, there was little doubt that nourishment would be no problem.
By the sixth month, too, it was hopeless to assume that anything
would go wrong with the process of restoration. Toshmere had
planned too well.
Underwood wondered what had become of Phyfe and Dreyer, if they
had been captured and killed, or if they still lived in the depths of
the ancient buildings beneath the city. There had been absolutely no
word. He had been kept in complete isolation since their tragic
failure. He spoke to no one except the silent guards and his fellow
technicians. He knew of none that he could trust, for he was certain
that among the scientists working beside him, there were those
whose duty it was to spy upon him. Craven, for example, had
become more sullen day by day, and now he avoided Underwood
almost continually, as if ashamed of the things that he believed in
and had done, but unable to renounce them or help himself. The
symptoms of hysteria were becoming constantly more evident.
Underwood looked for them in the other scientists, but he was not
skilled enough to detect all the signs. The only way was to play safe
and take no one into his confidence.
Life went on timelessly in the nightmare world. The light of day was
completely obscured by the force shell. As Underwood strolled out of
the museum building and looked up at its blackness, he recalled how
it had saved the world centuries ago, when mankind had once
before been on the verge of self-destruction in the dim beginnings of
the atomic age. Only by the discovery of the force shell, a field
impenetrable by any substance or radiation or force, had men been
saved from total annihilation.
But now man was faced by another potent force of destruction—his
own desire to submit to any leader who promised relief from
independent responsibility and action. The alien would certainly be
able to fulfill that promise where no man could, but was it worth the
risk of being saddled with a bloody dictatorship?
It was fantastic, Underwood thought, that he could find no way to
elude his guards and kill the growing monster. Variations in the
strength of the radiation might do it, but there was no possibility of
varying the radiation. The guards, whose leaders were technically
trained, had access to the records of the scientists, which not only
gave the details of previous work, but outlined each step until
Demarzule was restored. Underwood dared not attempt departures
of procedure from the written notes. The bath itself had been
surrounded by a transparent guard impervious to solid shot or
radiation weapons—even if he could have obtained any—nor could
poisons be placed in the nutrient solution.
There was simply nothing that could be done while Demarzule was
still in the nutrient bath. But on the day of his arising? A desperate,
last-ditch plan formed in Underwood's mind.
He explained to his guard, "When the Great One arises, it would be
well for someone to welcome him in his own tongue. Only a few of
us scientists are able to, and of those who can, I am the only one
here. With your permission, I'll be beside him and welcome him
when he rises."
The guard considered. "I'll relay your request to the First High
Prophet Hennessey. If it is deemed fitting you shall be appointed to
welcome the Great One."
Underwood wished that he had given Hennessey a warmer welcome
that first day when the fanatic prophet came to his office, but
Hennessey gave permission immediately. Underwood imagined the
Prophet taking considerable satisfaction in the irony of Underwood
being the first to welcome the Great One.
Mounted beside the narrow catwalk between the observation board
and the bath were the controls which would finally cut the radiation
and drain the nutrient solution as the process of restoration came to
an end. Here also were the water valves used to flush the bath when
it had first been constructed.
In this narrow space, Underwood could escape the watching eye of
his guard for an instant. He hoped to be able to cut the radiation
and drain the bath prematurely. If that couldn't be done, he might
fill the bath with water and drown Demarzule before the guards
could intervene or reach the shutoff valve. Underwood had managed
to secrete a small bar in his pocket with which he hoped to break
the valve after it was opened.
The massive form of Demarzule had been stirring like an embryo for
days now, and Underwood watched closely for the first attempt to
rise. That would be the earliest moment that he could hope to make
an attempt to destroy the Sirenian.
He wished he could confide in Illia, but there was no chance. He
feared she might have some desperate, dangerous plan of her own.
The color of the Sirenian's skin had turned a deep hue, like dark
redwood, and that appeared to be its natural tone. The hair upon
the head was coppery, darker than the skin. Demarzule's whole
appearance was one of might and strength even as he lay quiescent.
His features were bold, with wide-set eyes and sharp nose. The
mouth was stern, almost harsh.
Hysteria among the Disciples was mounting hourly. Instead of

flowing through the building along the balcony in their endless
stream, they poured in and stayed, hoping to be there for the rising
of the Great One. Some were pushed over and killed by the fall to
the floor below. They overflowed into the main hall and swarmed
about the masses of equipment. This was welcomed by Underwood,
who hoped that the pressing mob might damage some of the
equipment and thus bring about the end of Demarzule.
In any event, the hysteria was having its effects upon the guards,
who continued to watch the scientists. Their alertness and efficiency
were giving way to the same tension that filled the mobs within the
hall like a disease.
Underwood went sleepless for two days at the end, not daring to
miss his one chance. And hundreds of the faithful who jammed the
hall and thousands more who waited outside had already stood that
long waiting for the miracle.
It was in early dawn when Underwood caught the first faint motion
that indicated Demarzule was about to rise.
Underwood jerked a finger in the direction of the bath and looked
questioningly at the guard. The man nodded and Underwood raced
along the narrow catwalk.
There was no question of premature draining of the solution and
cutting the radiation. It was time for that now. Demarzule was
struggling upward, his lungs gasping in the first breath of Terrestrian
atmosphere which filled the upper part of the enclosure.
Underwood cut the radiation switch and twisted the valve on the
water line with a mighty wrench that tore the wheel from the shaft.
Water flooded into the chamber.
Demarzule struggled to a sitting position and stared as if dazed, his
countenance working fearsomely.
The Disciples saw him. A shout of ecstasy thundered through the
great hall and the empty rooms of the museum. And then, suddenly,
there was a new sound. A single voice rang out above all the rest.
"Strike now!" it shouted. "Strike down the invader. Destroy the
blasphemy of the Great One!"
Underwood's head twisted about. There on the balcony in the place
lately occupied by the Prophet, Hennessey, was Terry Bernard!
For an instant Underwood could not comprehend the meaning of it.
The gun in Terry's hand flashed red. Underwood's guard slumped in
his murderous rush and fell from the catwalk. He alone had seen the
sudden rise of water and realized its meaning.
The cries and curses and screams and prayers that filled the hall
made the previous commotion deathly silence by contrast. Sudden
beams of deadly fire shot through the air, and Underwood could
make no sense of it all.
Sides in the conflict began to appear. Underwood saw that some of
the technicians and scientists had weapons and had disposed of
their guards. Now they were firing carefully into the mob about the
equipment, picking off the armed leaders.
Inside the impenetrable enclosure, the giant Sirenian staggered
uncertainly as if stunned. The water was rising swiftly about his hips.
The air, rushing out the oxygen intake pipe, allowed the water to rise
in the otherwise hermetically sealed chamber.
A few minutes more and Demarzule would be cut off from the air
supply. How long it would take to drown him, Underwood did not
know. It would depend largely on his present rate of metabolism,
which was a great uncertainty. But could the mob be held off that
long? They had to be! He bent down and grabbed up the gun that
his pursuing guard had dropped.
In the background of his mind he wondered what this sudden attack
meant. How strongly organized was it, and who was behind it?
Apparently Terry had given the signal for attack, and many of the
scientists on the project had been prepared for it, yet Underwood
had been given not the slightest hint that such attack would take
place. He wondered why he had been left out.
The screaming of the hysterical Disciples was deafening as those in
front tried to force their way back from the line of battle, and those
in the rear tried to press forward to glimpse Demarzule.
Underwood leaped down to the floor in the sea of confusion and
found himself unable to determine which way the conflict was
moving. None of the scientists were near him, only the maddened,
unreasoning Disciples. He decided to stay near the water valve to
make certain that it was not shut off by any of the guards.
Then two figures surged up to him and one grasped his arm. "Del!
Come on, let's get out of here!"
He turned. Terry's blood-streaked face was almost unrecognizable.
His other hand clutched Illia's arm.
"You two go on," Underwood shouted. "Get out if you can. I've got
to stay—to make sure he drowns."
"The water's cut off! Can't you see?"

Underwood turned in horror. The water level was falling instead of
rising. Someone had cut it off at one of the other valves farther
along the line and had opened the drain. Air was being pumped
through, for Demarzule was standing rigidly now, looking down upon
the surging mass as if contemplating their fate. The bitter animal
struggle for survival was gone now from his face, and only a
mocking scorn was there as the mob battled before him.
"We've failed!" Underwood exclaimed. "It must have been Craven
who shut the water off. We haven't a chance now."
"Not if we stay here. Come on. We can lose ourselves in this crowd
and work our way outside. There's a ship waiting to take us across
to Phyfe. The Lavoisier is manned and ready to go."
"The Lavoisier! Where—?"
"Who knows? Go!"
Hopelessly, Underwood allowed himself to be pushed and jammed
into the thick of the mob by the frantic Terry. Signs of armed conflict
were dying. Underwood supposed that the scientists had been
subdued, for now the hall was completely filled with the Disciples. It
was impossible, he thought, that they could ever make their way out
without being apprehended. But even as doubts came, he knew that
he had to get out. He had to live to make another stand against the
Sirenian.
He looked back. Demarzule was standing erect now. Slowly his great
arms came up and his hands extended as if in blessing and
welcome, and the moaning of the ecstatic Disciples rose in wild
discordance.
Then out of those alien lips, amplified a thousand fold by the audio
system installed within the chamber to catch any uttered words,
there came an alien voice that only Underwood could understand.
And as the strange words poured forth he shuddered at their
implications.
"My people." Demarzule said. "My great and mighty people!"
CHAPTER NINE
Underwood turned as if driven back by the force of the conquering
voice of thunder that came from the throat of Demarzule.
No one was paying any attention to the three scientists now. The
faces of the Disciples were upturned toward the Great One, waiting
for further pronouncements.
Underwood, Terry and Illia shoved through the wide doors of the hall
against the crowd pressing from outside. As they fought through,
the enormous voice continued to assail their ears.
"I have triumphed over death," Demarzule exclaimed. "I have
conquered the ages, and now I come to you, my people. I have
come to lead you to the stars and to the Galaxies beyond the stars,
where your very name shall cause the creatures of distant worlds to
tremble."
Each word was like a knife stabbing into Underwood, for they
showed that Demarzule had already comprehended the situation—
and mastered it. And though the people did not understand the
words, the tone of his voice carried the meaning almost equally well,
and there were none in that mass of worshipping Disciples who
doubted that a new day of greatness had dawned for Earth.
All semblance of organization under the small-time prophets and
priests such as Hennessey had vanished. There had never been
much organization because people did not trust any man sufficiently
to compose a very tight or efficient organization.
This was to the benefit of the scientists. It would take time for
Demarzule to become aware of the opposition and the identity of the
scientists. But he must surely be aware of the attempt on his life,
Underwood thought, unless full consciousness had not returned until
the water had begun to subside in the chamber, and Demarzule had
not realized the significance of it.
But Underwood did not believe that. Demarzule had exhibited such
rapid grasp of the attitude of the Disciples that he probably
possessed a semantic accuracy in his thinking which would shame
the best of Earth's scientists.
The three were making more rapid progress now as they pushed out
into the part of the mob that could not see Demarzule. Under the
black dome of the force shell, as far as they could see, the area
between the building and the outer edge of the shell was filled with
struggling humanity. The words of Demarzule could be heard only
faintly.
"The north gate," Illia said. "That is the widest. Maybe the guard
system has broken down completely—"
Terry nodded. "It looks like it. That's the closest to our flier, anyway.
If we are challenged, let's carry Illia and explain she was injured in
the mob. That might get us through. If not, keep your gun ready."
Underwood assented. He felt as if this were some nightmare from
which he was struggling to awaken—unsuccessfully. He wondered
what had happened to the other scientists on the project, and to
those who had attempted the storming of the building. Had they all
perished in the short and futile battle?
He had to admit to himself that at times, during those long days
under the surveillance of the Disciple guards, he had wondered if
there wouldn't have been some chance of utilizing Demarzule's
science without danger. That hope, however, had been finally and
completely blasted by Demarzule's arising. The Sirenian had not
changed in half a million years.
As they savagely thrust through, Underwood considered the course
that would probably be followed by Demarzule. He would gather
about him a puppet organization of administrators who would take
on a priestly sanctification before the people because of their
nearness to the Great One. The organization would tighten about
the Earth, enfolding the willing devotees, ruthlessly wiping out small
centers of opposition that might spring up.
At the command of the Disciples would be the world's weapons and
factories. And added to these would be the fearful science and
unknown weapons of the Sirenian.
What force could hold back this avalanche?
The answer was: None. There was no force that could touch him,
nothing the scientists could do to prevent the unleashed forces of
Earth from sweeping the Galaxies.
Flight. That was the only recourse for those who wished to escape
the debacle. But it must be more than flight. However hopeless it
seemed, those of Earth's scientists who could be gathered must be
dedicated to the task of Demarzule's overthrow, the saving of
Earthmen from an insane course of conquest.
Close to the north gate, the distorting energies of the force shell
were led around a portion of space to form an opening in the wall.
Word of the rising of the Great One had spread like a virus and
thousands were gathered beyond the shell, trying in vain to force
their way in. All semblance of attempting to guard the entrances
seemed to have vanished as the trio forced their way through the
opening and out into the sunlight that seemed utterly blinding to Illia
and Underwood, who had not seen it for so long.
For a moment Underwood wondered if they could not have remained
inside the Carlson and taken a chance on shooting Demarzule when
he came out of the protecting shield about the bath. But he knew
better. Demarzule would not come out until the room was cleared
and the faithful were standing guard with their guns ready to blast
any would-be assassin.
No, they were on the only course open to them. They were
committed to it now; there was no turning back.
At last they came out into a relatively free space where they could
move rapidly. Underwood caught sight of the small three-man flier
atop a low rise, a mile from the museum.
"What about the others?" Underwood said as they ran. "Didn't any of
them get away?"
"I don't think so," Terry answered. "We didn't expect it. Our object
was to destroy Demarzule, and, failing that, to get you two."
The two running men, one with bandaged arm and the other with
bloodsmeared face, and the white-faced girl were attracting
unwelcome attention, but at last they came to the rise where the
flier lay, and climbed in. Without a lost motion, Terry worked the
controls and they whirled into the air.
From their elevation, Underwood looked back toward the museum,
the holy sanctuary of the Disciples. The roads leading to the site
were black with humanity as the faithful streamed to the building to
witness the Great One and hear his voice.
He turned to Terry. "Bring me up to date."

"They contacted me—I wasn't suspected by the police, you know—
and we organized a small group of the scientists we felt we could
trust. We told them all about Demarzule and our blunder in bringing
him back. We organized for the purpose of destroying him by any
means possible, but of course we had no means. The force shell
prevented direct attack on the Carlson, so we tried filtering in with
the Disciples. Four of us were caught and killed.
"We didn't try to communicate with you, because we felt it was too
dangerous, and knew that you would be doing anything possible. We
succeeded in getting enough of our number in for the end of the
show and passing weapons to some of the scientists on the project,
but we apparently lost all our men without doing damage to the
Great One. Only getting ourselves lost in that mob saved us three. I
suspect that they feel so secure in the protection of Demarzule now
that that is their only reason for not gassing the whole mob in order
to get us."
"What's your next move?" asked Illia.
"The Lavoisier came in two weeks ago for supplies. Most of the crew
are on our side, and the rest aren't there any more. Phyfe and
Dreyer are already aboard, as well as the rest of the scientists of our
group. All we can do is point the nose up and get going as fast as
we can travel. It may be only a matter of hours until Demarzule is
aware of us and sends a fleet in pursuit. After we get out into space,
the rest is up to the boss." He jerked a thumb in Underwood's
direction.
"What do you mean?" asked Underwood.
"I mean that as top-dog physicist and the only one besides us
somewhat non-combatant archeologists and semanticists who
understands the Sirenian lingo, not to mention your familiarity with
Demarzule, you got yourself elected chairman of this delegation."
Underwood laughed shortly and bitterly. "I'm responsible for the
mess, so I should be the one responsible for finding a way out. Is
that it?"
"We'll turn you over to the psychiatric department if you don't cut
that out," said Terry grimly.
"Sorry. I'm grateful, of course, that the rest of you think I could be
useful, but I'm afraid my brain is a complete blank on how to get
out."
"Maybe you think the rest of us aren't the same way," said Terry.
"But you're the most qualified of us all to recognize a means of
licking Demarzule when you see it."
Underwood stared ahead of them toward the expanding view of the
buildings where the scientists had held out against the Disciples. He
tried to picture what the past months had been for them, but he
could never know the hundreds of desperate escapes and skirmishes
with guards and officers, and swift murders in the depths below the
city.
Beside the clustered buildings the great laboratory spaceship,
Lavoisier, lay on the experimental grounds, shining in the early
dawn. Sudden bright spurts of light showed on the field. Illia saw it
first. "Gunfire!" she cried.
"They're being attacked!" Terry exclaimed. "We've got to get down
there or they may have to leave without us. Get out that pair of
heavy burners under your seat, Del. We'll have to go in shooting."
Underwood hauled out the weapons as the flier darted swiftly
toward the field. A concentrated knot of offense was being offered
from the building entrance nearest the ship, but other officers were
surrounding the ship behind the screen of the distant shrubbery.
"I'll fly over them," said Terry. "Give them a good blast with both
guns."
Underwood opened the port against the wind and pointed the noses
of the deadly weapons outward. He clicked the trigger and an
unending stream of fire hurled toward the earth, sweeping through
the lines of attackers as they crouched behind the shrubs and
fences. Then, swiftly, Terry spun the ship to avoid the building and
they zoomed upward. At that instant a crippling beam came from
below.
"We're hit!" Terry exclaimed. "It killed the motor. Hang on for a crash
landing. I'll try to make the port of the ship."
Underwood returned his attention to the guns as if nothing had
occurred. As the nose dipped, he fired into the building from which
the disabling shot had come. He thought he heard a scream of pain,
though it might have been only the sound of the wind against the
shell of the little flier.
They were falling fast now, heading for the open port of the large
spaceship. They could see some of the crew members and scientists
emerging, weapons ready to protect their landing. They sped down
below the level of the top of the hull and the vast sheets of plate
seemed to flow past the port of the flier like a river of steel.
It stopped flowing. They hit hard, and Terry yanked open the door.
They tumbled out in the midst of their defenders, while spurts of
flame showed in the sunlight all about them.
"Get in!" one of the men shouted. "We almost had to leave without
you. They'll be bringing reinforcements." It was Mason, the physicist.
Underwood nodded. "We're ready. Is everyone else aboard who is
going?"
"Yes."
There was a sudden cry beside Underwood and one of the crewmen
dropped his gun and clutched an arm in pain. Mason and Terry
clutched him in supporting arms and dragged him into the vessel.
Underwood clasped Illia's hand and hurried through the port. Behind
them the last of the men slammed the door and dogged it tight.
"Phyfe's waiting for you in the control room," Mason said. "We'll take
care of Peters, here. Terry had better stay for treatment also."
Underwood nodded and raced along the corridor with Illia. They
passed other men intent upon their own tasks. Some of them he
knew; others he had never seen before. He hoped that Phyfe and
Terry had chosen carefully. The remembrance of the biologist,
Craven, came to his mind. They came to the entrance to the control
room. Captain Dawson was in technical command, waiting for
instructions to take off. Apparently Mason was assuming charge of
the takeoff, for his voice came through the audio system as
Underwood entered. Phyfe nodded assent to Captain Dawson. "Take
it up!"
Almost instantly, the ship soared aloft.

"Wait!" Underwood exclaimed, as he entered the control room.
Phyfe and Dawson looked toward the door. "There can be no
waiting," said Phyfe. "We had almost given up you and Terry and
Illia. The police have been searching for us for weeks, and now that
we're out in the open they'll spare no force to take us."
"We can't go without the Stroid records," said Underwood. "Terry
tells me I've been elected to head this outfit. If that's so, then my
first order is to pick up every scrap of Stroid record and artifact that
has ever been found before we take off."
Dreyer came in and looked interestedly as Underwood spoke, but he
said nothing.
"Why?" said Phyfe. "I don't understand."

"There was a weapon," said Underwood, "a weapon that the
Sirenians were afraid of, which apparently was responsible for the
power of the Dragbora over them. If any trace of that weapon
remains in the Universe, our goal is to find it. It may be our one
hope of defeating Demarzule."
The others looked at him as if doubting his sanity, yet hoping he was
on the trail of a solution.
"But that was five hundred thousand years ago!" said Phyfe. "How
could we hope to find such a weapon that disappeared that long
ago? We have no clues—"
"We have the Stroid records. That's why I want them."
"But the Sirenians seemed to know nothing about the nature of the
weapon."
"We're not so sure of that. But even if that's so, there was the great
civilization of the Dragbora. We don't know that it is extinct, and we
know nothing of its location—but the weapon may be there. And the
clue to its location may be in the Stroid records."
Dreyer nodded and gave a violent puff of smoke. "He's right, Phyfe.
We hadn't thought of it, but that may be our one chance. At least it
gives us an objective instead of just plunging into purposeless
flight."
"I suppose so," Phyfe said doubtfully. "But I don't see how—"
"I'll take care of that. Show us where the records are. We'll get the
repository first, however; I want the whole thing brought aboard."
Underwood turned swiftly to Dawson and ordered the ship lowered
beside the temporary structure housing the repository near the
Stroid museum building. Then he stepped to the ship's interphone
and explained their maneuver. He called for twenty volunteers to
man scooters and weapons to cover those who were to transfer the
records.
Below them, on the ground, the police forces who watched their
prey escape stood puzzledly as the Lavoisier turned and moved
slowly across the group of buildings and began dropping again.
Three deadly police fliers hovered in the air about the great
spaceship.
It was the fliers that Underwood watched with intent study. The
twenty men he had selected out of the volunteers gathered around
the viewing plates with him.
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Chapter 8 Organometallic Complexes of Rhodium(I), Iridium(I)

POLYHEDRAL BORON HYDRIDES IN USE:

Igor B. Sivaev and Vladimir I. Bregadze

2. MAIN TYPES OF POLYHERAL BORON HYDRIDES.

up to 80 % [8,9]. Synthesis of numerous derivatives of the closo-decaborate anion has been

[B10H10]2- [B12H12]2- [CB11H12]-

Figure 1. Main types of stable polyhedral boron hydrides.

3. APPLICATION OF POLYHEDRAL BORON HYDRIDES

3.1. Boron Neutron Capture Therapy

3.1.1. General Principles

Table 1. Thermal neutron capture cross-sections of isotopes characterized

Isotope Capture Isotope Capture cross- Average content

L-para-boronophenylalanine sodium mercapto-closo-dodecaborate

Figure 2. Clinically used BNCT agents.

Figure 3. Principal scheme of BNCT agent.

3.1.2. Low Molecular Weight Boron Compounds

Nucleotides and Nucleosides

selectively trapped intracellularly as anabolically and catabolically stable non-toxic 5’-

Figure 4. Structures of some carborane-containing nucleosides.

Synthesis and biological evaluation of the first cobalt bis(dicarbollide) analogues of

Figure 5. Structures of cobalt bis(dicarbollide) based nucleosides.

COOH COOH COOH

Figure 6. Structures of some carborane-containing aminoacids.

Figure 7. Structures of anionic boron-containing aminoacids.

Figure 8. Structures of some boron-containing lactoses.

Porphyrins and Phthalocyanines

Figure 9. Structures of some boron-containing porphyrins.

Figure 10. Structures of some carborane-containing porphyrins.

Figure 11. Structures of some boron-containing phthalocyanines.

H2N NH2 H2N NH2

Figure 12. Structures of some carborane-containing acridines and phenanthridines.

Recently a series of Pt-based DNA metallointercalators with carborane-containing

Figure 13. Structures of some carborane-containing analogues of Hoechst 33258.

Figure 14. Structures of some carborane-containing polyamines.

3.1.3. High Molecular Weight Boron Delivery Agents

boronated macromolecules containing up to 100 boron cages, and 2) development linkage

3.1.3. Second Component: Neutron Sources

Figure 15. Structures of some carborane-containing analogues of cholesterol.

3.1.4. Clinical Status of BNCT

3.2. Boron Neutron Capture Synovectomy

Rheumatoid arthritis is an autoimmune disease characterized by recurrent swollen,

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