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Metal Complexes of Curcumin — Synthetic Strategies, Structures and

Medicinal Applications

Article in Chemical Society Reviews · May 2015

DOI: 10.1039/c5cs00088b · Source: PubMed

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TUTORIAL REVIEW
Metal complexes of curcumin – Synthetic strategies, structures
and medicinal applications
Simon Wanninger,a Volker Lorenz,a Abdus Subhanb and Frank T. Edelmann*a
Dedicated to Professor Karl-Heinz Thiele on the occasion of his 85th birthday
5

This Tutorial Review presents an overview on the synthesis, characterization and applications of
metal complexes containing curcumin (= 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-
3,5-dione) and its derivatives as ligands. Innovative synthetic strategies leading to soluble and
crystallizable metal curcumin complexes are outlined in detail. Special emphasis is placed on the
10 highly promising and exciting medicinal applications of metal curcumin complexes, with the three
most important areas being anticancer activity and selective cyctotoxity, anti-Alzheimer's disease
activity, and antioxidative/neuroprotective effects. Overall, this Tutorial Review provides the first
general overview of this emerging and rapidly expanding field of interdisciplinary research.

Key learning points

15 1. Curcumin and its derivatives.
2. Synthesis and characterization of metal curcumin complexes.
3. Non-medicinal applications of metal curcumin complexes
4. Medicinal applications of metal curcumin complexes
5. Anti-cancer activity of metal curcumin complexes
20

lower than that of Americans of the same age.3

1. Introduction Over the past few decades, numerous studies have explored the
medicinal properties of turmeric and curcumin, including
“From kitchen to clinic” or “Curry against Alzheimer” – These are
50 antitumoral, antimicrobial, anti-inflammatory, antioxidant,
only two of the recent sensational headlines associated with the
antihepatotoxic, antihyperlipidemic, antiviral, and anti-
various health benefits of curcumin. Curcumin1 (= 1,7-bis(4-
Alzheimer’s disease effects. In fact, turmeric has even been termed
25 hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a com-
the “multi-anti spice” in herbal medicine, and curcumin has been
ponent of the Indian spice turmeric, manufactured from the
referred to as “curecumin”.4,5 In more detail, the following diseases
rhizome of the perennial herb Curcuma longa that is widely
55 and disorders may be treated successfully with curcumin: Liver
cultivated in tropical countries in South and South East Asia, and biliary diseases, wounds and ulcers caused by injuries and
especially in China and India. Curcuma longa belongs to the diabetes, psoriasis, arthritis and rheumatism, sinusitis, heart
30 Zingiberaceae (ginger) family. Curcumin (= CurcH) is the major diseases and high blood cholesterol, diabetes, amyloidosis as well
component of three curcuminoids that give turmeric its
as cervical, colon and pancreatic cancer. The anticancer properties
characteristic yellow color and is used as a food colorant, flavoring
60 include suppression of cellular trans-formation, prevention of
and additive (E number E100). The minor curcuminoid cancer cell proliferation, and suppression of carcinogenic effects.6
components are demethoxycurcumin (= DMCurcH) and bis- Curcumin compounds alone or in combination with other
35 demethoxycurcumin (= BDMCurcH) in which one or both -OMe anticancer drugs have been reported to inhibit the clonogenicity of
functionalities at the outer phenol rings are removed. Very cancer cells and induce anti-proliferative and apoptotic effects on
recently, an improved separation of the three curcuminoids was 65 drug-resistant and sphere-forming cancer cells expressing stem
realized using a combination of normal-phase column and cell-like markers as well as reverse the chemoresistance. Thereby
phosphate-impregnated preparative-thin layer chromatographies.2
they improve the cytotoxic effects induced by diverse
40 Besides its widespread use as food flavor and colorant, turmeric chemotherapeutic drugs on these immature cancer cells. These
has been used in traditional Chinese and Ayurvedic medicine for beneficial health effects of curcumin are all well documented in
around 4000 years. Thus the headline “Curry against Alzheimer”, 70 the current literature. For example, in 2013 the journal "Current
although sounding modern and sensational, has its roots in this
Pharmaceutical Design" published a special issue entitled "Recent
traditional knowledge. It has been demonstrated that the incidents Progress and Novel Insights in Curcumin Research - From
45 of Alzheimer’s disease among elderly people of age 70-79 in rural Chemistry to Clinical Use”. Clinical studies in humans showed that
India, who eat curry dishes on a daily basis, is about 4.4 times

This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 0
 curcumin is generally safe even at high daily doses of up to 12
grams with only few side-effects.5 A severe problem encountered
in clinical trials involving curcumin is its poor bioavailability,
leading to low levels in plasma and tissues. The bioavailability of
5 curcumin in the form of food colorants or additives (spices) may
be higher due to the cooking process or the dissolution in oils. The
insolubility of curcumin in water, poor absorption, rapid
metabolism and systemic elimination have been shown to be the
main factors limiting its bioavailability. As a result, numerous
10 studies have been directed to increasing curcumin bioavailability,
including the use of absorption factors (e.g. piperidine/piperine),
the encapsulation of curcumin in the cavities of cyclodextrins, or
the use of nanoparticles6 and ceramic particles.7
A highly promising and innovative approach to deal with the
15 bioavailability issue and to achieve even more diverse potential
health benefits is the use of metal curcumin complexes. Curcumin
and the curcuminoids are rare examples of naturally occurring β-
diketone ligands. As such, they should be ideally suited to act as Fig 1 First paragraphs of the historic paper by Miłobędzka, von
chelating ligands toward a variety of metals and to form stable 55 Kostanecki and Lampe. Reproduced from ref. 8.
20 complexes. The past 10 years have witnessed a dramatic increase
At the first glance, curcumin is just another typical substituted β-
in studies directed to the synthesis, characterization and biological
diketone ligand closely related to acetylacetone. Like
investigation of metal curcumin complexes. Already it has become
acetylacetone, curcumin displays typical keto-enol-tautomerism as
clear that the potential medicinal applications are as diverse as
illustrated in Scheme 1.
those of curcumin itself. The three most exciting areas appear to be
25 selective cyctotoxity and anticancer activity, anti-Alzheimer's H
O O O O
disease activity, and antioxidative/neuroprotective effects. MeO OMe MeO OMe
However, highly promising results with metal curcumin
60 HO OH HO OH
complexes have also been reported in the fields of antiarthritic /
Scheme 1 Keto-enol tautomerism of curcumin.
antirheumatic activity, antimicrobial/antifungal activity, anti-
30 viral/anti-HIV activity and biological imaging/radioimaging. As
becomes evident from the list of references, many of these However, unlike acetylacetone, the central β-diketone
investigations have been published in journals which e.g. synthetic functionality is flanked by the sterically demanding unsaturated
chemists normally do not have on their screen. Notably, more than 65 phenolic groups, -CH=CH-C6H4(OH)(OMe)-3,4, which results in
50% of the references cited in this review appeared between 2012 an unusually wide and flat β-diketonate ligand. Thus the overall
35 and 2015. Thus it is a major goal of this Tutorial Review to serve shape of curcumin ligands with the two large wings attached to the
as a springboard for the readers to readily access the highly β-diketone unit may be compared to that of an eagle. In addition,
diverted literature in the area of metal curcumin complexes. the phenolic -OH groups are additional centers of potential
Overall, this Tutorial Review tries to provide the first general 70 reactivity which could lead to complications in metal complex
overview of this rapidly expanding field and to outline the most preparation (i.e. formation of insoluble polymers).
40 exciting current trends. Curcumin exists in the keto form in acidic and neutral pH media
and in the enol form in alkaline pH medium. A stable crystalline
2. The characteristics of curcumin-based ligands form of curcumin is long known in the literature. Recently,
75 however, two new metastable polymorphs (enol form) of curcumin
The chemical structure of curcumin was first identified in 1910 by
were reported that exhibit higher solubility as compared to the
Miłobędzka, von Kostanecki and Lampe (Fig. 1). Through
stable form. In the course of a recent study, the solubility and
chemical derivatization, these authors clearly established the
mechanical properties in these polymorphic systems have been
45 identity of curcumin as diferuloylmethane or 1,7-bis(4-hydroxy-3-
investigated. It was found that the hardness (H) is inversely
methoxyphenyl)-1,6-heptadiene-3,5-dione.8 They also prepared
80 proportional to the solubility of a polymorph. Effectively, this
two potentially useful derivatives, dicarbomethoxycurcumin and
study demonstrated that the hardness is a useful parameter
dicarboethoxycurcumin, by treatment of curcumin with two
(comparable to melting point and density) that correlates well with
equivalents of methyl- or ethylchloroformate, respectively, in the
the solubility of a polymorph. To summarize, a softer polymorph
50 presence of aqueous potassium hydroxide. These two derivatives
is more soluble (Fig. 2). It was pointed out that such a correlation
are particularly valuable in curcumin chemistry as they are easily
85 is helpful in systems like curcumin in which the Gibbs free
accessible in good yields and high purity.8
energies of the polymorphs are close to one another. 9

This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 1
 Fig. 3 Molecular structure of 1,7-bis(4-triphenylsiloxy-3-
35 methoxyphenyl)-1,6-heptadiene-3,5-dione (= Ph3SiCurcH).

Furthermore, new curcumin-derived O,N-chelating ligands can be

Fig. 2 Correlation between hardness and solubility of the three
obtained by replacing one of the β-diketone oxygen atoms by =N-
known curcumin polymorphs. Reproduced from ref. 9. Copyright OH (curcuminoxime), =N-NHC(O)NH2 (curcuminsemi-
2014 American Chemical Society. carbazone), and =N-NHC(S)NH2 (curcuminthiosemicarbazone).
40 Curcumin can also be modified in various other ways leading to
5 Possible variations of the basic curcumin ligand system are potentially new ligand systems. For example, Knoevenagel
manifold. Various changes of the substituents at the phenyl rings condensation of the active central methylene group of curcumin
are possible, e.g. by converting the phenolic -OH group into -OR with an aldehyde (e.g. salicylaldehyde) provides a non-enolizable
(R = Me: Me2CurcH, R = Et: Et2CurcH, R = nBu: Bu2CurcH), β-diketone which can be further treated with suitable amines, e.g.
-OC(O)Me (diacetylcurcumin = DACurcH), or -OC(O)OR (R = 45 thiosemicarbazide or substituted anilines, to afford the
10 Me, Et) functionalities. Even β-D-glucopyranos-1-yloxy moieties corresponding Schiff base derivatives. The resulting curcumin
have been successfully attached to the curcumin backbone.10 diketimine ligands have been successfully employed in the
Methylation at the central carbon atom of the β-diketone moiety is synthesis of a series of copper(II) complexes.11 An even more
also possible to give e.g. trimethylcurcumin (Me3CurcH). Table 1 sophisticated extension of these ligand modifications is the design
lists some of the most common curcumin ligands and their 50 of a macrocyclic tetraaza diacetyl curcumin ligand. This work
15 abbreviations used in this Tutorial Review. nicely demonstrates how far-reaching modifications of the
Table 1 Commonly used curcumin ligands and their abbreviations curcumin ligand system are possible. The reaction sequence is
used in this reviewCaption illustrated in Scheme 2.12

R1 R2 R3 Ligand Abbreviation
OMe H H CurcH
OMe / H H H DMCurcH / BDMCurcH
OMe Me H Me2CurcH
OMe Et H Et2CurcH
n
OMe Bu H Bu2CurcH
OMe Me Me Me3CurcH
OMe C(O)Me H DACurcH
H C(O)Me H DABDMCurcH

20 Most recently, in the course of our own studies of new metal

curcumin complexes, we succeeded in the synthesis and structural 55 Scheme 2 Synthetic route to metal(II) complexes containing a
characterization of the first triorganosilyl-substituted curcumin tetraazamacrocyclic diacetylcurcumin ligand.
derivative, 1,7-bis(4-triphenylsiloxy-3-methoxy-phenyl)-1,6-
heptadiene-3,5-dione (= Ph3SiCurcH). This com-pound is formed 3. How to prepare and characterize metal
25 in high yield upon treatment of an alkaline solution of curcumin curcumin complexes
with 2 equiv. of chlorotriphenylsilane. The bright yellow
compound shows a resonable solubility in a number of common Most studies dealing with metal curcumin complexes and their
organic solvents. X-Ray quality single-crystals of Ph3SiCurcH 60 applications have been published within the past 10 years.
could be grown from hot toluene. Fig. 3 clearly shows that the two Coordination compounds comprising curcumin and its derivatives
30 bulky triphenylsilyl substituents add a great deal of steric demand as ligands have been reported for most metallic elements in the
to the curcumin ligand system. Metal complex formation of this Periodic Table. Notably, well characterized alkali and alkaline
new curcumin ligand still awaits further exploration. earth metal curcumin complexes are scarce. Only very few
65 examples have been described for Na, Be, Mg, Ca, and Ba. The

2 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 paucity of well-defined alkali metal curcumin derivatives is reaction of [(η6-p-cymene)RuCl2]2 with curcumin in the presence
particularly surprising in view of the fact that such compounds are 60 of sodium methoxide, NaOMe. The compound forms an air- and
often formed and used as intermediates upon deprotonation of free moisture-stable solid which is soluble in chlorinated solvents,
curcumins by alkali metal hydroxides, alkoxides, acetates etc. alcohols, acetone, acetonitrile, and DMSO, clearly a positive effect
5 Among the other main group elements, boron derivatives form the of the spectator ligand p-cymene. In both cases the X-ray analyses
longest known and most thoroughly investigated class of confirmed the formation of the expected half-sandwich complex
compounds.13,14 Several aluminum15-17 and gallium18-20 65 containing an η6-arene ligand, one chloride and a chelating
compounds with curcumin ligands have also been described, while curcumin anion. Figure 4 depicts the molecular structure of (η6-p-
there are only a few scattered examples for curcumin complexes of cymene)RuCl(Curc).35
10 indium, tin, and lead.20 In the case of Groups 3-6, examples are
known for Y, La, Zr, V, and Cr, with a significant prevalence of
vanadyl species containing the V=O unit.20-23 However, there is a
clear accumulation of compounds containing middle and late
transition metals.24 Curcumin complexes have been described for
15 all metals in the Groups 7-12 except for osmium. By far the most
papers in this area deal with copper curcumin complexes,25-27
followed by zinc,28-30 nickel,31 iron,10,31 manganese,32,33 and
ruthenium34,35 species. For the remaining middle and late transition
metals, the number of well-characterized curcumin complexes is
20 significantly smaller.36-38 Recently, even technetium complexes
containing curcumin have been reported.39 Moreover, curcumin Fig. 4 Molecular structure of (η6-p-cymene)RuCl(Curc). Repro-
complexes have been prepared for several lanthanide elements2,40- 70 duced from ref. 35. Copyright 2012 American Chemical Society.
43
as well as thorium and uranium, with the latter all being uranyl The reason why the early study by Beck et al. has been discussed
(O=U=O) species. here in more detail is the following: This work already revealed
25 Pioneering work in this area was published in 1997 by Beck and some of the important general characteristics and potential
co-workers at the Ludwig-Maximilians-Universität in Munich.31 problems of transition metal curcumin chemistry. Most curcumin
As part of a series of publications entitled “Metal Complexes of 75 complexes are easily accessible using the general synthetic route
Dyes”, no less than twenty-eight new transition metal complexes with or without minor modifications. Yields are often very high,
containing the ligands curcumin (Curc), bis-demethoxycurcumin and in most cases the products are readily isolated in the form of
30 (BDMCurc), dimethylcurcumin (Me2Curc), trimethylcurcumin precipitates. However, crystallinity of the products is often low, as
(Me3Curc; this ligand contains a methyl group at the central is solubility in water and common organic solvents. Many
methylene functionality), and diacetylcurcumin (DACurc) were 80 curcumin complexes exhibit significant solubility only in highly
synthesized and characterized. The general synthetic protocol polar solvents such as pyridine, dimethylformamide (DMF), or
employed in this early study is applicable to the preparation of dimethylsulfoxide (DMSO). As a result, structural characteri-
35 virtually all metal complexes containing curcumin and its zation of metal curcumin complexes through X-ray diffraction
derivatives as ligands. The first step normally involves studies remains scarce. A SciFinder survey on the topic “metal
deprotonation of the free curcumin derivative by a suitable base 85 complexes of curcumin” yielded ca. 150 publications in which
such as ammonia, sodium hydroxide, sodium methoxide, sodium only 11 crystal structures of such complexes were reported. The
carbonate, sodium acetate or silver acetate. In the second step, the lack of structural information is particularly apparent for the
40 resulting anions are treated with metal halides in the appropriate homoleptic curcumin complexes. Homoleptic curcumin
molar ratios. This way, Beck et al. obtained the homoleptic complexes of the type M(Curc)2 and M(Curc)3 are known for
complexes Pd(Curc)2 and M(Me2Curc)2 (M = Ni, Cu) from the 90 various middle and late transition metals as well as some of the
metal(II) acetates, while homoleptic Fe(Curc)3 was made from rare-earth elements. Quite frequently, homoleptic transition metal
FeCl3 and 3 equiv. of in situ-prepared NaCurc. An even larger or lanthanide curcumin complexes are described as orange, red, or
45 series of new curcumin complexes was prepared starting from brown precipitates which lack solubility in most organic solvents
organotransition metal halides, including [(R3P)MCl2]2 (M = Pd, and are difficult to characterize.24 Accordingly, to our knowledge,
Pt; R = Et, nBu, Ph, tolyl), [(η5-C5Me5)MCl2]2 (M = Rh, Ir), [(η6-p- 95 none of these homoleptic curcumin complexes has been
cymene)RuCl2]2 (p-cymene = p-isopropyltoluene) and [(η3- structurally authenticated by X-ray diffraction!
C3H5)PdCl]2. All these reactions yielded well-defined complexes Now, what are the main lessons to be learned from the
50 containing one curcumin-type ligand per metal atom plus one or pioneering work by Beck and co-workers? Apparently, the
two different co-ligands (“spectator ligands”) such as allyl, crystallization of homoleptic ransition metal complexes
phosphines, pentamethyl-cyclopentadienyl, or p-cymene. 100 comprising only curcumin as ligands is severely hampered,
Characterization of the new complexes was based mainly on presumably through the formation of polymeric arrays by
spectroscopic methods (1H and 13C NMR, IR, UV/Vis) and interaction of the metal ions with the free phenolic -OH groups.
55 elemental analyses. Only in the case of (η6-p- This would be a possible explanation for the observed low
cymene)RuCl(Me2Curc), X-ray quality single-crystals could be solubility of such complexes in water and most of the common
obtained.31 The closely related curcumin complex (η6-p- 105 organic solvents. What can be done to overcome these obstacles
cymene)RuCl(Curc) was later prepared in a similar manner by without completely altering the curcumin ligand system?

This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 3
 Basically, two different successful strategies can be envisaged paragraphs.
which in many cases have already led to the formation of metal In recent years, the original synthetic protocol (deprotonation of
curcumin complexes which exhibit higher solubility and better curcumins, followed by treatment with suitable metal halide
crystallinity: 50 precursors) has been extended to the synthesis of a large number
5 1. A logical approach would be the blocking of the free phenolic of other main-group and transition metal complexes containing
–OH groups at the 4-positions of the phenyl rings. As mentioned curcumin and substituted curcumins as ligands. Only selected
above, this can be achieved by converting the phenolic -OH groups examples will be discussed here in more detail. A fairly large and
into -OR, -OC(O)R, or –OC(O)OR (R = Me, Et) functionalities. well-investigated group of early transition metal curcumin
Very recently, positive proof of this approach was provided by the 55 complexes contains the vanadyl group (V=O). The parent
10 successful synthesis and structural characterization of the complex, VO(Curc)2 (“vanadyl curcumin”), is easily accessible in
copper(II) complexes Cu(Et2Curc)2(1,4-dioxane) (Et2CurcH = 1,7- high yields (89%) on a 20 g-scale by treatment of vanadyl
bis(4-ethoxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) and acetylacetonate, VO(acac)2, with 2 equiv. of curcumin in
homoleptic Cu(Bu2Curc)2 (Bu2Curc = 1,7-bis(4-n-butoxy-3- dichloromethane solution in the presence of 2 M NaOH.
methoxyphenyl)-1,6-heptadiene-3,5-dione). These compounds 60 VO(Curc)2 is a rust-colored solid, which was characterized by IR,
15 were prepared in the usual manner from copper(II) acetate and 2 MS, magnetic moment and elemental analysis (Scheme 3). This
equiv. of the alkylated curcumins. Unlike previously reported remarkable compound was found to exhibit both promising
copper(II) curcumin complexes, X-ray quality single-crystals of antiarthritic and anticancer activity (cf. Section 5).21
Cu(Et2Curc)2(dioxane) could be grown from ethyl acetate/1,4-
dioxane solutions. As shown in Fig. 5, the central copper(II) ions
HO OH
20 are coordinated by two chelating diethylcurcumin ligands in a
square-planar coordination geometry. As a result of the large π- H 3CO OCH3
conjugated electron system, the ligands are almost planar. The O O
packing diagram of the complex showed that the adjacent V O

molecules are stacked through two types of π-π interactions along O O

H 3CO OCH3
25 the a and c axes with short distances of 3.846 and 3.897 Å. Single
crystals of the n-butyl derivative Cu(Bu2Curc)2 could even be HO OH
65
grown directly from ethyl acetate. The results clearly demonstrate Scheme 3 Schematic representation of VO(Curc)2 (“vanadyl
that the solubility of homoleptic metal curcumin complexes can be curcumin”).
significantly improved by blocking the phenolic -OH groups of the
30 parent curcumin ligand.25,26 No other metal curcumin complex motif has been chemically
modified to such an extent than vanadyl curcumin.20-23 In
70 particular, a considerable number of vanadyl mono(curcumin)
complexes comprising suitable co-ligands (spectator ligands) have
been synthesized, characterized and investigated for their
biological activity. Mainly bi- and tridentate N-donor ligands
related to 2,2’-bipyridine, phenanthroline, bis(2-pyridyl-
75 methyl)amine and terpyridine and their derivatives have been
employed as spectator ligands. Most of these vanadyl complexes
were prepared in a straightforward manner following a general
synthetic protocol in which vanadyl sulfate, VOSO4, is first treated
with barium chloride to give a solution of vanadyl chloride, VOCl2.
80 After removal of the by-product barium sulfate, the filtrate is
treated with equimolar amounts of curcumin and the respective bi-
Fig. 5 a) Keto-enol tautomers of the ligand diethylcurcumin (1,7- or tridentate ligand to afford chlorovanadyl complexes like e.g.
bis(4-ethoxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione); b) VO(Curc)(phenanthroline)Cl as shown in Scheme 4a. Closely
molecular and c) crystal structure of the copper(II) curcumin related cationic vanadyl mono(curcumin) complexes can be
35 complex Cu(Et2Curc)2(dioxane). Reproduced from refs. 25 and 26. 85 prepared from reactions of an equimolar mixture of VO(acac)2, the
2. The second potentially successful approach is the synthesis of respective bi- or tridentate ligand and sodium perchlorate. A
heteroleptic complexes containing suitable spectator ligands in typical example containing a ferrocenylmethyl-substituent at the
addition to curcumin. Chances to isolate soluble and crystallizable spectator ligand backbone is shown in Scheme 4b.22,23
curcumin complexes apparently increase if only one curcumin
40 ligand is present in such heteroleptic metal complexes. Suitable
ligands to complement the coordination sphere of the metal ions in
addition to curcumin include, but are not limited to, pyridine, 2,2’-
bipyridine, phenanthroline, terpyridine derivatives, tertiary
phosphines, cyclopentadienyl ligands and h6-coordinated arenes
45 like cymene or hexamethylbenzene. Typical examples for this
spectator ligand approach will be discussed in the following

4 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 a) b) + (ClO 4) - 40 Among the late transition metals, ruthenium provides
MeO OH
OH particularly instructive and successful examples for the spectator
OMe ligand approach to well-characterized and nicely crystalline
mono(curcumin) complexes. Following the successful synthesis
N
N
O O
O
and structural caracterization of (η6-p-cymene)RuCl(Me2Curc)35
O
V
N V 45 (vide supra), the synthetic protocol was applied to a number of
O Fe O
N
Cl N cationic ruthenium mono(curcumin) complexes containing not
only the η6-bonded arene ligand (p-cymene or hexamethyl-
OMe benzene) but also the bulky phosphine ligand 1,3,5-triaza-7-
OH
MeO OH phosphaadamantane (= PTA) (cf. Fig. 7a). In this case, the crystal
Scheme 4a,b Typical examples of vanadyl mono(curcumin) 50 and molecular structures of three new complexes, [(η6-p-
complexes containing tridentate co-ligands. cymene)Ru(Curc)(PTA)][SO3CF3], [(η6-hexamethylbenzene)Ru-
(Curc)(PTA)][SO3CF3], and [(η6-p-hexamethylbenzene)Ru-
Some technetium and rhenium curcumin complexes have recently (BDMCurc)(PTA)][SO3CF3] could be authenticated by X-ray
5 been reported.39 It was found that curcumin reacts with the bromide diffraction! Fig. 7b depicts the molecular structure of the cation in
precursors fac-[M(CO)3Br3]2− (M = Tc, Re) through the β- 55 [(η6-hexamethylbenzene)Ru(Curc)(PTA)][SO3CF3]. These results
diketonate moiety to generate, under mild synthetic conditions, the clearly emphasize the importance of careful spectator ligand
aqua complexesOrganometallics
fac-M(CO)3(H2O)(Curc). The aqua ligand in both design in the chemistry of metal curcumin complexes.34 Article
complexes is labile and can be easily replaced at room temperature
against human ovarian carcinoma cells relative to nontumorous
10 by triphenylphosphine to generate
human embryonic the cells.
kidney corresponding tricarbonyl
monophosphine complexes fac-M(CO)3(PPh3)(Curc) (M = Tc,
■ RESULTS
Re). Excess of phosphine
formation of the Synthesis
new dicarbonyl
ANDunder
leads DISCUSSION
reflux in methanol to the
bis(phosphine) complexes
and Characterization of Ruthenium cis- Com-
trans-M(CO)2(PPh plexes. The desired ruthenium(II) arene complexes 1−6 were
3)2(Curc). Apparently, in the tricarbonyl
prepared in high yield in a single step (Scheme 2), in which the
15 complexes the phosphine ligand, which has a large trans effect,
substitution of chloride ligand with PTA in the ruthenium
labilizes the trans carbonyl which is quantitatively
coordination environment is achieved byreplaced
applyingby a salts,
silver
second phosphine ligand.
i.e. AgX, whereTheX rhenium
= SO3CF3bis(phosphine)
, PF6. complex
was also prepared using the precursor mer-trans-
Re(CO)3(PPh3)2Scheme
Cl. In 2.thisSynthesis of Complexes
case, the incoming 1−6bidentate donor a)
20 ligand curcumin displaces the Cl and one of the CO ligands. All
complexes were isolated in high yield and characterized by
elemental analysis, spectroscopic methods, and, in the case of cis-
trans-M(CO)2(PPh3)2(Curc), X-ray crystallography (Fig. 6). All
complexes were found to be soluble in dichloromethane,
25 chloroform, benzene, and toluene, slightly soluble in methanol and
ethanol, and insoluble in water. The bis(phosphine) complexes
were even stable in solution for months as shown by HPLC and
NMR. In solutions of the monophosphine complexes, however, a
gradual release of the coordinated phosphine ligand was noted over
30 time, more intense in solvents with coordinating potential like
dimethylsulfoxide (DMSO). After all, this is another nice example b)
illustrating how heteroleptic metal curcumin complexes with good 60 Fig. 7 a) Schematic representation of cationic (η6-arene)ruthenium
solubility and crystallinity can be designed through the right choice mono(curcumin) complexes containing PTA as co-ligand; X- = PF6-,
SO3CF3-; b) Molecular structure of the cation in [(η6-hexamethyl-
of spectator ligands.39
benzene)Ru(Curc)(PTA)][SO3CF3]. Reproduced from ref. 34.
OH Copyright 2014 American Chemical Society
OCH3
65 Low solubility and poor crystallinity also characterize the
Complexes 1−6 are air stable and soluble in alcohols,
Ph
Ph
Ph
acetone, acetonitrile, and DMSO and slightly soluble inhomoleptic lanthanide complexes of the type Ln(Curc)3 (Ln = Sc,
2,40-42
P
O chlorinated solvents. The IR spectra of 2 and 5 display aY, La-Lu). Here, too, the spectator ligand approach proved to
OC
M strong, sharp absorption at 825 and 826 cm−1 due to the PF6be highly useful. Scheme 5 illustrates the successful combination
OC
P
O counteranion,13 whereas the spectra of 1, 3, 4, and 6 contain aof curcumin (+ diglucosylcurcumin), anions (NO3-) and spectator
Ph Ph characteristic absorption pattern in the region 1000−1200
Ph
cm−1, typical of a noncoordinated O3SCF3 anion.14 The 701Hligands (4’-phenylterpyridine and 4’-(1-pyrenyl)terpyridine)
NMR OCHspectra
3 of 1−6 display all the expected signals due to thewhich was assembled in the coordination sphere of the large
M = Tc, Re coordinated arene rings, curc or bdcurc ligand, and PTA. Thelanthanide anions La3+ and Gd3+. Due to their large ionic radii,
35 OH
resonances due to the PTA ligand are shifted to lower field withsteric saturation
Figure 1. Molecular
of the structures of 1 (top),
coordination 3 (middle),
sphere of theand 6 (bottom).
lanthanide ions
Fig. 6 Schematic representation
respect to those ofoftheuncoordinated
curcumin complexes cis-
PTA, confirming its Counterions and solvates have been omitted for clarity. Selected bond
trans-M(CO)2(PPh 3)2(Curc) (M = Tc, Re) and molecular 15 structure
31 of is evenlengths
more (Å)
important
and than
angles in the
(deg) for case
1: of transition
Ru1−O2, 2.082(2);metals.
Ru1−O1, This
coordination to the ruthenium center. The P NMR spectra 3+
cis-trans-Re(CO)of2(PPh
1, 2,3)4,2(Curc).
and 5, Reproduced
containing thefrom ref. 39.moiety, display75 ais due 2.089(2);
p-cymene to the factRu1−P1,
that Ln2.308(1);
ions generally
Ru1−η6, prefer high
1.713(1); coordination
O1−Ru1−O2,
Copyright 2014 singlet
American Chemical Society.
centered at ca. −26 ppm, whereas 3 and 6 with the numbers89.13(6);
such P1−Ru1−O2,
as 8 or 9. As 83.43(5);
a result P1−Ru1−O1,
of this favorable88.89(5).
ligandSelected
design,
bond lengths (Å) and angles (deg) for 3: Ru1−O2, 2.080(2); Ru1−
hexamethyl moiety show a resonance at −32 ppm, in the rangethe crystal structures of both 4'-phenylterpyridine
6 derivatives
O1, 2.092(2); Ru1−P1, 2.324(1); Ru1−η , 1.702(1); O1−Ru1−O2, could
typical of related compounds and in accordance with the 87.78(7); P1−Ru1−O2, 82.07(5); P1−Ru1−O1, 87.88(5). Selected
existence of only one species in solution.16 The ESI mass bond lengths (Å) and angles (deg) for 6: Ru1−O2, 2.086(6); Ru1−
This journal isspectra
© TheofRoyal Society
1−6 show of Chemistry
two main [year]
peak envelopes, that of highest Journal Name, [year], [vol], 00–00 | 5
O1, 2.091(5); Ru1−P1, 2.328(2); Ru1−η6, 1.707(6); O1−Ru1−O2,
relative intensity corresponding to the intact [Ru(arene)(curc/ 87.9(2); P1−Ru1−O2, 83.2(2); P1−Ru1−O1, 86.9(2).
bdcurc)(PTA)]+ species and the other being due to the
[Ru(arene)(curc/bdcurc)]+ fragment formed upon PTA
 be determined by X-ray diffraction.43 boron-containing compounds. Here too, a characteristic red
OR'
coloration is observed due to the formation of boron-curcumin
complexes. In this case it was possible to confirm the deep red
OMe
O phenylboronic acid-curcumin complex by single-crystal X-ray
N
N O O
45 diffraction. The X-ray study clearly showed that the curcumin acts
O
R= ; as a chelating ligand to the tetrahedrally coordinated boron to
R N Ln
O produce a tetrahedral boronate to which one methanol molecule is
N O O
N added, consistent with the coordination geometry observed in
O
OMe
rosocyanine (Fig. 8).46
Ln = La, Gd
OH OR' HO OH
O
R' = H (Curc), HO MeO OMe
HO
OH O O
B
Scheme 5 Schematic representation of lanthanide
MeOH
mono(curcumin) complexes containing 4’-phenylterpyridine and 4’-
50
5 (1-pyrenyl)terpyridine as spectator ligands.

4. Non-medicinal / analytical applications of

metal curcumin complexes
The oldest known application of curcumin complexes is related
to the spectrophotometric detection of trace amounts of boron in
10 various media,44 including biological materials45 (e.g. foodstuffs,
plants and blood plasma), natural water and sea water, soil, iron
and steel, as well as materials relevant to nuclear technology, such
as uranium metal, uranium oxide and aluminum. As early as 1866, Fig. 8 Schematic representation and molecular structure of the
Schlumberger discovered an intensely red dye which he named phenylboronic acid-curcumin complex. Reproduced from ref. 46.
Copyright 2012 The Royal Society of Chemistry.
15 “rosocyanine”. This dye was formed when curcumin reacted with
boric acid, B(OH)3, in alcoholic solution in the presence of a strong 55 Yet another potentially useful non-medicinal application of
mineral acid. At that time, the molecular structure of curcumin had metal curcumin complexes, especially those of nickel, involves
not even been established. Today it is well established that their use in the electrochemical modification of electrodes for
rosocyanine is a cationic 2:1 complex formed from curcumin and oxidation reactions. The catalytic oxidation of methanol on a
20 boric acid in which the central boron atom is tetrahedrally glassy carbon electrode which was electrochemically modified by
coordination by two curcumin anions (Scheme 6). Anions can be 60 a conductive Ni(II)-curcumin complex film was first reported in
chloride and hydrogensulfate.13 Similar complexes containing only 1995.47 In the course of this study, it was found that a glassy carbon
curcumin ligands bonded to boron are formed e.g. with BF3·Et2O electrode modified by this Ni(II)-curcumin film can act as a very
and boronic acids, RB(OH)2. Also notable in this context is a effective catalyst for the oxidation of alcohols. Deposition of the
25 closely related compound named “rubrocurcumin”. This red dye is nickel(II) curcumin complex was simply performed by contacting
formed when the reaction of curcumin with boric acid or borates is 65 the clean electrode surface with a freshly prepared solution of
carried out in the presence of oxalic acid. In contrast to the cationic curcumin, a Ni(II) salt and 0.1 M NaOH. Electropolymerization of
rosocyanine, rubrocurcumin is a neutral compound in which boron the nickel-curcumin complex and oxidation of methanol were
is tetrahedrally coordinated by one curcumine and one oxalate studied by cyclic voltammetry. The modified electrode was shown
30 ligand. Similar products can be obtained e.g. by replacing oxalic to provide a durable catalytic surface which allows the
acid with citric acid.13,14 70 voltammetric oxidation of methanol: In 0.1 M NaOH electrolyte
the resulting anodic peak is at 0.59 V (vs. SCE). In contrast,
a) b) electrooxidation was not possible at bare glassy carbon electrodes,
HO OH
HO OH
at least before the onset of the electrolyte decomposition.
MeO OMe
O O
MeO OMe Electrocatalytic oxidation of ethanol, propanol and butanol could
O O

O
B
O
X B 75 be achieved quite efficiently in the same manner.47 The surface
O O
MeO OMe morphologies of the nano-structured Ni(II)-curcumin-modified
HO OH
O O carbon electrodes have been studied by scanning electron
X = Cl , HSO 4 microscopy (SEM) and atomic force microscopy (AFM). The
Scheme 6 Schematic representation of a) rosocyanine and b) results (Fig. 9) showed that the deposited Ni(II)-curcumin films
35 rubrocurcumin. 80 had a nano-globular structure in the range of 20-50 nm.48 More
recently, Ni-curcumin-modified glassy carbon or carbon paste
Solid rosocyanine forms green-black microcrystals with a metallic
electrodes have been successfully employed in the electrocatalytic
luster. Its intense red color allows the colorimetric detection of
oxidation of various biologically and pharmaceutically relevant
boron even at ppm levels. Recently, the method has been extended
molecules and drugs. The substrates included glucose and fructose,
to develop a rapid and facile thin-layer chromatography staining
85 several amino acids, the antibiotic amoxicillin, and some non-
40 method for the qualitative analysis of boronic acids and related

6 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 steroidal anti-inflammatory drugs such as indomethacin, 45 and (3) changes in the serum acid phosphatase level during the
mefenamic acid, and diclofenac. As a result, the modified disease course. The serum gold levels were also determined at
electrodes could be used as sensors for the determination of different dose levels.37 Today, virtually all metal curcumin
glucose and fructose with good response at low detection limits. complexes are being investigated with biological and medicinal
5 The method also provided a sensitive, simple, and time-saving studies in mind. Notable is an impressive increase of relevant
amperometric procedure for the analysis of antibiotic and anti- 50 contributions to this field in the past 3-5 years.
inflammatory drugs in pharmaceutical preparations and biological
5.1. (Photo)cyctotoxicity and anticancer activity
media.49
Not surprisingly, this area has become the hottest topic in the
field in the past three years, although initial findings on anticancer
activity of metal curcumin complexes date back until the year
55 1998. In the following years, several transition metal complexes of
curcumin and curcuminoid ligands have been prepared and
successfully tested in vitro and in vivo for antitumor effects.
Among a series of vanadyl (V=O), Co(II), Ni(II) and Cu(II)
curcumin complexes, the copper(II) derivatives turned out to
60 exhibit the highest selective cytotoxicity and also showed
significant reduction in solid tumor volume in ascites tumor-
bearing mice. IC50 values of 6.6-11.1 µM in Ehrlich ascites tumor
cells were reported for such copper(II) curcumin complexes. Also
notable among these earlier results is the readily accessible and
65 versatile vanadyl compound VO(Curc)2 (“vanadyl curcumin”)
10 Fig. 9 SEM images of a nano-structured Ni(II)-curcumin-modified which was first reported in 2004. This simple though highly
carbon electrode at two different magnifications (50.000x and remarkable compound showed antirheumatic activity in
60.000x). Reproduced from ref. 48. Copyright 2008 Elsevier B. V. synoviocytes, angiogenesis inhibition in smooth muscle cells and
There are also a few unusual applications of metal curcumin promising anticancer potential in mouse lymphoma cells (L1210).
complexes in materials science. Notable is a recent report about the 70 At the same time, VO(Curc)2 proved to be exceptionally non-toxic
15 synthesis and characterization of ZnO nanoparticles via thermal and showed no negative symptoms during a 1-month treatment
decomposition of a zinc curcumin complex. Treatment of an period at doses up to 2.0 mmol kg-1 day-1.21 Tests of the closely
ethanolic solution of zinc nitrate with curcumin in a 1:2 molar ratio related vanadyl curcuminoid complexes VO(DMCurc)2,
afforded the dinuclear zinc complex [Zn(Curc)(OH)]2 which could VO(BDMCurc)2, VO(DACurc)2, and VO(DABDMCurc)2 in all
be employed as a single-source precursor for the production of 75 cases revealed similar cytotoxicity in mouse lymphoma cells as for
20 ZnO nanoparticles. Thermal decomposition of the precursor was vanadyl curcumin.20
complete in less than 1 h at a heating rate of 10 °C/min. Full Until now, anticancer activity has been reported for metal
characterization of the resulting nanoparticles revealed the curcuminoid complexes of the Group 13 elements Al, Ga and In,
formation of monodispersed hexagonal zincite structure with an the first-row transition metals V and Fe-Zn, the second-row
average size of 117 ± 4 nm.30 80 transition metals Ru and Pd, as well as some rare-earth metals. The
majority of the complexes studied are vanadyl (V=O) and
copper(II) derivatives, followed by zinc complexes. Notable
25 5. Medicinal applications of metal curcumin
among the main-group metal complexes is a study reporting the
complexes
synthesis and characterization of 68Ga-labeled curcumin and
Without any doubt the most exciting aspect of metal curcumin 85 curcuminoid complexes as potential radiotracers for cancer
complexes is the finding that many of them exhibit very diverse imaging. The complexes 68Ga(Curc)+ and 68Ga(DACurc)+ as well
and highly promising health effects similar to curcumin itself. Thus as a related complex containing bis(dehydroxy)curcumin were
30 it is not surprising that this section constitutes the most important evaluated for their uptake by A549 lung cancer celles. All three
part of this Tutorial Review. One of the first biological complexes showed a quite high uptake in the lung cancer cells
investigations on metal curcumin complexes was published as 90 which was at least equivalent to the respective free curcuminoids,
early as 1987 and comprises an antiarthritic study of the orally thus confirming their potential applications a cancer-detecting
active gold(III) curcumin complex [Au(Curc)2]Cl. This complex radiotracers.18 As mentioned in Section 3, a considerable number
35 was prepared in a simple manner by mixing curcumin with of vanadyl curcumin complexes comprising a variety of spectator
gold(III) chloride in a 2:1 molar ratio in ethanol and characterized ligands have been synthesized and fully characterized. These
by elemental analysis, magnetic moment, IR and electronic 95 complexes have been extensively and successfully studied for the
spectral studies. It remained unclear, however, wether or not the photoinduced anticancer activity.22,23 Photodynamic therapy is a
chloride ion is directly coordinated to gold, as the conductivity of promising and non-invasive method for treatment of various
40 the complex could not be determined due to its poor solubility in cancers. The treatment involves the combined use of a
all common organic solvents. Antiarthritic studies on rats were photosensizer, visible light and molecular oxygen to generate
carried out using three parameters: (1) assessment of remission in 100 reactive oxygen species (= ROS, cf. also Section 5.3) which are
adjuvant-induced polyarthritis by measurement of paw volume, (2) cytotoxic. Under optimal conditions, the ROS will damage only
X-ray studies to see the anatomical changes of the affected limb, the photoexposed cancer cells while leaving the unexposed healthy

This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 7
 cells unaffected.22 Very recently, the utility of heteroleptic vanadyl apoptosis signal transduction and enhancement of cell death in
curcumin cmplexes as photodynamic therapy agents has been 60 human prostate cancer cell lines (LnCaP, PC3, and DU145) and
explored in a series of studies with highly promising results. suggested the potential of this design strategy in the improvement
Virtually all complexes studied showed remarkable of the metal-based drugs cytotoxicity.36 The copper(II) complexes
5 photocytotoxicity in selected cancer cells (e.g. HeLa, a cell line Cu(Et2Curc)2(1,4-dioxane) (Et2CurcH = 1,7-bis(4-ethoxy-3-
often used in cancer research, as well as Hep G2 and 3T3 cells) in methoxyphenyl)-1,6-heptadiene-3,5-dione) and Cu(Bu2Curc)2
visible light, while being relatively non-toxic in the dark. 65 (Bu2Curc = 1,7-bis(4-n-butoxy-3-methoxyphenyl)-1,6-
Mechanistic studies revealed either singlet oxygen (1O2) or heptadiene-3,5-dione) have already been mentioned in Section 3
hydroxyl radicals as the reactive oxygen species. The results also because of their increased solubility and crystallinity due to
10 suggested light-induced cell death by the curcumin complexes via blocking of the phenolic –OH groups through alkylation. Both
an apoptotic pathway.22,23 complexes showed significantly enhanced antitumor activity
Notable among late transition metal curcumin complexes 70 against three human cancer cell lines (ASPC-1 (pancreatic
exhibiting antitumor activity are particularly ruthenium, carcinoma), MCF-7 (breast cancer) and HeLa (cervical cancer)) in
palladium, copper and zinc derivatives.26-29,34-36 Well-defined comparison with the free ligands. These findings once again
15 ruthenium complexes for which antitumor activity has been underlined the importance of exploring the coordination chemistry
reported, include (η6-p-cymene)RuCl(Curc) and (η6-p-cymene)- of curcumin derivatives as an effective method to improve their
RuCl(DMCurc)35 as well as the novel cationic ruthenium 75 antitumor activity.26 Scheme 6 illustrates three advanced copper
mono(curcumin) complexes containing an η6-bonded arene ligand curcumin complexes comprising N-ferrocenylmethyl-L-amino
(p-cymene or hexamethylbenzene) and the bulky phosphine ligand acids as co-ligands. The DNA photocleavage activity,
20 1,3,5-triaza-7-phosphaadamantane (= PTA) in addition to the photocytotoxicity and cellular localization in HeLa and MCF-7
curcuminoid ligands (cf. Fig. 7).34 When tested in vitro, both (η6- cancer cells of these complexes have been studied. All three
p-cymene)RuCl(Curc) and (η6-p-cymene)RuCl(DMCurc) 80 complexes exhibited high photocytotoxicity with low dark
displayed good antitumor activity in colon-rectal tumor (HCT116), toxicity, thus showing a remarkable photodynamic effect leading
breast (MCF7) and ovarian carcinoma cell lines (A2780 and to apoptosis of the cancer cells.27
25 A2780cisR), whereas human glioblastoma (U-87) and lung
OH
carcinoma (A549) cells were less sensitive. This indication of
NH S
selectivity was seen as a positive feature for future developments. O O O O O O O O O
Cu Cu Cu
A DNA docking study of (η6-p-cymene)RuCl(Curc) revealed the O O O
HN HN HN
same mechanism of action that has been established in Pt
30 chemotherapy.35 The ruthenium η6-arene-PTA-curcumin
Fe Fe Fe
complexes showed not only superior solubility properties due to
the sophisticated ligand design but also superior cytotoxicites
compared to other classes of related compounds. On the cancer cell O O
lines tested (human ovarian carcinoma A2780 cells and the O
=
35 A2780cisR variant with acquired resistance to cisplatin), these new O HO OH
Ru compounds were found to be ca. 100-fold more cytotoxic, with OCH3 OCH3

IC50 values being typically ≤1 μM, while maintaining an excellent Scheme 6 Schematic representation of copper(II) curcumin
selectivity index (i.e., they are considerably less cytotoxic to non- 85 complexes comprising N-ferrocenylmethyl-L-amino acids as
spectator ligands.
tumorous human embryonic kidney cells). It is interesting to note,
40 that in this case the presence or absence of peripheral methoxy Highly promising results have also been obtained with
groups in curcumin and the different arene rings did not strongly heteroleptic zinc curcumin complexes as non-classical anticancer
influence the biological activity. However, the PTA ligand appears agents. In this case, special disubstituted 2,2’-bipyridine ligands
to significantly improve the pharmacological properties of the 90 were employed as spectator ligands to provide good solubility and
curcumin-modified ruthenium(II)−arene complexes. It has been crystallinity. The complexes shown in Scheme 7 were synthesized
45 pointed out that the superior cytotoxicity and selectivity index in by treatment of the chloro precursors with curcumin in the
comparison to clinically used cis-platin clearly warrants further presence of triethylamine. The dinonyl-2,2’-bipyridine derivative
development of these complexes.34 In the case of palladium, could be structurally authenticated through X-ray diffraction,
antitumoral effects of the heteroleptic cationic complex [(bipy- 95 being yet another successful example of the spectator ligand
9)Pd(Curc)][CF3SO3] (bipy-9 = dinonyl-2,2’-bipyridine) have approach (cf. Section 3).28,29
50 been studied in more detail. This compound was synthesized with
the aim to determine a synergism around the palladium metal
center in order to improve the performances of the single
components, namely the bipyridine derivative and the curcumin,
which are both biologically active ligands. In fact, the study
55 revealed a greatly increased biological activity of the palladium
complexes. The combined test data confirmed/validated the
significance of curcumin complexation to a metal center and its
conjugation to another functionalized bioactive ligand in the

8 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 R R
R R R R 45 remarkable photocytotoxicity in HeLa cancer cells giving IC50
ZnCl2 CurcH
N N N N
triethylamine N N values that were comparable to that of the established
Zn Cl photodynamic therapy (PDT) drug Photofrin®. The glycosylated
bipy-9, (R = C9H19) Zn
bipy-OH, (R = CH 2OH) Cl Cl
O O
curcumin complexes showed higher solubility in aqueous media
but had only moderate photocytotoxicity in visible light. These
OH OH
OCH3 OCH3
50 curcumin complexes are essentially non-toxic in the dark but
(bipy-9)Zn(Curc) become highly cytotoxic upon photoactivation. Moreover,
(bipy-CH 2OH)Zn(Curc)

Scheme 7 Synthesis of heteroleptic, pentacoordinated Zn(II)

coordination of curcumin to Ln(III) ions increases the hydrolytic
curcumin complexes. stability and photocytotoxicity of curcumin. Clearly this work
opens up a new area of research on the photochemotherapeutic
5 When tested in vitro towards different human prostate cancer 55 applications of curcumin and its lanthanide complexes. It was
cell lines (DU145, LNCaP and PC- 3), both new Zn(II) curcumin shown that nuclear localization of the complexes in HeLa cells
complexes showed promising and selective anticancer properties. could enable the complexes to bind the chromosomal DNA and
In particular the dinonyl-2,2’-bipyridine Zn(II) curcumin complex damage the nuclear DNA on photoactivation. With a significant
showed the strongest growth inhibition in all cell lines, being even photodynamic therapy effect, the curcumin lanthanide complexes
10 more effective than free curcumin in a neuroblastoma cell line 60 could serve the dual purpose of detecting a tumor while remaining
(LAN-5). Furthermore, the curcumin ligand makes the complexes dormant inside the cells in the dark until subjected to
fluorescent, a feature enabling investigation of their interaction photoactivation causing apoptotic cellular death selectively in the
with DNA through optical methods. The presence of intrinsic photo-exposed cells while leaving the unexposed cells unaffected.
fluorescence in (bipy-9)Zn(Curc) and (bipy-CH2OH)Zn(Curc) In contrast, lanthanide-based MRI agents can be used only for
15 allows the combination of anticancer properties with an excellent 65 tumor detection but not for any tumor damage.43
tool for investigating their mechanism of action through optical 5.2. Anti-Alzheimer’s disease activity
methods in a single molecule, without additional external
agents.28,29 Based on these encouraging results, a series of new Another important area of research involving metal curcumin
Zn(II)-curcumin-based heteroleptic complexes have been complexes is directed toward the imaging/radioimaging and
20 synthesized and fully characterized, with the aim to improve the possible treatment of Alzheimer’s disease (AD). Alzheimer’s
bioactivity of the potential antitumor agent (bipy-9)Zn(Curc). 70 disease is a progressive, degenerative, and devastative disorder
Several structural changes were made starting from the reference which attacks the brain's nerve cells (neurons), resulting in
complex (bipy-9)Zn(Curc), in order to introduce new progressive loss of memory, thinking, language skills, and
functionalities, such as electrostatic and/or covalent interactions. judgment. AD is the most common cause of dementia among
25 Keeping the dinonyl-2,2’-bipyridine ligand, two different Zn(II) people of age 65 or older. It appears well established that the
species were obtained: a tetracoordinated Zn(II) cation with BF4- 75 gradual loss of brain function characteristic for AD is connected to
as counterion and a dimeric neutral complex bridged by a sulfate two main forms of nerve damage. One form is the development of
anion. Moreover, other N,N’-chelating ligands such as so-called neurofibrillary tangles or b-sheet-rich fibrils inside the
phenanthroline (= phen) were employed. The antitumor activity of neurons. These are insoluble twisted fibers formed by aggregation
30 all new Zn(II) complexes was tested in vitro against a human of the tau protein. Outside and around the neurons, so-called b-
80 amyloid plaques, sticky clumps of cellular material and fragments
neuroblastoma cell line (SH-SY5Y). The results showed that all
complexes exhibited strong cytotoxic activity. In particular, the of the amyloid-b-peptide called Ab, can form. The aggregation can
ionic tetrafluoroborate Zn(II) complex [(bipy-9)Zn(Curc)]BF4 and be induced by multiple factors, including the presence of free
the neutral phenanthroline based Zn(II) derivative radicals, oxidative stress, and the presence of excessive metal ions.
35 (phen)Zn(Curc)Cl (Scheme 8) showed the strongest growth Metal ions which are believed to be potential risk co-factors in
inhibition, being even more effective than the model complex 85 neurodegenerative disorders like AD include Al3+, Mn2+, Fe3+,
(bipy-9)Zn(Curc).29 Cu2+ and Zn2+. The involvement of these metal ions in
neurodegenerative disorders has been confirmed by post-mortem
analyses of brain tissues. Apparently, Al3+ has the most harmful
C9H19 C9H19 effect in terms of fibrillation and b-amyloid plaque formation.15
N N 90 During the past 10 years, strong evidence has been accumulated
N N
Zn
Zn Cl that curcumin is an efficient natural drug for treatment of AD either
O O BF 4 O O by scavenging free radicals or by blocking the Ab-aggregation.19
Due to its lipophilic character, curcumin can cross the blood-brain
HO OH
HO OH barrier, destabilize the preformation of b-amyloid fibrils, and
OCH3 OCH3
OCH3 OCH3
(phen)Zn(Curc)Cl 95 eventually bind to plaques and inhibit formation of b-amyloid
[(bipy-9)Zn(Curc)]BF 4
fibrils.17 Being a natural b-diketone derivative, curcumin is also
40 Scheme 8 Schematic representation of the Zn(II)-curcumin-based
well established to strongly chelate the metal ions Al3+, Mn2+. Fe3+,
antitumor agents [(bipy-9)Zn(Curc)]BF4 and (phen)Zn(Curc)Cl.
Cu2+ and Zn2+. Thus a number of recent studies has been directed
Unprecedented photoactivated anticancer activity has also been to the use of metal curcumin complexes as inhibitors of metal-
reported for the lanthanide complexes depicted in Scheme 5. It was 100 induced neurotoxicity with the goal of developing new diagnostic
found that these lanthanide curcumin complexes display tools for AD and eventually new therapeutic agents against this
disease that affects millions of patients worldwide.

This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 9
 One interesting aspect in this area of research is the
development of potential radiotracers for imaging of Alzheimer’s
disease based on metal curcumin complexes. In this respect,
several gallium, technetium, and rhenium complexes of curcumin
5 and some of its derivatives have been investigated. In the case of
gallium, 68Ga- labeled complexes of curcumin as well as Fig. 10 Fluorescence microscopy images (magnification 20×) of
diacetylcurcumin (DACurcH) and bis(dehydroxy)curcumin have almost adjacent closely located sections from Alzheimer’s disease
been synthesized and fully characterized. Gallium-68 was chosen brain stained with (A) complex fac-Re(CO)3(PPh3)(Curc), (B)
because it is a generator-produced radionuclide with suitable 60 complex cis-trans-Re(CO)2(PPh3)2(Curc), and (C) curcumin. The
arrows indicate cross sections of a blood vessel running through
10 energy and half-life (T1/2 = 67.7 min) useful for many applications
the tissue that serve as the anatomical mark for positioning the
in nuclear medicine. The radiotracers were prepared by reaction of plaques on the slice. Reproduced from ref. 39. Copyright 2013
68
Ga3+ obtained from a 68Ge/68Ga generator with 1 mg/mL American Chemical Society.
curcumin ligand solutions. A first evaluation of their affinity to
synthetic β-amyloid fibrils was performed to show the potential 65 Other metal curcumin complexes that have been investigated as
15 application of these new labeled curcuminoids in this diagnostic potential agents to combat Alzheimer’s disease contain the metals
field. The results were encouraging since 68Ga(Curc)+ and Al,15-17 Ga, Cu and Zn.16,19 Several Al(III)-curcumin complexes,
68
Ga(DAC)+ maintained a high affinity for synthetic β-amyloid e.g. [Al(Curc)(EtOH)2](NO3)2, have been synthesized and
fibrils.18 Promising results have also been obtained with characterized by various spectroscopic and analytical methods. It
technetium and rhenium. The synthesis and characterization of 70 was revealed that curcumin strongly interacts with the Al3+ ion.
20 curcumin complexes of the [M(CO)3]+ (M = Re, 99mTc) core and Curcumin is thus capable of scavenging Al3+ and preventing this
imidazole or isocyanocyclohexane as monodentate spectator metal ion from interacting with proteins like Ab, thereby
ligands have been reported. The complexes were synthesized by weakening the Ab toxicity and oxidative stress.16,17 Silk protein
treatment of the [NEt4]2[Re(CO)3Br3] precursor with curcumin to has been used as a model protein to study the influence of curcumin
generate the intermediate aqua complex fac-Re(CO)3- 75 on the Al(III)-induced fibrillation of neurodegenerative proteins.
25 (Curc)(H2O), followed by replacement of the labile coordinated Using the silk fibroin model, it was shown that Al(III)-curcumin
water by the monodentate ligand. The chemistry was successfully complexes could effectively inhibit the b-sheet formation and even
transferred at 99mTc tracer level. Three of these curcumin reverse the conformation of the silk protein, which suggests that
complexes were successfully tested for selective staining of β- Al(III)-curcumin complexes could be used as novel agents to
amyloid plaques of Alzheimer’s disease. The binding affinity for 80 prevent proteins from formation of amyloid fibrils and perhaps
30 β-amyloid plaques was examined following standard staining even removing the preformed amyloid deposits.15 Several
procedures. In a closely related study, both the monophosphine and copper(II) and zinc(II)-curcumin complexes have also been
bis(phosphine) curcumin rhenium complexes fac- investigated in order to gain a better understanding of the possible
Re(CO)3(PPh3)(Curc) and cis-trans-Re(CO)2(PPh3)2(Curc) were role of curcumin in the AD treatment e.g. by scavenging reactive
also found to show selective binding to b-amyloid plaques of 85 oxygen species (ROS), blocking Ab-aggregation and chelating
35 Alzheimer’s disease. Figure 10 shows the results of the in vitro metal ions.15,16
staining of human post-mortem AD fixed brain sections with the 5.3. Antioxidative/neuroprotective activity
complexes fac-Re(CO)3(PPh3)(Curc) (A) and cis-trans-
Closely related to the anti-Alzheimer’s disease activity of metal
Re(CO)2(PPh3)2(Curc) (B) as they appear under the fluorescence
microscope. The results of staining with plain curcumin (C) are curcumin complexes is their activity as innovative and relatively
40 also shown as a positive control. It was found that both complexes 90 non-toxic antioxidants. It is well established that insufficient levels
bind selectively to the plaques, allowing clear visualization of both of antioxidants in the human body cause oxidative stress which
diffused and dense core ones. Even though quantitative means the damage of cell structures and cell functions through
comparison of binding affinities between the curcumin complexes highly reactive oxygen species (ROS), in particular free radicals.
and curcumin is not possible because of differences in fluorescence Typical examples for ROS include the superoxide radical anion
95 (O2-•), the hydroxyl radical (OH•), and the perhydroxyl radical
45 intensity, it is clear that the rhenium complexes fac-
(HO2-•), as well as hydrogen peroxide (H2O2) and nitric oxide
Re(CO)3(PPh3)(Curc) and cis-trans-Re(CO)2(PPh3)2(Curc) stain
(NO). For example, excessive production of the free radical NO in
amyloid plaques in a mode similar to curcumin. These results
the brain has been shown to induce neurotoxicity. Oxidative stress
indicated that rhenium tricarbonyl and dicarbonyl curcumin
seems to play a crucial role in neurodegenerative diseases such as
complexes retain affinity for β-amyloid plaques in the presence of
100 amyotrophic lateral sclerosis (ALS) as well as Parkinson’s,
50 suitable monodentate ligands in their coordination sphere and may
serve as a scaffold for the development of a 99mTc-radiodiagnostic Alzheimer’s and Huntington’s disease. Typical for
for Alzheimer’s disease. The fact that the complexes maintain the neurodegenerative diseases is progressive loss of the structure or
affinity of the mother compound curcumin for β-amyloid plaques function of neurons and eventually even the death of neurons.
prompts for further exploration of their chemistry and biological Thus, antioxidants are considered to be important as
55 properties as radioimaging probes.39 105 neuroprotective agents. In this respect, it is well established that
curcumin can act as a potent antioxidant by effectively scavenging
free radicals. As a logical extension, several metal curcumin
complexes have also been investigated for their antioxidant
capacity. Thus far, antioxidant properties have been reported for

10 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 curcumin complexes of gallium, indium and vanadyl,19,20 as well tetrahedral one during its reaction with superoxide radical. This
as manganese32 and copper.33 Particularly instructive from a 60 allows for the compound to remain intact and undergo many redox
chemist’s point of view is an earlier study describing the synthesis cycles and hence act as a very efficient antioxidant. On the other
and characterization of dual function vanadyl, gallium and indium hand, the homoleptic 1:2 complex Cu(Curc)2 is planar but rigid and
5 curcumin complexes.20 In the course of this study, eight new metal hence cannot undergo the distortions and therefore is a less
curcumin complexes were synthesized, characterized and tested powerful antioxidant. These findings clearly underline the need for
for biological effects such as antioxidant potential, cyctotoxicity, 65 further synthetic studies and the fine-tuning of the biological
and glucose-lowering activity. In addition to the known vanadyl activities of metal curcumin complexes through ligand
complex VO(Curc)2 ("vanadyl curcumin"), the analogous vanadyl variations.33 In a series of related studies, several manganese(II)
10 complexes VO(DMCurc)2, VO(BDMCurc)2, VO(DACurc)2, and curcumin complexes have been evaluated for their neuroprotective
VO(DAB-DMCurc)2 were prepared. The new Group 13 metal activity, including SOD activity and radical scavenging ability.32
derivatives comprised homoleptic Ga(Curc)3 and Ga(DACurc)3 as 70 A central role among the compounds employed in these studies
well as In(Curc)3 and In(DACurc)3. The basic idea behind chosing played the easily accessible manganese(II) complexes
to prepare these pairs of compounds was to test the hypothesis that Mn(Curc)(OAc)(H2O) and Mn(DACurc)2. The results supported
15 free radical scavenging would be at least partially impaired in the an important role of manganese in importing SOD activity and the
acetylated complexes as compared to those containing the parent enhancement of radical scavenging activity. For example, both
curcuminoid ligands. The question was, whether the blocking of 75 Mn(II) complexes showed more effective NO radical scavenging
the phenolic -OH groups by acetylation would affect the than the respective ligands curcumin and diacetylcurcumin.
cytotoxicity and the antioxidant potential of the complexes. In the Therefore it was concluded that Mn(Curc)(OAc)(H2O) and
20 case of antioxidant activity, the answer is Yes, while the Mn(DACurc)2 could have potential advantages as neuroprotective
acetylation did not affect the cyctotoxicity. All complexes were agents in the treatment of acute brain pathologies associated with
also tested for their antioxidant activity using the so-called Trolox 80 NO-induced neurotoxicity and oxidative-stress-induced neuronal
(6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid) equi- damages such as epilepsy, stroke and traumatic brain injury. Both
valent antioxidant capacity (TEAC) assay. This assay is based on manganese complexes also catalyzed the conversion of superoxide
25 ABTS+· (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)- to hydrogen peroxide and oxygen. Questions remained, however,
diammoniuim salt) radical cation decolorization, as measured if their stability is good enough for therapeutic purposes. Thus in
spectrophotometrically.20 Comparison of the antioxidant potential 85 the Mn(II) case, too, further fine-tuning of the biological activities
revealed that the ligand was the predominant determinant for through careful ligand design appears highly desirable.32
antioxidative potential. It was indeed found that the activity of Finally, an innovative recent approach to new curcumin-based
30 VO(DACurc)2 and VO(DABDMCurc)2 was very low as compared antioxidants involves the in situ synthesis and surface
to the other vanadyl complexes. The acetylated gallium and indium functionalization of gold nanoparticles (AuNPs) with curcumin
complexes Ga(DACurc)3 and In(DACurc)3 also exhibited only 90 and their antioxidant properties. The curcumin-functionalized
one-third of the antioxidant activity of the parent curcumin AuNPs were synthesized by direct reduction of HAuCl4 using
complexes Ga(Curc)3 and In(Curc)3. The results clearly confirmed curcumin in the aqueous phase without the need of using any other
35 the initial hypothesis that free aromatic ring reducing agents. It was found that under these conditions curcumin
-OH groups would be important for high antioxidant capacity of acts both as a reducing and capping agent, stabilizing the gold sol
such complexes.20 95 for many months. Moreover, these curcumin-capped AuNPs also
A predominant cellular free radical is the superoxide radical showed good antioxidant activity which was confirmed by the 2,2-
anion (O2-•). It is involved in various degenerative changes, diphenyl-1-picrylhydrazyl radical test. Thus, the surface
40 particularly at low antioxidant concentrations. An important functionalization of AuNPs with curcumin may pave a new way of
naturally occurring antioxidant is the metalloenzyme superoxide using the curcuminoids towards possible drug delivery and
dismutase (SOD), which controls the formation of the superoxide 100 therapeutics. Moreover, the conjugation of curcumin appears to be
radical anion and catalyzes its conversion to hydrogen peroxide, a possibility to increase the bioavailability of curcumin.38
which can then be reduced to water by the enzymes catalase and/or
5.4. Other medicinal applications of metal curcumin complexes
45 peroxidase. In this context, several curcumin complexes of copper
and manganese have been examined for their SOD activity, free A literature survey of the field revealed a surprising variety of other
radical-scavenging ability and antioxidant potential. In the case of promising and innovative medicinal applications of metal
copper(II) complexes, the distorted orthorhombic 1:1 complex 105 curcumin complexes containing very different metals. Chances are
Cu(Curc)(OAc)(OH) (OAc = acetate) and the square-planar that metal curcumin complexes will become “multi-anti” agents
50 homoleptic 1:2 complex Cu(Curc)2 have been investigated. It was like curcumin itself. The following paragraph intends to give a
found that, depending on the coordination geometry, these two brief overview of the diverse potential applications. Each entry is
complexes exhibit different SOD activities, free radical- followed by a list of the metals which have thus far been employed
neutralizing abilities and antioxidant potentials. The 1:1 Cu(II)- 110 as well as a short description of one or two characteristic studies.
curcumin complex Cu(Curc)(OAc)(OH) with the larger distortion
55 from the square-planar structure showed a nearly ten times higher Antiarthritic/Antirheumatic activity (V, Au)
SOD activity than the 1:2 complex Cu(Curc)2. From this study it Antiarthritic/antirheumatic activity has been reported for vanadyl
was concluded that the 1:1 complex would be able to undergo and and gold complexes of curcumin. As mentioned earlier, one of the
sustain the distortion from square planar geometry to the distorted 115 first reported biological studies of metal curcumin complexes ever
included the five-coordinate curcumin-gold(III) complex

This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 11
 [Au(Curc)2]Cl. Its anti-arthritic properties were assessed in an the hydroxyl linkage, retaining the magnetic moment of Co as well
adjuvant-induced rat polyarthritis model. The anatomical changes as the diaryl heptanoid chromophore group of curcumin with the
were compared from the X-ray pictures of the affected limb in the loading percentage of ~89% (Fig. 12a and 12b). These samples
rats. In the result, greatly reduced paw swelling was seen after 3 55 were then subjected to the gram negative bacterium Escherichia
5 weeks of treatment with [Au(Curc)2]Cl (30 mg kg-1 day-1 by coli, and the antimicrobial activity of nano-Co:curcumin was
injection).37 The vanadyl compound is the readily accessible and found to be much enhanced as compared to only Co and only
very versatile “vanadyl curcumin”, VO(Curc)2, which was first curcumin (Fig. 12c). The synthesized system exhibited a
reported already in 2004. Besides having other beneficial effects, combination of the ability of curcumin to penetrate the cell barrier
VO(Curc)2 was found to be more than twice as effective as an 60 and render antimicrobial action along with the chelating capacity
10 antiarthritic agent as curcumin alone.21 of the nano-Co:curcumin complex. Thus it was shown that in the
same way that strong metal–ligand bonds are vital for the
Antimicrobial and antifungal activity (Ca, Sn, Pb, Zr, VO, Cr, efficiency of metal chelators towards toxic metals, these strongly
Mn, Fe, Co, Rh, Ni, Cu, Zn, Cd, Hg, Eu, Sm, Dy, Th, UO2) bound metal complexes may prove to be better antimicrobial
Various metal complexes containing curcumin and curcumin- 65 agents, binding them to the bacterial cell walls.50
15 derived ligands (e.g. curcumin-based diketiminate ligands) have
been studied for their antimicrobial activity. Antimicrobial activity
of numerous complexes against the bacteria Escherichia Coli,
Staphylococcus aureus, Bacillus subtilis, Hay bacillus, Salmonella
typhi, Pseudomonas aeruginosa, and Shigella flexneri has been
20 screened. Frequently, these studies also include an in vitro
screening of the antifungal activity against e.g. Aspergillus niger,
Aspergillus flavus, Aspergillus heteromorphus and Penicillium
verruculosum. In the case of the homoleptic middle and late
transition metal curcumin complexes, only the cobalt complex
25 showed mild antibacterial efficiency toward some of these
bacteria.24 In contrast, excellent antibacterial activity against Hay
bacillus and Echerichia coli was found for the heteroleptic
lanthanide complexes Ln(Curc)3L (Ln = Eu, Sm, Dy; L = 1,10- a, b)
phenanthroline-5,6-dione) (Fig. 11). The study showed that these
30 rare-earth metal complexes should have great potential in the
exploration of new chemotherapy agents.40 A common finding in
all relevant studies was that the studied metal curcumin complexes
exhibited a better activity against bacteria and fungi than the free
ligand. Clearly, however, much more work is needed to establish
35 more general trends and the most effective metal/ligand
combinations.

c)
Fig. 11 Antibacterial diameters of curcumin (1) and the hetero- Fig. 12 Interaction between curcumin and Co nanoparticles (black
leptic lanthanide curcumin complexes Ln(Curc)3L (Ln = Eu, Sm, circular cartoon). Fig. 12a) shows the interaction at the hydroxyl
40 Dy; L = 1,10-phenanthroline-5,6-dione). Reproduced from ref. 40. 70 site of curcumin wherein the diaryl-heptanoid group is shown by
Copyright 2008 Elsevier B. V. dotted circles. Fig. 12b) shows the type of bonding. Fig. 12c)
shows the culture plates for nano-Co:curcumin at t = 0 (a), 3 h (b),
An innovative aspect in this field is the construction of novel 6 h (c), 9 h (d) and finally 12 h (e). A systematic decrease in the
antimicrobial agents from metal nanoparticles and curcumin. In a microbial growth is observed, which almost reaches 0% after 12 h
75 of dosage. Reproduced from ref. 50. Copyright 2011 Elsevier B. V.
recent study it was clearly pointed out that the most important
45 future research in antimicrobial therapy is to develop novel Antiosteoporotic activity (Eu, Gd, Lu)
materials which could work as effective antimicrobials. In this Potential antiosteoporotic activity was recently reported for three
context, using a direct reduction method (reaction of cobalt(II) homoleptic rare-earth metal curcumin complexes.2 As was pointed
chloride with NaBH4 in aqueous solution), 10 nm Co nanoparticles out in this study, it is long known that lanthanide ions have a high
were synthesized and further functionalized with curcumin. The 80 affinity for bone. Moreover, lanthanides have been shown to
50 characterization showed FCC (= face-centered-cubic) structured inhibit the formation of osteoclasts (i.e. the cells responsible for
Co nanoparticles to be electrostatically bound to curcumin using bone resorption) and to have a proliferative effect on osteoblasts

12 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 (i.e. the cells responsible for bone formation). In this context, the 60 complex is potentially useful for early tumor detection.25 In a
homoleptic compounds Ln(Curc)3 (Ln = Eu, Gd, Lu) were similar manner, the photophysical properties of two new rare-earth
prepared in a straightforward manner by treatment of the metal curcumin complexes, La(Curc)3(pyridine)2 and
corresponding hydrated lanthanide nitrates, Ln(NO3)3×6H2O, with Eu(Curc)3(pyridine)2, have been studied both experimentally and
5 3 equiv. of curcumin in methanol. The products were isolated in theoretically. The results suggested that the two Ln complexes
the form of dark red solids in 69-93% yield and characterized by 65 exhibited two-photon absorption in the range 700–860 nm in
1
H NMR (Lu) and mass spectrometry. Subsequently, the toxicity dimethylsulfoxide (DMSO) solution, presenting a significant
of these complexes was investigated in MG-63 cell lines, an enhancement of single-/two-photon excited fluorescence and two-
osteoblast-like cell line derived from a human osteosarcoma, for photon absorbing cross-section values compared with the free
10 potential activity as antiosteoporotic agents. It was found that the ligand. Additionally, two-photon microscopy fluorescent imaging
three lanthanide curcumin complexes have a promising toxicity 70 of MCF-7 cancer cells labeled with these complexes revealed their
toward MG-63 cells similar to cis-platin (cis-diammine- potential application as a biological fluorescent probe. In the
dichloroplatinum(II)), but their use in the treatment of osteoporosis course of this study, MCF-7 cells were labeled with both the
could be limited by their low solubility and by possible Eu(III) complex and propidiumiodide (PI), a commercially
15 dissociation of the curcumin ligands from the Ln(III) ions in vivo.2 available organic dye. Fig. 13 shows the bright green colored
75 Eu(III) complex outside the nuclei and the red-colored dye PI
Antiviral/Anti-HIV activity (B, Cu) inside the nuclei. It is also clearly seen that the green fluorescent
Antiviral screenings have been carried out e.g. with boron and signal of the Eu(III) complex is very stable against photobleaching
copper derivatives of curcumin. A copper curcumin complex was throughout the imaging period of 150 s compared with PI (the red
20 found to be useful for the development of a vaginal gel against viral fluorescence signals of PI disappeared in 90 s).42
infections. Also notable is an early report about the inhibition of
the HIV-1 and HIV-2 proteases by curcumin and several curcumin
boron complexes. It was found that curcumin itself is a modest
inhibitor of the HIV-1 (IC50 = 100 µM) and HIV-2 (IC50 = 250 µM)
25 proteases. This modest activity could be enhanced more than 10-
fold by using rosocyanine (cf. Section 4). Intermediate activities
were found for rubrocurcumine and the complexes formed from 80
curcumin and BF3·Et2O or boric acid + citric acid.14

30 Biological imaging and radioimaging (Ga, Tc, Re, Cu, Ln)

Various biological studies on metal curcumin complexes are
directed toward their use in biological imaging and radioimaging.
A typical example is the homoleptic copper(II) diethylcurcumin
complex Cu(Et2Curc)2(dioxane) (Et2Curc = 1,7-bis(4-ethoxy-3-
35 methoxyphenyl)-1,6-heptadiene-3,5-dione) depicted in Fig. 5. It Fig. 13 Fluorescent imaging of MCF-7 breast cancer cells labeled
was emphasized in this and related studies, that materials with with the Eu(III) complex Eu(Curc)3(pyridine)2 (green) and PI (red) at
large two-photon absorption cross-sections have become different times under continuous light exposure (all the scale bars
increasingly important for bioimaging of living cells and tissues. 85 represent 10 mm). Reproduced from ref. 42. Copyright 2012 The
Royal society of Chemistry.
Compared with single-photon absorbing materials, the molecular
40 excitation by the simultaneous absorption of two photons presents Other promising uses of metal curcumin complexes which have
several advantages that include high confined excitation capacity, been documented in only a handful of recent studies include e.g.
intrinsic three-dimension resolution, and the possibility of imaging drug formulation with ceramic particles (Ba), the treatment of
at an increased penetration depth in tissue, with reduced photo- 90 gastric ulcers (Zn) and iron deficiency (Fe),10 protein
damage and background fluorescence.25,42 In this context, the determination (La) and the development of innovative vaginal gels
45 linear photophysical properties, two-photon absorption, and (Cu). Some of these medicinal applications are in their infant stage,
photostability behavior of the copper complexes Cu(Et2Curc)2- but all of them are definitely worth further exploration.
(dioxane) and Cu(Bu2Curc)2 have been investigated. The
experimental results showed that the complexes exhibit a large 6. Conclusions
two-photon absorption cross-section in the near-infrared region,
50 high quantum yield and photostability and low cytotoxicity. The in 95 In summary, this Tutorial Review provides the first general
vitro study utilized the human breast cancer MCF-7 cell line that overview of the emerging and rapidly expanding field of metal
was imaged by two-photon fluorescence microscopy. The tumor curcumin complexes and their various applications. Innovative
targeting capability of Cu(Et2Curc)2(dioxane) and Cu(Bu2Curc)2 synthetic protocols leading to soluble and crystallizable metal
on tumor-bearing nude mice in vivo demonstrated its high targeting curcumin complexes are highlighted. Although numerous
55 capability to test cancerous cells. The results suggested that these 100 complexes of curcuminoid ligands with various main group, d-
Cu(II) complexes are promising probes for in vivo imaging. In transition and f-elements have been reported, there is still a striking
particular, the unsolvated homoleptic complex Cu(Bu2Curc)2 paucity of structurally authenticated representatives. Here the
showed good photostability and excellent tumor targeting spectator ligand approach is expected to provide valuable new
capability to the tested cancerous cells, which shows that this insights in the future. In recent years, highly exciting and

This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 13
 promising medicinal applications of metal curcumin complexes 60 13 H. J. Roth and B. Miller, Arch. Pharm., 1964, 297, 660-673, and
have been reported. The three most important areas are selective references cited therein.
14 Z. Sui, R. Salto, J. Li, C. Craik and P. R. Ortiz de Montellano, Bioorg.
(photo)cyctotoxity and anticancer activity, anti-Alzheimer's Med. Chem., 1993, 1, 415-422.
disease activity, and antioxidative/neuroprotective effects. 15 T. Jiang, G.-R. Zhou, Y.-H. Zhang, P.-C. Sun, Q.-M. Du and P. Zhou,
5 Curcumin metal complexes could serve the dual purpose of 65 RSC Adv., 2012, 2, 9106-9113.
detecting cancer and causing apoptotic cellular death selectively in 16 T. Jiang, L. Wang, S. Zhang, P.-C. Sun, C.-F. Ding, Y.-Q. Chu and P.
Zhou, J. Mol. Struct., 2014, 1004, 163-173.
the photo-exposed cells leaving the unexposed cells unaffected. In
17 F. Ahmadi, A. A. Alizadeh, N. Shahabadi and M. Rahimi-Nasrabadi,
contrast, the lanthanide-based MRI agents are only useful for Spectrochim. Acta A: Mol. Biomol. Spectr., 2011, 79, 1466-1474.
tumor detection but not for any tumor damage. Metal-curcumin 70 18 E. Ferrari, R. Benassi, S. Sacchi, F. Pignedoli, M. Asti and M. Saladini,
10 complexes already play an important role in the treatment of J. Inorg. Biochem., 2014, 139, 38-48.
Alzheimer’s disease e.g. by scavenging reactive oxygen species 19 M. Asti, E. Ferrari, S. Croci, G. Atti, S. Rubagotti, M. Iori, P. C.
Capponi, A. Zerbini, M. Saladini and A. Versari, Inorg. Chem., 2014,
(ROS), blocking Ab-aggregation and chelating neuro-toxic metal
53, 4922-4933.
ions. Curcumin-metal complexes as well as surface functionalized 75 20 K. Mohammadi, K. H. Thompson, B. O. Patrick, T. Storr, C. Martins,
metal nanoparticles with curcumin may pave a new way of using E. Polishchuk, V. G. Yuen, J. H. McNeill and C. Orvig, J. Inorg.
15 the curcuminoids towards possible drug delivery, therapeutics and Biochem., 2005, 99, 2217-2225.
excellent anti-oxidants. Moreover, antiarthritic/antirheumatic, 21 K. H. Thompson, K. Böhmerle, E. Polishchuk, C. Martins, P. Toleikis,
J. Tse, V. Yuen, J. H. McNeill and C. Orvig, J. Inorg. Biochem., 2004,
antimicrobial/antifungal, antiosteo-porotic and antiviral activities
80 98, 2063-2070, and references cited therein.
have been reported for certain metal curcumin complexes, 22 B. Balaji, B. Balakrishnan, S. Perumalla, A. A. Karande and A. R.
indicating that these compounds have the potential of becoming Chakravarty, Eur. J. Med. Chem., 2014, 85, 458-467, and references
20 “multi-anti” agents in the future like curcumin itself. cited therein.
23 B. Banik, K. Somyajit, G. Nagaraju and A. R. Chakravarty, Dalton
85 Trans., 2014, 43, 13358-13369, and references cited therein.
Acknowledgements 24 M. S. Refat, Spectrochim. Acta Part A: Mol. Biomol. Spectr., 2013,
105, 326-337, and references cited therein.
Financial support of the authors' own work by the Otto-von-
25 Z. Pi, J. Wang, B. Jiang, G. Cheng and S. Zhou, Mater. Sci. Eng. C,
Guericke-Universität Magdeburg is gratefully acknowledged. 2015, 46, 565-571, and references cited therein.
Special thanks are due to Ms. Desirée Schneider and Christoph 90 26 J. Wang, D. Wei, B. Jiang, T. Liu, J. Ni and S. Zhou, Trans. Met.
25 Seidel for preparing the ChemDraw Schemes. We thank Professor Chem., 2014, 39, 553-558, and references cited therein.
Edgar Haak for valuable discussions and for critically reading the 27 T. K. Goswami, S. Gadadhar, B. Gole, A. A. Karande and A. R.
Chakravarty, Eur. J. Med. Chem., 2013, 63, 800-810.
manuscript. 28 D. Pucci, T. Bellini, A Crispini, I. D’Agnano, P. F. Liguori, P. Garcia-
95 Orduña, S. Pirillo, A. Valentini and G. Zanchetta, Med. Chem.
Notes and references Commun., 2012, 3, 462.
29 D. Pucci, A. Crispini, B. Sanz Mendiguchía, S. Pirillo, M. Ghedini, S.
a
Chemisches Institut der Otto-von-Guericke-Universität Morelli and L. De Bartolo, Dalton. Trans., 2013, 42, 9679-9687, and
30 Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany. E- references cited therein.
mail: [email protected].; Fax: +49 391 6712933; Tel: +49 100 30 M. I. Khalil, M. M. Al-Qunaibit, A. M. Al-zahem and J. P. Labis,
Arabian J. Chem., 2014, 7, 1178-1184.
391 6758327 31 F. Kühlwein, K. Polborn and W. Beck, Z. Anorg. Allg. Chem., 1997,
b
Department of Chemistry, Shah Jalal University of Science and 623, 1211-1219.
Technology, Sylhet, Bangladesh 32 Y. Sumanont, Y. Murakami, M. Tohda, O. Vajragupta, H. Watanabe
35 105 and K. Matsumoto, Biol. Pharm. Bull., 2007, 30, 1732-1739, and
1 B. B. Aggarwal, C. Sundaram, N. Malani and H. Ichikawa, Curcumin: references cited therein.
The Indian Solid Gold, Springer, New York 2001. 33 A. Barik, B. Mishra, A. Kunwar, R. M. Kadam, L. Shen, S. Dutta, S.
2 Y. Mawani and C. Orvig, J. Inorg. Biochem., 2014, 132, 52-58. Padhye, A. K. Satpati, H.-Y. Zhang and K. I. Priyadarsini, Eur. J. Med.
3 G. P. Lim, T. Chu, F. Yang, W. Beech, S. A. Frautschy and G. M. Cole, Chem., 2007, 42, 431-439, and references cited therein.
40 J. Neurosci., 2001, 21, 8370-8377. 110 34 R. Pettinari, F. Marchetti, F. Condello, C.Pettinari, G. Lupidi, R.
4 R. Waranyoupalin, S. Wongnawa, M. Wongnawa, C. Pakawatchai, P. Scopelliti, S. Mukhopadhyay, T. Riedel and P. J. Dyson,
Panichayupakaranant and P. Sherdshoopongse, Cent. Eur. J. Chem., Organometallics, 2014, 33, 3709-3715, and references cited therein.
2009, 7, 388-394. 35 F. Caruso, M. Rossi, A. Benson, C. Opazo, D. Freedman, E. Monti, M.
5 A. Goel, A. B. Kunnumakkara and B. B. Aggarwal, Biochem. B. Gariboldi, J. Shaulky, F. Marchetti, R. Pettinari and C. Pettinari, J.
45 Pharmacol., 2009, 75, 787-809. 115 Med. Chem., 2012, 55, 1072-1081.
6 M. M. Yallapu, M. Jaggi and S. C. Chauhan, Drug Discovery Today, 36 A. Valentini, F. Conforti, A. Crispini, A. De Martino, R. Condello, C.
2012, 17, 71-80, and references cited therein. Stellitano, G. Rotilio, M. Ghedini, G. Federici, S. Bernardini and D.
7 P. Anand, A. B. Kunnumakkara and B. B. Aggarwal, Mol. Pharm., Pucci, J. Med. Chem., 2009, 52, 484-491.
2007, 4, 807-818. 37 K. K. Sharma, S. Chandra and D. K. Basu, Inorg. Chim. Acta, 1987,
50 8 J. Miłobędzka, S. von Kostanecki and V. Lampe, Ber. Dtsch. Chem. 120 135, 47-48.
Ges., 1910, 43, 2163-2170. 38 D. K. Singh, R. Jagannathan, P. Khandelwal, P. M. Abraham and P.
9 M. K. Mishra, P. Sanphui, U. Ramamurty and G. R. Desiraju, Crystal Poddar, Nanoscale, 2013, 5, 1882-1893.
Growth Des., 2014, 14, 3054-3061, and references cited therein. 39 C. Triantis, T. Tsokatos, C. Tsoukalas, M. Sagnou, C. Raptopoulou, A.
10 E. Ferrari, B. Arezzini, M. Ferrali, S. Lazzari, F. Pignedoli, F. Terzis, V. Psycharis, M. Pelecanou, I. Pirmettis and M. Papadopoulos,
55 Spagnolo and M. Saladini, Biometals 2009, 22, 701-710. 125 Inorg. Chem., 2013, 52, 12995-13003.
11 J. Annarjai, S. Srinivasan, K. M. Ponvel and P. R. Athappan, J. Inorg. 40 Y.-M. Song, J.-P. Xu, L. Ding, Q. Hou, J.-W. Liu and Z.-L. Zhu, J.
Biochem., 2005, 99, 669-676, and references cited therein. Inorg. Biochem., 2009, 103, 396-400.
12 J. Rajesh, A. Gubendran, G. Rajagopal and P. Athappan, J. Mol. 41 M. A. Subhan, K. Alam, M. S. Rahaman, M. A. Rahman and M. R.
Struct., 2012, 1010, 169-178. Awal, J. Sci. Res., 2014, 6, 97-109.

14 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]
 42 S.-S. Zhou, X. Xue, J.-F. Wang, Y. Dong, B. Jiang, D. Wei, M.-L. Wan
and Y. Jia, J. Mater. Chem., 2012, 22, 22774-22780.
43 A. Hussain, K. Somyajit, B. Banik, S. Banerjee, G. Nagaju and A. R.
Chakravarty, Dalton Trans., 2013, 42, 182-195.
5 44 J. Atnarez, A. Bonilla and J. C. Vidal, Analyst, 1983, 108, 368-373.
45 I. Ikeuchi and T. Amano, Chem. Pharm. Bull., 1978, 26, 2619-2623.
46 K. Lawrence, S. E. Flower, G. Kociok-Köhn, C. G. Frost and T. D.
James, Anal. Methods, 2014, 4, 2215-2217.
47 A. Ciszewski, G. Milczarek, B. Lewandowska and K. Krutowski,
10 Electroanalysis, 2003, 15, 518-523, and references cited therein.
48 M. Y. Elahi, M. F. Mousavi and S. Ghasemi, Electrochim. Acta, 2008,
54, 490-498.
49 R. Ojani, J.-B. Raoof and S. Zamani, Bioelectrochem., 2012, 85, 44-
49, and references cited therein.
15 50 S. Hatamie, M. Nouri, S. K. Karandir, A. Kulkarni, S. D. Dhole, D. M.
Phase and S. N. Kale, Mater. Sci. Eng. C, 2012, 32, 92-97.

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 50

Simon Wanninger was born in Volker Lorenz was born in

Füssen, Germany in 1988. He Remda, Germany, in 1963. He
5 obtained his BSc in obtained his diploma degree
environmental- and energy from the TH Merseburg and
process engineering in 2015. 55 his PhD from the University of

His Bachelor thesis on the Halle-Wittenberg in 1994

curcumin-complexes was his (with Karl-Heinz Thiele). This
10 first work in the laboratory. was followed by postdoctoral
Now he likes to travel and then work with John J. Eisch at
start with his master degree. 60 Binghampton University
Volker Lorenz
Simon Wanninger (USA) in 1994/95 (titano-
15 cene and zirconcene
compounds). He is currently Senior Researcher in the Edelmann
65 group. His research interests include silsesquioxane and metalla-
silsesquioxane chemistry as well as alkaline earth metal and
lanthanide compounds for catalytic applications and materials
20 science.

70

Abdus Subhan received his Frank T. Edelmann was born

25 PhD from Osaka University, in Hamburg, Germany, in
Japan in March 2003. In 2004 1954. He studied chemistry at
he had been a Venture Business 75 the University of Hamburg,

Laboratory (VBL) postdoctoral where he obtained his diploma

fellow at Materials and Life degree in 1979 and PhD in
30 science, Faculty of 1983 under the guidance of
Engineering, Osaka University Prof. Ulrich Behrens. After 2
for a year. Then he joined Shah 80 years of postdoctoral research

Jalal University of Science and with Josef Takats (University

Technology, of
35 Abdus Subhan Sylhet, Bangladesh as faculty. Frank T. Edelmann Alberta), John W. Gilje
In 2010 he visited Osaka (University of Hawaii) and
Kyoiku University, Japan as visiting researcher to study the PL 85 Tristram Chivers (University of Calgary) he finished his
properties of mixed metal nano composite oxides. He had been habilitation at the University of Göttingen in 1991 in the group
National Research Foundation (NRF) postdoctoral fellow at of Herbert W. Roesky. In 1995 he was appointed Full Professor
40 Andong National University, South Korea for a year (2010-11), of Inorganic Chemistry at the Otto-von-Guericke-University in
where he studied novel macrocyclic metal complexes. He had been Magdeburg. His main research interests are in organolanthanide
BK21 postdoctoral fellow at Seoul National University, South 90 and -actinide chemistry, silicon chemistry (silsesquioxanes and
Korea for six months (2012-13). At present he is a Professor of metallasilsesquioxanes), and fluorine chemistry. His work is
Chemistry at Shah Jalal University of Science and Technology, documentated in over 350 scientific papers, 2 books and several
45 Sylhet, Bangladesh. His major research field includes novel metal patents. In 2008 he was awarded the "Terrae Rarae 2008 Award"
complexes of materials and biological importance as well as for his "eminent work in coordination chemistry of the rare earth
structure and spectroscopy of multi-metal nanocomposite oxides. 95 elements"

16 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]

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