Metabolitos Secundarios

METABOLISM
150 PHYTOCHEMISTRY
AROMATIC ACIDS
CO2
Photo-
Glycoside formation,
Starch synthesis
pentosans,
Glucose Erythrose
ascorbic acid
Fructose
Glycerates Amino acids
Isoprenoid compounds
18 (monoterpenes,
sesquiterpenes, IPP DOX
diterpenes, steroids, Amino acids
carotenoids, rubber) Proteins
Alkaloids
MVA Aromatic Isothiocyanates
compounds Cyanogenetic
Fatty acid Pyruvate Aromatic compounds
Fats amino acids Various
spiral
Phenylpropane heterocyclic
derivatives nitrogen
Malonyl-CoA Acetyl-CoA compounds
Malonyl CoA Lignin
Polyketides
Anthraquinones
Aromatic compounds of
mixed origin (e.g. flavonoids)
TCA
Amino acids
cycle
Porphyrins (chlorophyll)
Cytochrome systems
giving ATP
Chorismic acid Some naphthoquinones and anthraquinones
OH OH OH OH OH
METABOLISM OH
Some benzoquinones Dehydroshikimic acid
Phenylpyruvic acid
COOH
Prephenic acid HO OH
HOHO
p-Hydroxyphenylpyruvic acid Hydrolysable
OH CH CH COOH
Dehydroshikimic acid Hydrolysable
AROMATIC ACIDS
and naphthoquinones tannins
HO OH HO
Caffeic acid
tannins
Phenyllactic acid Shikimic acid p-Hydroxyphenyllactic
COOH acid
Catechol Phloroglucinol Salicylic acidShikimic acid
Gallic acid COOH
Gallic acid
acidChorismic Some (unsaturated
acid cinnamic acid naphthoquinonesside-chain)
and anthraquinones
Two common aromatic acids are benzoic
trans-Cinnamic acid and Condensed tannins oftenCH
HO CHfree
occur COOH
CH2 Chorismic acid Some naphthoquinones and anthraquino
and combined
Coumarinsin considerable amounts in drugs such as balsams
CH Prephenic acid 178 PHARMACOPOEIAL AND RELATEDMeO DRUGS OF BIOLOGICAL ORIGIN
C6 C3 unit of flavonoids
CH OH Ferulic acid
Some benzoquinones Phenylpyruvic2 acidHO CH CH p-Hydroxyphenylpyruvic
COOH acid Xanthones acid
OH Prephenic
Common
and occurrence are those having phenolic or other groupings inSome
naphthoquinones addition to a carboxyl
COOH group;
COOHsuch are: Of
benzoquinones
Some benzoquinones Phenylpyruvic acid acid
p-Coumaric p-Hydroxyphenylpyruvic acid plant
salicyclic acid (o-hydroxybenzoic acid), protocatechuic acid (3,4-dihydroxybenzoic
and naphthoquinones acid), veratric acid
COOH
compo
and Phenyllactic acid
naphthoquinones (p-Hydroxycinnamic acid) p-Hydroxyphenyllactic acid
Thymol
(3,4-dimethoxybenzoic acid), gallic acid (3,4,5-trihydroxybenzoic acid) and 3,4,5-trimethoxybenzoic Chapte
OMe OMe
5-Hydroxyferulic acid
OH
acid. trans-Cinnamic Phenyllactic acid
acid
p-Hydroxyphenyllactic acid
OH OH Condensed
OH tannins OMe
HO OH CH CH COOH HO CH CH CH2 OH Lignin of MonocotyledonsVeratric
Protocatechuic ALC
19
Coumarins Benzoic
CHO Eugenol Hydroquinone acid acid
acid
trans-Cinnamic
Derived from cinnamic acid, one acid alcohol
finds p-coumaric
p-Coumaryl acid (p-hydroxycinnamic acid), ferulic acid
C C unit of flavonoids
6 3 Condensed tannins Alcoho
HO MeO
Caffeic acid HO CH CH COOH Xanthones either
(hydroxymethoxycinnamic
Coumarins
acid), caffeic acid (hydroxycinnamic acid) and
COOH 3,4,5-trimethoxycinnamic acid.
Some benzoquinones ally ha
CH CH COOH
0 Salicylaldehyde p-Coumaric acid and naphthoquinones HO C 6 C3 unit of
CH flavonoids
CH COOH manni
HO CH CH COOH HO CH acid)
(p-Hydroxycinnamic CH CH2 OH Lignin of Gymnosperms groups
HO CH CH HO COOH OH Xanthones trihydr
Fig. 21.1 Lignans
Simple phenolic compounds. OH MeO
(e.g. Podophyllotoxin, Some benzoquinones group
MeO MeO Sinapic acid –CHO
p-Coumaric acid pinoresinol)
Ferulic acid Coniferyl alcohol Gallic acid and naphthoquinones
Cinnamic acid
remain
a
CH CH COOH
m
g
METABOLISM
HO OH t
OH g
–
Gallic acid Cinnamic acid
AROMATIC ACIDS r
o
CH CH COOH CH CH COOH t
Chlorogenic or caffeotannic acid is a condensation product of
M
caffeic acid and quinic acid. It occurs in maté, coffee, elder L
OMe
flowers, lime flowers, hops and nux vomica and is converted OH OH
e
r
into a green compound, which serves for its detection, when an p-Coumaric acid Ferulic acid c
178 PHARMACOPOEIAL AND RELATED DRUGS OF BIOLOGICAL ORIGIN
aqueous extract is treated with ammonia and exposed to air. i
c
CH CH COOH HO COOH COOH
COOH COOH Of interest are opines, a group of substances formed by a host o
plant after infection with Agrobacterium spp.; a number of these C
COOH
compounds are di- and tri-carboxylic acids. For further
H details seeH H H
Chapters 13 and 14. OH M
HO OH HO OH
OH OMe H OH T
OH H OH
OH OMe w
Quinic acid
Protocatechuic Veratric ALCOHOLS Caffeic acid Shikimic acid t
19
Benzoic
acid acid acid d
Alcohols possess one or more hydroxyl groups HO and exist
COOH naturally in a
OH o
COOH either the free state or combined as esters. Like phenols they gener-
ally have common names ending in ‘ol’ (e.g. ethanol, glycerol and b
CH CH COOH r
mannitol). They can be classed according to the number ofO hydroxyl
C OH
groups present: monohydric alcohols-oneHOhydroxyl, dihydric-two,O
p
HO OH trihydric-three and polyhydric-four or more. Furthermore
OH each hydroxyl i
OH group may be classed as primary: –CH2OH (e.g. ethanol), secondary: a
Chlorogenic
–CHOH– (e.g. isopropanol) or tertiary: COH (e.g. t-butanol). Theacid s
Gallic acid Cinnamic acid
remainder of the molecule may be saturated or unsaturated, aliphatic i
O
METABOLISM
AROMATIC ACIDS
METABOLISM
AROMATIC ACIDS
METABOLISM
ALCOHOLS
Monohydric aliphatic alcohols
Principally combined as esters e.g. methyl salicylate in oil of wintergreen and methyl and ethyl esters
responsible for some fruit aromas.
Esterified long-chain alcohols are constituents of some pharmaceutically important animal waxes and
include cetyl alcohol (C16H33OH), ceryl alcohol (C26H53OH) and myricyl alcohol (C30H61OH).
Carnauba Wax BP which contains myricyl cerotate.

Geraniol Citral Limonene
Nerol Camphor
Citronellol Linalool
OH
VOLATILE OILS AN
22
CH2OH CHOMonoterpenes OH O
METABOLISM CH2OH CHO OH

CH2OH CHO OH OH
OH OH
OH OH
CH2OH CHO
OH OH OH
ALCOHOLS OH
Menthol
OH
Menthone
Citronellal -Myrcene Limonene -Phellandrene
OH OH -Terpineol
n
Monohydric terpene alcohols Geraniol Citral Nerol 2 Linalool
Citronellol Linaloo
22
Geraniol CitronellalGeraniol
Citral -Myrcene Nerol Citral Limonene Nerol
Citronellol -Phellandrene
Linalool Citronellol
-Terpineol Menthol
Rubber Geraniol Citral
O -Carotene
Nerol Citronellol Linalool
HOHC O Carotenoids
Isoprene as a OH
fundamental structural unit 3
OH O OH
OH OH O C CH
OH O
OH O H2C CH2 O
OH OH
Constituents of volatile oils OH
Isoprene
Menthol Menthone Citronellal
Citronellal Carvone -Myrcene
-Myrcene -Pinene
Limonene
Limonene Camphor -Phellandrene
-Phellandrene Borneol Cineole
-Terpineol -Terpin
Citronellal Menthol -Myrcene Menthone
Limonene Carvone-Phellandrene -Pinene-Terpineol Borneol
Triterpenes
-Myrcene -Phellandrene Camphor
-Terpineol
Non-cyclic: geraniolCitronellal Limonene
in otto of rose, its isomer nerol in oils of orange and bergamot
O
and linalol both free
COOH O
and combined as linalyl acetate in oils of lavender
O and rosemary
O
OH O O O OH
O OH O OH
OH O O OH
Monocyclic : terpineol
O and its acetate
O
in oil of neroli and menthol and its acetate in oil of peppermint OH
OH MentholO MenthoneOH Carvone -Pinene Borneol
O Menthol Menthone Carvone -Pinene Borne
Menthol CamphorMenthone Carvone
Cineole Thymol -Pinene SabineneBorneol Thujone
Dicyclic: abundant in the Coniferae (e.g. sabinol and its acetate in Juniperus sabina). In the dicotyledons
Squalene CH
O
oil of rosemary contains
Camphor HOborneol and
Menthol its
Cineole esters.
Menthone Thymol
Carvone -Pinene
Sabinene Thujone
Borneol
O
CH
O
OCH3 OH O OH
CHO
METABOLISM
ALCOHOLS
178 PHARMACOPOEIAL AND RELATED DRUGS OF BIOLOGICA
Monohydric aromatic alcohols
COOH COOH
COOH
Benzyl alcohol, C6H5CH2OH, and cinnamyl alcohol, C6H5CH=CHCH2OH, occur both free and as
esters of benzoic and cinnamic acids in balsams such as Tolu and Peru. OH OMe
178 OH
PHARMACOPOEIAL ANDOMe
RELATED DRU
Protocatechuic Veratric
19
Benzoic
Coniferyl alcohol, which forms an important component of the lignin
acid
molecule. acid acid
COOH
COOH COOH
CH CH COOH
OH
HO OH OH
Protocatechuic
19Gallic acid
OH Benzoic
acid acid
Cinnamic acid
H. Hatakeyama and T. Hatakeyama
Lignin Structure, Properties, and Applications
Scheme 2 Examples of chemical structures of acidolysis lignin

Scheme 2 Examples of chemical structures of acidolysis lignin
Scheme 3 Examples of chemical structures of hydrogenolysis of lignin
follows: 4-n-propylguaiacol (28), dihydroconiferyl alcohol (29), 4-n-propylsyringol

(30), dihydrosinapyl alcohol (31), 4-methylguaiacol (32), 4-methylsyringol (33),
4-ethylguaiacol (34) and 4-ethylsyringol (35) (see Scheme 3).
TABLE 1 | Chemical composition of the 40–60 mesh from cork, phloem approxim
and xylem of Quercus suber L. Mean values of two samples. SM 240
(% oven dry material) Cork Phloem Xylem
triple st
sections
Ash 0.7 3.1 1.5 microsco
Total extractives 10.4 6.2 8.4 taken wi
Dichloromethane 4.1 0.1 0.6
Ethanol 2.9 1.9 2.8 Lignin
Water 3.4 4.2 5.0 Milled l
Total lignin 27.1 38.4 23.6 accordin
Klason lignin 26.2 36.0 20.6 granulat
Soluble lignin 0.9 2.4 3.0 agate bal
Suberin 30.1 – – ball mill
MONOSACCHARIDES 5 min o
Arabinose 2.0 0.9 0.6 dioxane-
Xylose 6.4 15.5 13.7 under ag
Mannose 0.4 0.1 0.6 supernat
Galactose 1.1 0.8 1.1 The resid
Glucose 9.0 16.5 28.7
a solutio
g−1 of r
water (2
dried an
described in Pereira (2013), and the lignin was determined using
in a 1,2-
the suberin-free material (according to TAPPI T222 om-11).
of solven
matter, t
Anatomical Observation the solut
A sample of each tissue was impregnated with DP1500 was sepa
polyethylene glycol, and transverse microscopic sections of in dieth
Frontiers in Plant Science | www.frontiersin.org 3
FIGURE 5 | Main structures present in the lignins from Q. suber cork, phloem and xylem: A, β-O-4′ alkyl-aryl ethers; Aox , α-oxidized β–O–4′ aryl ethers;
A′ , β-O-4′ alkyl-aryl ethers with acylated γ-OH; B, phenylcoumarans; C, resinols; D, dibenzodioxocins; E, open β–1′ structures; F spirodienones; I,
cinnamyl alcohol end-groups ; I′ , γ-acylated cinnamyl alcohol end-groups; J, cinnamaldehyde end-groups; FA, ferulate moieties; H, p-hydroxyphenyl
units; G, guaiacyl units; S, syringyl units; S′ , oxidized syringyl units unit bearing a carbonyl group at Cα.
Fig. 1 Total utilization of bio-resources from wood
Lignin is an important polymeric substance, (C6–C3)n, laid down in a matrix of cellulose microfibrils to
strengthen certain cell walls. It is an essential component of most woody tissues and involves vessels,
tracheids, fibres and sclereids.
Lignans are dimeric compounds formed essentially by the union of two molecules of a phenylpropene
derivative.
METABOLISM
DRUGS CONTAINING ACIDS, ALCOHOLS AND ESTERS
ROSELLE - Hibiscus sabdariffa - Flor de Jamaica
Free acids including citric, tartaric and malic acids and the lactone of hydroxycitric acid
Phenolic compounds include anthocyanins involving

the glycosides of delphinidin and cyanidin
METABOLISM
ROSELLE - Hibiscus sabdariffa - Flor de Jamaica
Free acids including citric, tartaric and malic acids and the lactone of hydroxycitric acid
Phenolic compounds include anthocyanins involving

the glycosides of delphinidin and cyanidin
METABOLISM
Tamarind pulp - Tamarindus indica
The pulp contains free organic acids (about 10% of tartaric, citric and malic), their salts (about 8% of
potassium hydrogen tartrate), a little nicotinic acid and about 30–40% of invert sugar.
COOH
COOH
plant a
COOH
CH CH COOH compou
METABOLISM
Chapte
OH OMe
HO OH
OH OMe
OH
DRUGS CONTAINING ACIDS, ALCOHOLS AND ESTERS Protocatechuic Veratric ALC
19
Benzoic
Gallic acid
acid Cinnamic acid
acid
acid
Alcoho
COOH CH CH COOH CH CH COOH either t
ally ha
ARTICHOKE LEAF - Cynara scolymus - Alcachofa CH CH COOH
mannito
groups
HO OH OMe trihydri
OH OH OH group m
Phenolic acids are important constituents and include chlorogenic acid,Gallic
caffeic acid and cynarin
acid p-Coumaric acid
(1,
Cinnamic acid
5-di-
Ferulic acid
–CHOH
remaind
O-caffeoylquinic acid) or arom
CHCH CHCH COOH COOH HOCH COOH
CH COOH COOH
text.
Flavonoids include luteolin-7-B-D-glucoside and the 7-B-D-rutinoside. H H

Mono
H H
Lower
OH OMe
HO OH HO OHme
e.g.
OHOH HOHOH H OH
respons
p-Coumaric acid
Caffeic acid Ferulic
Quinic acidacid constitu
Shikimic acid
include
cyl alco
CH CH COOH HO COOH COOH
OH of ester
Carnau
H H C
O H OH
H
OH HO
HO OH O Mono
HO OH
OH H OH
OH H OH These
which
Caffeic acid Quinic acid Shikimic acid
Chlorogenic acid tal stru
METABOLISM
ARTICHOKE LEAF - Cynara scolymus - Alcachofa
Phenolic acids are important constituents and include chlorogenic acid, caffeic acid and cynarin (1, 5-di-
O-caffeoylquinic acid)
Flavonoids include luteolin-7-B-D-glucoside and
the 7-B-D-rutinoside.
hole or cut and carefully dried. It is required to contain not less
D. Ferreira et al than brown when
(eds) Phytochemistry 2005, 66, 1969–2120,
ripe and transversely
(Pt 1); 2124– COOH
rugose.gamottin
Seeds are wrinkled givingcytochrome P450 enzym
2291 (Pt 11) COOH and FC26) inactivate plant a
2% of volatile
8 oil. The
2 North AmericanOroot is derived from A. atro-
O the ‘ribbed’ of
O
the common name.
COOH CYP3A4 and CYP3A5) resulting in an increased ora
O 2 1 C6 H5Features of the powdered CH CH COOH compou
urpurea and the Chinese from a number of species under the name C H drug include numerous anisocytic stomata
METABOLISM
2
7 1 6 5 C6ofH5various drugs used to treat cancer, hypertension, h
3 Chapte
COUMARINS ANDwith GLYCOSIDES
3
an-mu6 or tangkuei.
4 3 6
OH between three H and six subsiduary cellsallergies.on bothHowever,
epidermi;unnamed
OH uniseri-constituents
OMe of the juic
H HO OH
The rhizomes
5 are vertical and up to 5 cm O in diameter, greyish-brown ate covering trichomes composed of two small
been basal
OHshown cells and a longer,
to activate the
OMe efflux pump controlling
O O coumarin (the lactone OH
reddish-brown in colour, bearing leaf and stem scars at the apex. -pyrone
O Derivatives of benzo- such as
bent, somewhat warty terminal cell; few mediated
O aof glandular drug transportwith
trichomes whicha secretes absorbed drug
DRUGS CONTAINING ACIDS, ALCOHOLS AND ESTERS Protocatechuic Veratric ALC
19
Benzoic gut. of
Flavone
ntwined, longitudinally furrowed, roots occur onO-hydroxycinnamic
Isoflavone the lower surface. acid),
Flavonol aesculetin,
two- umbelliferone
Flavanone
to three-celled stalk and scopoletin
andacid Gallic
Chalconehead
biseriate four studies
Inacid
vitro
acid cells; have demonstrated
prismatic Cinnamic acid
acid reduced absorp
(2-phenyl- -chromone) (3-phenyl- -chromone)
he fracture is uneven and the transverse surface shows brown spots, crystals of calcium oxalate associated with the vascular tissue; papil-
are phenolic but they are included here with the phenolic derivatives CH are therefore
CH COOH
21
are common in plants both in the free state and as glycosides. Not all tine, cyclosporin, losartan, digoxin and fexofenadine.
antagonistic and CH explain
CH
Alcoho
the unpredic
COOH either t
dicating secretory cells, situated in the spongy,forradiate, off-white lose epidermal cells of the petals; lignified COOH fibrous anther fragments;
convenience.
OHother features, numer-
Some 1000 natural
OMe
coumarins have been isolated. grapefruit juice on drug bioavailability. For reports
ally on
hat
ark. Microscopy of the powder shows, among spherical–ovoid pollen grains about 25 m The across with1999,
three pores and
NETTLE
us simple starch RO LEAF - Urtica
grains 2–4 Om, yellowish-brown dioica
Coumarin- Ortiga
itself has been found in about
a smooth exine.
150 species belonging to over Lancet, 353,
CH 1335;
CH Pharm. J., 1999, 262,
COOH 57
mannito
30 secretory
different
RO
canals,
families,O although it is probably present in the undamaged 1998, No. 43, 22. groups
ork cells and lignified reticulately thickened vessels. OH
HO OH OMe trihydri
Considerable recent work on the genus has resulted in the isolation Constituents. Coumarin derivatives OH
occur OHin melilot although cou- OH group m
a number The constituents and
of furanocoumarins of nettle have been
their glycosides; extensively
the formulae of marin researched.
itself is not They
present include
to anyGallic aacid
extentnumber
inp-Coumaric ofacidacids
the living plant. Itsuch
arises
Cinnamic
as
acid
Ferulic acid
–CHOH
OH O Table 21.2 OH Hydroxy
O and methoxy coumarins.
ergapten, chlorogenic,
angelicin, archangelicin (a diester) and apterin are given in when the plant is crushed, or the dried material treated with water, by remaind
caffeoylmalic, caffeic, malic and fumaric. Flavonoids include quercetin and its glycosides or arom
g. 21.8, and those ofNaringenin;
marmesin R and
= H psoralen in Fig.Compound
13.2. These com-
Hesperetin; the action
R = H Additional of a -gluconidase enzyme
groupings CHCH CH specific
Occurrence
COOH to cis-o-hydroxycin-
isoquercitrin and rutin CH COOH HOCH COOHCH COOH COOHtext.
ounds are reported to have potent coronary vasodilator effects and are namic acid glucoside giving first the unstable hydrolytic product
Naringin; R = rhamno-glucosyl Hesperidin; R = rhamno-glucosyl
(Flavanones) (Flavanones)
lcium antagonists. Monoterpenes constitute the major components HO
Umbelliferone at 7 (above) acid, which then cyclizesBelladonna
coumarinic to coumarin and stramonium
producing (Solanaceae):
the Daphne mezereu
(Thymeliaceae); Ferula species yielding asafoetidaMono and ga
0–90%) of the volatile oil. well-known ‘new-mown hay’ odour. The trans-isomer H remainsH H (Compositae) H
OH OH many
OH (see
other
OMe Umbelliferae, chicory
OMe leaves Lower
There are official limits for foreign matter, loss onHerniarin drying ( 10%), CHunchanged 3O at 7
and is isolated as melilotoside
Lavandula spicaF. Bourgoud
HO
(Labiatae), etOH
Rutaal.,
graveolens
HO (Umbelliferae)
OHmea
e.g.
OH HOHOH H OH
tal ash ( 10%) and HO acid-insoluble
O ash ( 2.0%). HO O Phytochem. Anal., 1994,
MeO
5 , 127; P.O
OH
Bradley British
Compositae Herbal Compendium, respons
OH Aesculetin OHat 7
HO at 6, HO OMe (Hippocastanaceae), certain Rosaceae and F
Horse-chestnut
p-Coumaric acid
Caffeic acid Ferulic
Quinic acidacid constitu
Shikimic acid
(Oleaceae) include
OR Scopoletin CH3O at 6, HO at 7 MeO Roots of gelsemium, oat, jalap, scammony, scopolia cyl
andalco
be
CH CH COOHleaves ofHO tobacco, COOH
COOHstramonium, chicory and many of
others
OH O OH O OMeOCH O3 OH ester
Fraxin CH3O at 6, HO at 7, O-glucose at 8 Fraxinus spp. (Oleaceae) Carnau
Quercetin; R = H Chicoriin Luteolin
CH Sinensetin
4 3O at 6, O-glucose at 7
5 (Flavone) Cichorium intybus herb
6 3 (Flavone)
Hyperoside; R = galactosyl H H C
O H OH
H
7
CO 8 CO OH CO HO HO OH O Mono
Isoquercitrin; R = glucosyl HO OH
O O O OH O H OHOH H OH These
Rutin; R = rhamno-glucosyl
which
(Flavonols) -Pyrone Coumarin Bergapten
Caffeic acid Quinic acid Shikimic acid
Chlorogenic acid tal stru
(a furanocoumarin)
O
METABOLISM
OH O
OH

Menthol Menthone Carvone -Pinene Borneol
TOLU BALSAM - Myroxylon balsamum - Ortiga

O
Tolu
O Balsam is obtained by incision from the trunk
OH
Tolu contains Oabout 80% of resin derived from resin
Camphor
alcohols combined
Cineole
with cinnamic
Thymol
and benzoic acids.
Sabinene Thujone
The drug is rich in free aromatic acids and contains
about 12–15% of free cinnamic OCH3 OH
and about 8% of free benzoic acid OCH3
CH CH CH2
CH CH CH
CHO CH3 CH2
Cinnamaldehyde Anethole Eugenol

METABOLISM
PHENOLS AND PHENOLIC GLYCOSIDES
The largest group of plant secondary metabolites
From simple structures with one aromatic ring to highly complex polymeric substances such as tannins
and lignins.
Important constituents of some medicinal plants and in the food industry they are utilized as colouring
agents, flavourings, aromatizers and antioxidants.
(1) simple phenolic compounds, (2) tannins, (3) coumarins and their glycosides, (4)
anthraquinones and their glycosides, (5) naphthoquinones, (6) flavone and related
flavonoid glycosides, (7) anthocyanidins and anthocyanins, (8) lignans and lignin.
METABOLISM
hypericum (q.v.) are phloroglucinol derivatives.
METABOLISM OH
OH
OH OH
COOH
HO OH
(1) simple phenolic compounds
Catechol Phloroglucinol Salicylic acid
Phenolic compounds in this group often also possess

CH2
alcoholic, aldehydic and carboxylic acid groups
CH
CH2 OH
OH
Glycoside formation is common, and the widely

Thymol
distributed glycoside coniferin and other derivatives OMe
PLE PHENOLIC
of phenolic COMPOUNDS 21 9precursors of lignin
cinnamic alcohols are OH OH
OH
NNINS 225 Eugenol Hydroquinone
CHO
UMARINS AND GLYCOSIDES 23 3
THRAQUINONES AND GLYCOSIDES 23 5
PHTHOQUINONES AND GLYCOSIDES 25 0 Salicylaldehyde
the leaves of Gaultheria spp. and its derivatives are the urushiol OH COOH
phenols of the poison oak and poison ivy (q.v.). Derivatives of
METABOLISM
resorcinol (m-dihydroxybenzene) constitute the narcotic principles
of cannabis and the glucoside arbutin involves quinol (hydroqui- HO OH
none, p-dihydroxybenzene). The taenicidal constituents of male OH
Catechol Phloroglucinol Salicylic acid
fern, the bitter principles of hops and the lipophilic components of
PHENOLS AND PHENOLIC GLYCOSIDES: SIMPLE PHENOLIC COMPOUNDS
hypericum (q.v.) are phloroglucinol derivatives.
CH 2
Thymol
CH
OH OH OH SIMPLE PHENOLIC COMPOUNDS 21 9
CH2 OH
OH COOH OH OH
TANNINS 225
CHO
COUMARINS AND
ThymolGLYCOSIDES 23 3
HO OH
ANTHRAQUINONES
PHENOLS
AND
AND
GLYCOSIDES
PHENOLIC
OMe
23 5
GLYCOSIDES
SIMPLE PHENOLIC COMPOUNDS 21 9 OH OH
Catechol Phloroglucinol Salicylic acid OH
TANNINS 225 NAPHTHOQUINONES AND GLYCOSIDES
Eugenol 25 0
Hydroquinone Salicylaldehyde
CHO
COUMARINS AND GLYCOSIDES 23 3 CHROMONES AND XANTHONES 25 1 Fig. 21.1
Table 21.1 CH2
Examples of phenolic glycosides.
ANTHRAQUINONES AND GLYCOSIDES 23 5
VANILLA AND VANILLIN Simple phenolic comp
CH FLAVONE AND RELATED FLAVONOID
NameOH CH2 NAPHTHOQUINONES
OH Examples of sources AND GLYCOSIDESGLYCOSIDES
25 0 25 2
Salicylaldehyde
Products of hydrolysis The phenolic com
CHROMONES AND XANTHONES 25 1 Fig. 21.1
ANTHOCYANIDINS AND
Simple phenolic GLYCOSIDES 25 9
compounds. aldehydic and carbox
Salicin FLAVONESalix AND
and Populus
RELATEDspp. Viburnum prunifolium
FLAVONOID Salicyl alcohol, glucose phenylpropane), vani
Thymol GLYCOSIDES 25 2 BILBERRY FRUIT 26 0
Populin (benzoyl-salicin) OMe Populus tremula Salicyl
The phenolic compounds alcohol,
in this benzoic
group often acid,
also possess glucose
acids, such as salicyl
alcoholic,
Arbutin ANTHOCYANIDINS AND GLYCOSIDESSTILBENES
25 9 26 0 is common, and the
OH Ericaceae and Rosaceae Hydroquinone, glucose
aldehydic and carboxylic acid groups; they include eugenol (a phenolic
OH
OH
Phloridzin Rosaceae,
BILBERRY FRUIT including
26 0 spp. of Malus phenylpropane), vanillin (a phenolic aldehyde) and various pheno
Phloretin, glucose derivatives
lic of phenoli
Eugenol Hydroquinone LIGNANS AND acids,LIGNIN 26 ferulic
such as salicylic, 0 and caffeic acids. Glycoside formation
of the best-known sim
CHO
Trilobatin Malus, Spiraea
STILBENES 26 0 Phloretin,
is common, and the widely glucose
distributed glycoside coniferin and other
Coniferin Coniferae
LIGNANS AND LIGNIN 26 0
derivatives of phenolicConiferyl alcohol,
cinnamic alcohols glucose
are precursors of lignin. Some
of the best-known simple phenolic glycosides are listed in Table 21.1.
Gaultherin Gaultheria, Betula and Monotropa Methyl salicylate, primeverose
Syringin
Salicylaldehyde Particularly in Oleaceae Methoxyconiferyl alcohol, glucose
Glucovanillin
Fig. 21.1 Vanilla spp. and some Gramineae Vanillin, glucose
Simple Gein
phenolic compounds. Geum spp. Eugenol, vicianose (glucose + arabinose)
Glucogallin Rheum spp. Gallic acid, glucose
The Hamamelitannin
phenolic compounds in this group often also possess Hamamelis
alcoholic, virginiana Gallic acid (2 mols), hamamelose
aldehydic and carboxylic acid groups; they include eugenol (a phenolic
METABOLISM
VANILLA AND VANILLIN

PHENOLS AND PHENOLIC GLYCOSIDES 223
lkaline solution. A petroleum spirit extract has a blue OH OMe OH

enhanced by UV light. The upper ash limit for the BP OMe
%.
ar and wood tar are used in the treatment of psoriasis.
H C O CH2OH COOH
AND VANILLIN
21
Vanillin Anisyl alcohol p -Hydroxybenzoic acid
lla Pods) consists of the carefully cured fully grown
uits of Vanilla fragrans (Salis.) Ames (syn. V. planifolia O
chidaceae) (Mexican or Bourbon vanilla) and of V. tahit- O H
vanilla). The fruits of other species, such as V. pompona
vanilla), are also used but to a much more limited extent. O
grans is grown, in a semi-wild state, in the woods of
co, its natural home. Vanilla is cultivated in Réunion (or H C O
auritius, Seychelles, Madagascar, Java, Ceylon, Tahiti,
Martinique and Indonesia. China and India are now Piperonal Vitispirane
ers and due to oversupply prices have fallen dramatically Fig. 21.4
few years. Constituents of vanilla.
capsicums’ below) should be absent.
O
METABOLISM
MeO
N
H
Allied drugs. Japanese Chillies are probably derived
scens and are about 3–4 cm long. They possess about o
PHENOLS AND PHENOLIC GLYCOSIDES: SIMPLE the
PHENOLIC
pungency of COMPOUNDS
the African Chillies, but are now no lon
HO cially relevant.
HO O
CAPSICUM Bombay Capsicums are ascribed to C. annuum L. T
MeO
H thicker and tougher
N than in the chillies, and the pedicel
N H
bent. They are much less pungent than African chillies.
MeO
HO Natal Capsicums are larger than the Bombay variety
O Capsaicin
8 cm long. They have a very bright red, transparent peric
Capsaicin derivate dimer
much less pungent than chillies.
O
MeO Uses. Capsicums are used as a condiment under
Cayenne pepper.N The drug is given internally in atonic d
H
O flatulence. It is used externally as a counter-irritant, in
O HOointment, plaster, medicated wool, etc., for the relief of
HOlumbago, etc. Capsaicin creams are available for the re
branched
sugar chain branched osteoarthritis, post-herpetic
H neuralgia and painful diabet
sugar chain (Pharm. J., 1998,N 260 , 692).
MeO
Capsianoside structure O
Fig. 21.5 FurtherCapsaicin
reading derivate dimer
De AK (ed), Hardman R (series ed) 2003 Medicinal and aroma
Some constituents of capsicum.
Vol 34, Capsicum, the genus Capsicum. CRC Press/ Taylor a
METABOLISM
178 PHARMACOPOEIAL AND RELATED DRUGS OF BIOLOGICA
Monohydric aromatic alcohols
COOH COOH
COOH
Benzyl alcohol, C6H5CH2OH, and cinnamyl alcohol, C6H5CH=CHCH2OH, occur both free and as
esters of benzoic and cinnamic acids in balsams such as Tolu and Peru. OH OMe
178 OH
PHARMACOPOEIAL ANDOMe
RELATED DRU
Protocatechuic Veratric
19
Benzoic
Coniferyl alcohol, which forms an important component of the lignin
acid
molecule. acid acid
COOH
COOH COOH
CH CH COOH
OH
HO OH OH
Protocatechuic
19Gallic acid
OH Benzoic
acid acid
Cinnamic acid
METABOLISM
PHENOLS AND PHENOLIC GLYCOSIDES: TANNINS
Substances present in plant extracts which were able to combine with protein of animal hides, prevent their
putrefaction and convert them into leather.
This definition excludes simpler phenolic substances, often present with tannins, such as gallic acid, catechins
and chlorogenic acid, although they may under certain conditions give precipitates with gelatin and be partly
retained by hide powder.
Most true tannins have molecular weights of from about 1000 to 5000.
Many tannins are glycosides.
Two main groups of tannins: these are the hydrolysable tannins and the condensed tannins (proanthocyanidins).
and hexahydroxydiphenic acids which are united by ester linkages and tellimagrandins 1 and 2 are known to be involved in the product
to a central glucose molecule. A simple tannin illustrating this point of over 150 compounds.
is one derived from a species of sumac (Rhus), with a possible As an example, many plants of the Onagraceae e.g. Oenoth
structure as shown in Fig. 21.6. Like gallic acid their solutions turn spp. contain in addition to tellimagrandin, the dimer oenothein B
METABOLISM
blue with iron salts. They were formerly known as pyrogallol tan- trimer oenothein A; these macrocyclic ellagitannins are also produ
nins, because on dry distillation gallic acid and similar components in callus cultures of O. lacinata and are of interest for their antic
are converted into pyrogallol. Two principal types of hydrolysable cer and polygalacturonase-inhibiting properties (S. Taniguchi et
tannins are gallitannins and ellagitannins which are, respectively, Phytochemistry, 1998, 48, 981).
composed of gallic acid and hexahydroxy-diphenic acid units. C-glucosidic ellagitannins are common in a number of fami
PHENOLS AND PHENOLIC GLYCOSIDES: TANNINS Ellagic acid (the depside of gallic acid) can arise by lactonization of including the Myrtaceae, Hamamelidaceae, Punicaceae and Rosac
OH
OH
HO
HO
Hydrolysable tannins
OH O CO
HO COOH
HO OH OC O O G G G
HOOC OH
H2C
O
G G
Formed from several molecules of phenolic acids such as COR OH
OH
OH
G
O
O
O G
O G
OH
Gallic acid; R = OH
Ellagic acid Hexahydroxydiphenic acid Gallitannin of Rhus sp.
gallic and hexahydroxydiphenic acids which are united -D-Glucogallin;
HOCH2
O
R = HO O
by ester linkages to a central glucose molecule. HO
OH O
H
HO OH HO OH CO OH
HO OH OH
n
Gallitannins: rhubarb, cloves, red rose petals, bearberry leaves, CO G
G; n = 1
G; n = 2
CO
O G G G; n = 3
Chinese galls, Turkish galls, hamamelis, chestnut and maple. H 2C O O G
OH O
HO
O O
Ellagitannins: pomegranate rind, pomegranate bark, HO

O
C
O
O CH2
O
CO
H
CO
HO C R
O O O HO OH
myrobalans, eucalyptus leaves, kousso, some G O G
HO HO OH OH
Australian kinos, chestnut (Castanea spp.) and oak bark. OH

Tellimagrandin 1; R = OH
O
Geraniin
Tellimagrandin 2; R = ( )-OG
Fig. 21.6
Examples of hydrolysable tannins and their component acids.
METABOLISM
Hydrolysable tannins
galls, Turkish galls, hamamelis, chestnut and maple. mimosa), oak and hamamelis
Ellagitannins: pomegranate rind, pomegranate bark, myrobalans, euca- 2. Roots and rhizomes: krameria (rhatany) and male fern
lyptus leaves, kousso, some Australian kinos, chestnut (Castanea 3. Flowers: lime and hawthorn
METABOLISM
spp.) and oak bark. 4. Seeds: cocoa, guarana, kola and areca
5. Fruits: cranberries, grapes (red wines), hawthorn
Condensed tannins (proanthocyanidins) 6. Leaves: hamamelis, hawthorn and tea, especially green
Unlike hydrolysable tannins, these are not readily hydrolysed to sim- 7. Extracts and dried juices: catechu, acacia and mangr
PHENOLS AND PHENOLIC GLYCOSIDES: TANNINS pler molecules and they do not contain a sugar moiety. They are related East Indian kino, butea gum and eucalyptus kino.
OH
OH OH OH
Condensed tannins (proanthocyanidins)
HO O HO O HO O
OH OH
OH OH OH
These are not readily hydrolysed to simpler OH OH OH OH
( )-Catechin ( )-Epicatechin
Flavan-3,4-diol structure
molecules and they do not contain a sugar moiety
OH OH
OH OH
Catechins, which also occur with the tannins and
HO O HO O
flavan-3,4-diols (leucoanthocyanidins) are OH
OH
OH OH OH
intermediates in the biosynthesis of the OH
OH OH
HO O
HO O
polymeric molecules. OH
OH OH
OH OH
OH HO O
On treatment with acids or enzymes condensed A dimeric procyanidin

OH
tannis are converted into red insoluble compounds OH
known as phlobaphenes. A trimeric procyanidin

Fig. 21.7
Structures associated with condensed tannins.
galls, Turkish galls, hamamelis, chestnut and maple. mimosa), oak and hamamelis
Ellagitannins: pomegranate rind, pomegranate bark, myrobalans, euca- 2. Roots and rhizomes: krameria (rhatany) and male fern
lyptus leaves, kousso, some Australian kinos, chestnut (Castanea 3. Flowers: lime and hawthorn
METABOLISM
spp.) and oak bark. 4. Seeds: cocoa, guarana, kola and areca
5. Fruits: cranberries, grapes (red wines), hawthorn
Condensed tannins (proanthocyanidins) 6. Leaves: hamamelis, hawthorn and tea, especially green
Unlike hydrolysable tannins, these are not readily hydrolysed to sim- 7. Extracts and dried juices: catechu, acacia and mangr
PHENOLS AND PHENOLIC GLYCOSIDES: TANNINS pler molecules and they do not contain a sugar moiety. They are related East Indian kino, butea gum and eucalyptus kino.
OH
OH OH OH
HO O HO O HO O
OH OH
OH OH OH
1. Barks: cinnamon, wild cherry, cinchona, willow, OH OH OH OH
( )-Catechin ( )-Epicatechin
acacia (wattle, mimosa), oak and hamamelis Flavan-3,4-diol structure
2. Roots and rhizomes: krameria (rhatany) and male

OH OH
fern OH OH
3. Flowers: lime and hawthorn HO O HO O
OH
4. Seeds: cocoa, guarana, kola and areca OH
OH
OH OH
OH
5. Fruits: cranberries, grapes (red wines), hawthorn OH OH
HO O
HO O
6. Leaves: hamamelis, hawthorn and tea, especially OH
OH OH
green tea. OH OH
OH HO O
7. Extracts and dried juices: catechu, acacia and A dimeric procyanidin
OH
mangrove cutches, East Indian kino, butea gum and
OH
eucalyptus kino. A trimeric procyanidin
Fig. 21.7
Structures associated with condensed tannins.
METABOLISM
https://u.osu.edu
https://wines
2291 (Pt 11) There are official limits for foreign matter, loss on drying ( 10%), unchang
CYP3A4 and CYP3A5) resulting in an increased oral bioavailability
total ash ( 10%) and acid-insoluble ash (drugs2.0%).
of various Phytoch
used to treat cancer, hypertension, heart disease and
METABOLISM
COUMARINS AND GLYCOSIDES allergies. However, unnamed constituents of the juice have recently
been shown to activate the efflux pump controlling P-glycoprotein-
Derivatives of benzo- -pyrone such as coumarin (the lactone of mediated drug transport which secretes absorbed drugs back into the
PHENOLS AND PHENOLIC GLYCOSIDES: COUMARINS AND GLYCOSIDES
O-hydroxycinnamic acid), aesculetin, umbelliferone and scopoletin gut. In vitro studies have demonstrated reduced absorption of vinblas-
are common in plants both in the free state and as glycosides. Not all tine, cyclosporin, losartan, digoxin and fexofenadine. The two effects
are phenolic but
Derivatives they are included heresuch
of benzo-α-pyrone with the phenolic derivatives
as coumarin are therefore
(the lactone antagonistic and explain
of O-hydroxycinnamic the aesculetin,
acid), unpredictable action of
for convenience. Some 1000 natural coumarins have been isolated. grapefruit juice on drug bioavailability. For reports on this research see
umbelliferone
Coumarin itself hasand
beenscopoletin are150
found in about common in plants
species belonging both inThethe
to over free 1999,
Lancet, state353,
and1335;
as glycosides.
Pharm. J., 1999, 262,5 573; HerbalGram,
4
30 different families, although it is probably present in the undamaged 1998, No. 43, 22. 6 3
7
In ammoniacal solution these compounds have a blue, blue–green or violetCO
fluorescence 8 CO
O O
Table 21.2 Hydroxy and methoxy coumarins.
Compound Additional groupings Occurrence

-Pyrone Coumarin
Umbelliferone HO at 7 (above) Belladonna and stramonium (Solanaceae): Daphne mezereum
(Thymeliaceae); Ferula species yielding asafoetida and galbanum, and
many other Umbelliferae, chicory leaves (Compositae)
Herniarin CH3O at 7 Lavandula spica (Labiatae), Ruta graveolens (Umbelliferae) and certain
Compositae
Aesculetin HO at 6, HO at 7 Horse-chestnut (Hippocastanaceae), certain Rosaceae and Fraxinus
(Oleaceae)
Scopoletin CH3O at 6, HO at 7 O
Roots of gelsemium, oat, jalap, scammony, scopolia and belladonna; O
H
leaves of tobacco, stramonium, chicory and many others
Fraxin CH3O at 6, HO at 7, O-glucose at 8 Fraxinus spp. (Oleaceae)
Chicoriin CH3O at 6, O-glucose at 7 O
Cichorium intybus herb CH 3
O
Considerable recent work on the genus has resulted in the isolation Constituents. Coumarin derivatives occur in melilot although co
of a number of furanocoumarins and their glycosides; the formulae of marin itself is not present to any extent in the living plant. It aris
METABOLISM
bergapten, angelicin, archangelicin (a diester) and apterin are given in when the plant is crushed, or the dried material treated with water, b
Fig. 21.8, and those of marmesin and psoralen in Fig. 13.2. These com- the action of a -gluconidase enzyme specific to cis-o-hydroxyci
pounds are reported to have potent coronary vasodilator effects and are namic acid glucoside giving first the unstable hydrolytic produ
PHENOLScalcium AND PHENOLIC
antagonists. MonoterpenesGLYCOSIDES:
constitute the major COUMARINS AND
components coumarinic GLYCOSIDES
acid, which then cyclizes to coumarin producing t
(80–90%) of the volatile oil. well-known ‘new-mown hay’ odour. The trans-isomer remai
There are official limits for foreign matter, loss on drying ( 10%), unchanged and is isolated as melilotoside (see F. Bourgoud et a
total ash ( 10%)
Celery fruit. Apium; Apii Fructusand acid-insoluble ash ( 2.0%). Phytochem. Anal., 1994, 5 , 127; P. Bradley British Herbal Compendium
Celery fruits contain 2–3% of oil consisting of terpenes with smaller quantities OCH3
of the anhydride of sedanonic acid, the lactone of sedanolic 6 acid

5 and
4
3
phenols.
7
CO 8 CO CO
The fruits also contain a number of coumarins,O furanocoumarins and O O O
coumarin glycosides. -Pyrone Coumarin Bergapten
(a furanocoumarin)
CO CO
Celery fruits are official in the BHP and have a long-standing Ouse in theOtreatment of rheumatic
O
diseases;
O the
H CH3
therapeutic action appears to be potentiated by Taraxacum (q.v.).
O CH3
O OCOCH3
OR1 H3 C
CH3 H O- -methylbutyroyl
OR2
Angelicin
Archangelicin: R1 = R2 = angeloyl Visnadin

Apterin: R1 = H; R2 = gluc. (Coumarin + C5 unit)
Fig. 21.8
Coumarin and derivatives. (Coumarin + C5 -unit)
gative drugs. Also certain vegetable and animal dyestuffs such as mad-
der and cochineal were of great economic importancehad beentheused as a test for identity before the underlying chemistry
before
When such substances occur as glycosides, the sugar may be
cids isolated from melilot include introduction of synthetic dyestuffs. Later the chemical was
attached in various positions. See formulae for carminic acid and
known.
similarity
21
of
METABOLISM
c acid), caffeic acid and other minor these purgative drugs and dyestuffs became apparent, as illustrated by H
glucofrangulin. Some examples the offoranthraquinone
formulae emodin (the derivatives
aglycone of a are
number of purgative glyco- Anthran
volatile compounds and flavonoids
given in Table 21.3. Oxanthrones
21
sides of Rhamnus spp.) and alizarin (the aglycone of a dyestuff of the
ification testAnthraquinone derivatives
the madder often orange-red compounds, which The formula given shows that these are intermediate products between
areplant).
PHENOLS AND
for melilot indicates
mayacidsometimes
o-coumaric bedrug.
in the genuine
PHENOLIC GLYCOSIDES: ANTHRAQUINONES AND GLYCOSIDES
observed in situ (e.g. in the medullary rays of anthraquinones and anthranols. They give anthraquinones on oxidation
minimumrhubarb
0.3%, involves absorbance OH O OH O OH O
and Fairbairn’s modification of the Bornträger test accomplishes this
O
and cascara). They are usually soluble in hot water or dilute
ed methanolic extract of the powder. OH 8 1
alcohol. Bornträger’s test is often used for their detection. The pow- by means of hydrogen peroxide. An oxanthrone has been reported as a
uses of the drug have yet to be firmly 7 9 2
dered drug is macerated with an immiscible organic solvent, ether constituent of cascara bark. 4H
HO Me
6 10 3
O O
Emodin Alizarin 5 4
e the dried seeds of Dipteryx odo-
a Aubl.) and Dipteryx oppositifolia O H H
Table
t is a native 21.3 andAnthraquinone
of Guiana Brazil Substances of the anthraquinone
glycosides type were the first to be recognized,
and aglycones. Anthraquinone Anthron
enezuela, while the latter is found in both in the free state and as glycosides. Further work showed that natu-
are large trees bearing single-seeded ral products also contained reduced derivatives of the anthraquinones
2
Aglycone
(oxanthrones, anthranols and anthrones) and compounds formed by
e (May and Glycoside
June), they are opened and theAglycone
union of two anthroneSugar OH Groups Other groups
molecules (i.e. the dianthrones). Occurrence O
old without further treatment, they are Because glycosides are often easily hydrolysed, the earlier workers 2H
produced in Ruberythric near its bor- tended
Venezuela andacid to isolate products
Alizarin of hydrolysis rather than
Primeverose 1,2the primary glyco-
– Rubia tinctorum
Rubiadin
n northern Brazil and parts of Guiana. sides.
primeveroside The following aglycones
Rubiadin have long been established:
Primeverose 1,3 chrysopha-
2-methyl Rubia tinctorum
valued, areRubiadin
known as ‘Angostura’ nol or chrysophanic acid from rhubarb and cascara; aloe-emodin from
glucoside and Rubiadin Glucose 1,3 2-methyl Rubia tinctorum
both Angostura and Para rhubarb
uantities ofChrysophanein and senna; rhein from rhubarb and senna; emodin or frangula-
Chrysophanol Glucose 1,8 3-methyl O
Rheum and Rumex spp.
hey are macerated for 24 h in rum and emodin from rhubarb and cascara. Improved extraction methods,
Rheochrysin Physcion
developed by Stoll andGlucose
his colleagues, led to the1,8
isolation of the 3-methyl 6-methoxy
main Rheum spp.
causes a crystalline deposit of coumarin
Glucorhein Rhein
senna glycosides, Glucose
sennosides A and B, in 1941. 1,8
Since this date 3-carboxylic acid
many Rheum, Rumex and Cassia spp.
eds are said to be ‘frosted’. Angostura
Gluco aloe-emodin Aloe-emodin
new glycosides Glucose
including C-glycosides and 1,8
various stereoisomers 3-hydroxymethyl
have Rheum and Cassia spp.
erce both black and frosted.
long, 10 mm Glucochrysaron
wide and 5 mm thick. been Chrysarone
isolated and theirGlucose
structures determined. 1,2,7 6-methyl Rheum rhaponticum
Glucofrangulin
bluntly pointed A sur-
at the other. The Emodin
In monocotyledons,Glucose, rhamnose
anthraquinone derivatives1,6,8
are found only in3-methyl
the Rhamnus spp.
Frangulin
longitudinally, Emodinin the formRhamnose
a crystalline encrus- Liliaceae, of the unusual C-glycoside 1,6,8 3-methyl
barbaloin. Among Rhamnus spp.
dicotyledons they occur in the Rubiaceae, Leguminosae, Polygonaceae,
H OH O
variety. AMorindin
transverse section shows Morindone Primeverose 1,5,6 2-methyl Morinda spp. (Rubiaceae)
–
yellowish-brown, planoconvex, oily Rhamnaceae,
Islandicin Ericaceae, – Euphorbiaceae, Lythraceae, 1,5,8 Saxifragaceae,
6-methyl Oxanthrone
Penicillium islandicum Dianthro
Carminic
taste, aromatic acid
and bitter. Scrophulariaceae
– and Verbenaceae.
Glucose They appear 1,3,4,6
to be absent from5-carboxylic
the acid 8-methyl Cochineal
Bryophyta, Pteridophyta and Gymnosperms but occur in certain fungi
METABOLISM 236 PHARMACOPOEIAL AND RELATED DRUGS OF BIOLOGICAL ORIGIN
PHENOLS AND PHENOLIC GLYCOSIDES: ANTHRAQUINONES AND GLYCOSIDES
OH is recommended, and after filtration aqueous ammonia or c
soda is added, when a pink, red or violet colour in the aqueous
after shaking indicates the presence of free anthraquinone d
tives. If glycosides only are present, the test should be modifi
first hydrolysing with alcoholic potassium hydroxide soluti
H 2 m acid. When alkali is added to powdered drugs or to section
Anthranol red colour produced serves to locate the anthraquinone deriv
21 in the tissues (e.g. in the medullary rays of cascara bark). If the
being tested contains either very stable anthraquinone glycosi
O O
8 1 reduced derivatives of the anthranol type, Bornträger’s test w
7 9 2
4H negative.
Anthraquinones containing a free carboxylic acid group (e.g.
6 10 3
5 4
can be separated from other anthraquinones by extraction fro
O H H organic solution with sodium bicarbonate solution.
Anthraquinone Anthrone
2H
Anthranols and anthrones
O These reduced anthraquinone derivatives occur either free or com
2H as glycosides. They are isomeric and one may be partially con
to the other in solution. The parent substance, anthrone, is a pal
low, non-fluorescent substance which is insoluble in alkali; its is
O anthranol, is brownish-yellow and forms a strongly fluorescent
tion in alkali. Anthranol derivatives, such as are found in aloes
similar properties, and the strong green fluorescence which aloe
in borax or other alkaline solution has long been used as a te
its identification. Anthranols and anthrones are the main consti
H OH O of chrysarobin, a mixture of substances prepared by benzene e
Oxanthrone Dianthrone tion from the material (araroba) found in the trunk cavities of th
Fig. 21.9 Andira araroba. If a little chrysarobin is treated on a white tile
Interrelationship of anthraquinone derivatives. drop of fuming nitric acid, the anthranols are converted into a
used as a general test for aloes. (Friars’ Balsam).
Small quantities of aloe-emodin are sometimes present in aloes, and There appears to be little variation of the major constituents of the
METABOLISM
Cape aloes also contains aloinosides A and B, which are O-glycosides leaf exudate of A. ferox depending on geographical location of the plant
of barbaloin; aloinoside B has rhamnose attached via an oxymethyl but selection of high-yielding strains giving a high production of aloin
group at C-3. In A. barbadensis free and esterified 7-hydroxyaloins (25%) is recommended for commercial cultivation (B.-E. van Wyk
et al., Planta Medica, 1995, 61 , 250).
PHENOLS AND PHENOLIC
A and B are characteristic GLYCOSIDES:
10-C-glucosyl-anthrones. These compounds ANTHRAQUINONES AND GLYCOSIDES
are responsible for the violet-purple colours given in various specific
tests for Barbados aloes (see H. W. Rauwald et al., Planta Med., 1991, ‘Aloe vera’ products See Chapter 20.
57, Suppl. 2, A129).
ALOESThe resin of aloes, reputed to have a purgative action, has been peri- Further reading
Reynolds T (ed), Hardman R (series ed) 2004 Medicinal and aromatic plants –
odically investigated from the end of the nineteenth century onwards. industrial profiles, Vol 38. Aloes – the genus Aloe. CRC Press, Taylor and
In South African spp. (e.g. A. ferox) aloesin (now often referred to as Francis Group, Boca Raton, FL, 408 pp.
Aloes is the solid residue obtained by evaporating the liquid which drains from the transversely cut leaves of
various species of Aloe Gluc
O 10 CH3
CH3 O C
HO O OH H
HO R1O OR2
CH3 O O O
10 CH2OH Aloesol derivative

(a 10 R diastereoisomer) CH3
H H
C Gluc OCH3
H C OH O CH3
HO C Aloenin A: R1 = H; R2 = glucosyl
HO C H O O Aloenin B: R1 = glucosyl;
R2 = glucosyl-2-p-coumarate
H C OH CH3 O
H C Aloesin
(Aloeresin B)
Fig. 21.15 CH2OH
Constituents of aloes Barbaloin
METABOLISM
PHENOLS AND PHENOLIC GLYCOSIDES: FLAVONE AND RELATED FLAVONOID GLYCOSIDES
PHENOLS
The flavonoids which occur both in the free state and as glycosides are the largest group AND PHENOLIC
of naturally occurring GLYCOS
phenols FLAVONOIDES
2 O
8 O O
O 1 C6 H5
7 1
2 2 C6 H5 C6 H5
3
3
6
OH H
4 3 6
5 H
O O
O O O
Flavone Isoflavone Flavonol Flavanone Chalcone
OH OMe
RO O RO O
OH
OH O OH O
METABOLISM
phenols
Clasificación
The flavonoids which occur both in the free state and as glycosides are the largest group of naturally occurring
Ensayo de Shino
O O
O O O
Chalconas Flavonas Flavanonas
O O O
OH OH OH
O O
Catequinas Flavonoles Flavanonoles
O
O O O
OH
Nota: La prueba la dán positiva sus
O O
Antocianinas Auronas
con el anillo benzopirona. P.ej. las c
Rotenoides
Gross M 2004 Flavonoids and cardiovascular disease. Pharmaceutical Biology of up to 5 mm, quadrilocular and four-seeded. A persistent toothed
42 (Supplement): 121–135 calyx covers up to three-quarters of the fruit. Features of the powder
Neuhouser ML 2004 Flavonoids and cancer prevention: what is the evidence include covering and glandular trichomes from the calyx and numer-
METABOLISM
in humans? Pharmaceutical Biology 42 (Supplement): 36–45
ous diverse fragments from the pericarp and seeds—all detailed in the
Pietta P-G 2000 Flavonoids as antioxidants. Journal of Natural Products 63(7):
1035–1042 official monographs.
Extensive studies on the phytochemistry have involved flavonoids
PHENOLS AND PHENOLIC GLYCOSIDES: FLAVONE AND
(of which the RELATED FLAVONOID
BP specifies a minimum GLYCOSIDES
content of 0.08% calculated as
AGNUS CASTUS FRUIT casticin), also vitexin, penduletin and kaempferol; diterpenes includ-
The BP/EP, BHP drug consists of the whole, ripe, dried fruit of Vitex agnus ing rotundifuran (Fig. 21.19) and vitexilactone; and various iridoids
castus L., family
The flavonoids Verbenaceae.
which occurSynonyms
both in include
the free Chaste
statetree,and
Chaste including aucubin
as glycosides (Fig.largest
are the 24.1). The latter isof
group used as a reference
naturally in the
occurring
phenols
Table 21.5 Flavonoid types and examples.
Type Compound Nature Occurrence
Flavone Chrysin Dihydroxy 5,7 Prunus, Populus (heartwood and Balm of Gilead Bud)
Flavone Butin Trihydroxy 7,3 ,4 Butea monosperma seeds (antifertility activity)
Flavone Apigenin Trihydroxy 5,7,4 Parsley, Roman chamomile flower
Flavone Luteolin Tetrahydroxy 5,7,3 ,4 Reseda luteola and as glycosides in celery, peppermint,
wild carrot etc.
Flavone Fisetin Tetrahydroxy 3,7,3 ,4 Yellow cedar wood and the dyestuff sumac
Flavonol Quercetin Pentahydroxy 3,5,7,3 ,4 As the rhamnoglucoside rutin and as many other
glycosides
Flavonol Kaempferol Tetrahydroxy 3,5,7,4 Senna
Flavonone Eriodictyol Tetrahydroxy 5,7,3 ,4 Yerba santa (Hydrophyllaceae)
Flavonone Liquiritigenin Dihydroxy 7,4 Liquorice
Chalcones Unstable isomers of flavonones Family Rutaceae and liquorice
Xanthone Gentisin 1,7-Dihydroxy-3-methoxy Gentiana and Swertia spp.
Isoflavone Formononetin Dihydroxy 7,4 Cimicifuga rhizome, red clover flower
Genistein Trihydroxy 5,7,4 Red clover flower, as glucoside in Genista
Biflavone Amentoflavone Hexahydroxy 2 × (5,7,4 ) Ginkgo, hypericum, Rhus spp.
RO O
OH
OH OMe
METABOLISM
RO O RO
OH O O OH O
PHENOLS AND PHENOLIC GLYCOSIDES: FLAVONE AND RELATED FLAVONOID
OH GLYCOSIDES
Naringenin; R = H Hesperetin; R = H
CALENDULA FLOWER: Calendula officinalis (Flavanones) (Flavanones)
OH O OH O
Flavonoids, triterpenoids, essential oil and polysaccharides are the OH
principal constituents of calendula flowers. OH
The flavonoid
Naringin;mixture involves quercetin and isorhamnetin
R = rhamno-glucosyl Hesperidin;derivatives.
R = rhamno-glucosyl
HO O HO O
(Flavanones)
Triterpenoid saponins Nota: La
(Calendulosides A–F) are glycosides based prueba
(Flavanones) la dán positiva sustancias
on oleanolic acid-3-O-β-d-glucuronide and OH
OH
are present in variable proportions (2–10%). con el anillo benzopirona. P.ej. las chalconas
OR
OH OH
no O
la dán positiva, pero
OHlas
OH
flavonas
O
y
flavanonas
Quercetin; R = H
sí. Luteolin
HO O HO O MeO
(Flavone) O
OH Hyperoside; R = galactosyl OH
Isoquercitrin; R = glucosyl Alejandro Martínez M.
OR Rutin; R = rhamno-glucosyl MeO
(Flavonols)
OH O OH O OMe O
O OH OH
Flavone Isoflavone Flavonol
Ensayo de Shinoda
METABOLISM OH
OH
OMe
RO O
PHENOLS AND PHENOLIC GLYCOSIDES: FLAVONE AND RELATED
RO
RO
FLAVONOID
O
O
GLYCOSIDES
RO O
OH
CALENDULA FLOWER: Calendula officinalis OH O OH O

OH O OH O
Naringenin; R = H Hesperetin; R = HHesperidin; R = rham
Naringin; R = rhamno-glucosyl
Flavonoids, triterpenoids, essential oil and polysaccharides are the principal (Flavanones)
constituents of calendula flowers. (Flavanones
Naringin; R =rhamno-glucosyl Hesperidin; R = rhamno-glucosyl
Nota: La
The flavonoid mixture involves quercetin and isorhamnetin prueba la
(Flavanones) dán positiva
derivatives. sustancias (Flavanones)
con el anillo benzopirona. P.ej. las chalconasOH
no la dán positiva, pero las flavonas y
HO OH O HO O OH
flavanonas sí. OH
HO O HO
OR O
OHM.
Alejandro Martínez 16 OH
OH O OH O
OR Quercetin; R = H Luteolin
(Flavone)
Hyperoside; R = galactosyl
OH O OH O
Isoquercitrin; R = glucosyl
Quercetin; R = H Rutin; R = rhamno-glucosyl Luteolin
(Flavonols) (Flavone)
Hyperoside; R = galactosyl
Isoquercitrin; R = glucosyl O OH OH
RO O
OH
OH OMe
METABOLISM
RO O RO
OH O O OH O
PHENOLS AND PHENOLIC GLYCOSIDES: FLAVONE AND RELATED FLAVONOID
OH GLYCOSIDES
ELDER FLOWER: Sambucus nigra (Flavanones) (Flavanones)
OH O OH O
Flavonoids (up to 3.0%) are predominantly flavonols and their gly- OH
cosides: rutin predominates with smaller OH
quantities of isoquercetrin, astragalin and hyperoside together with the aglycones quercetin and kaempferol.
Naringin; R = rhamno-glucosyl Nota: HO La Hesperidin;
O
prueba R
la= rhamno-glucosyl
dán HO sustancias
positiva O
(Flavanones) OH
(Flavanones) OH
con el anillo benzopirona. P.ej. las chalconas
OR
no
OH
la dán positiva, pero las flavonas y
OH OH O
OH O
flavanonas sí.
Quercetin; R = H Luteolin
HO O HO O MeO
(Flavone) O
OH Hyperoside; R = galactosyl OH
Alejandro Martínez M.
Isoquercitrin; R = glucosyl 16

(Flavonols)
OH O OH O OMe O
O OH OH
RO OO O
O O OH
Flavone Isoflavone Flavonol Flavanone Chalcone
METABOLISM
nyl- -chromone) (3-phenyl- -chromone)
OH O OH O
OH Naringenin; R = H OMe Hesperetin; R = H
RO
ELDER O
FLOWER: Sambucus nigra RO O
OH
OH
Flavonoids (up to 3.0%) are predominantly flavonols and their glycosides: rutin predominates with smaller OH
quantitiesOH O
of isoquercetrin, OH together
astragalin and hyperoside O with the aglycones quercetin and kaempferol.
HO
Nota: La O
prueba la dán HO sustancias
positiva O
Naringenin; R = H Hesperetin; R = H OH OH
Naringin; R = rhamno-glucosyl con el anillo
Hesperidin; benzopirona. P.ej. las chalconas
R = rhamno-glucosyl
OR
no la dán positiva, pero las flavonas y
OH O OH O
OH
flavanonas sí. OH OMe
Quercetin; R = H Luteolin
(Flavone)
HO O HO Hyperoside;OR = galactosyl MeO O
OH OH Martínez M.
Alejandro
Isoquercitrin; R = glucosyl 16OMe

(Flavonols)
OH O OH O OMe O
Quercetin; R = H O
LuteolinOH OH Sinensetin
Fagopyrum esculentum originated in Central Asia and by the Middle dilator. It has been employed in the treatment of angina pectoris and
Ages was being cultivated in Europe as a source of grain and green bronchial asthma, but its use appears to be limited by undesirable side-
METABOLISM
fodder. It has been cultivated in the UK and is now found wild on reactions.
wasteground as an escape. The fresh plant contains a photosensitizing
agent, which, if consumed by animals exposed to sunlight, can cause
them damage. ANTHOCYANIDINS AND GLYCOSIDES
PHENOLS
The plant AND
is a little-branched, glabrousPHENOLIC
herb often with reddishGLYCOSIDES:
stems ANTHOCYANIDINS AND GLYCOSIDES Reconocimiento d
and producing a cymose paniculate inflorescence with pink or white Anthocyanidins are flavonoids structurally related to the flavones.
powderAnthocyanidins are flavonoids

include anomocytic stomata, structurally
epidermal papilla-like projec- related tothethe
ments and flavones.
actual
antocianinas
flowers. Dark green leaves, paler on the lower surface, are broadly Their glycosides are known as anthocyanins. These names are derived
triangular in outline, cordate–saggitate and acuminate. Features of the from the Greek antho-, flower, and kyanos, blue. They are sap pig-
colour of the plant organ is determined by the pH
tions over the veins, numerous calcium oxalate cluster crystals up to of the sap. For example, the blue colour of the cornflower and the red O H
100PHARMACOPOEIAL ANDvascular
m and small prismatic crystals, RELATED tissueDRUGS
of leaf andOF BIOLOGICAL
stem, of roses is dueORIGIN
to the same glycosides and both of these plants on O H
spherical pollen grains and corolla fragments. hydrolysis with hydrochloric acid yield cyanidin hydrochloride.
HO O
Rutin (see above) is the most important therapeutic constituent of
the herb and the BP/EP requires a minmum content of 4.0% deter- the characteristic odour R of the berries being trans-2-hexenal,
O Gl i
et
Table
mined 21.6chromatography
by liquid Common with anthocyanidins.
absorbance measurements at Cl pH=3
HO3-methylbutyrate
2 and ethyl 2-methylbutyrate.
O O Gl i
350 nm. 1 + 1 OH
For the dried
2 fruits,
6 the BP/EP specifies a minimum tannin cont
Anthocyanidin R
Buckwheat is used in the R
treatment of various Occurrence of glycosides
circulatory disorders, 5 4 Acido
R pyrogallol Base
O H
including varicose veins, chilblains and retinal bleeding. of 1.0% expressed
OH as and for the fresh fruits a minim
O
of OH
0.30% anthocyanins expressed as cyanidin-3-glucoside chlori
Pelargonidin H H Flowers of Pelargonium Anthocyanidin structure HO O
Silybin and silymarin The latter is determined by absorption measurements at 528 nm on
(Geraniaceae)
A number of flavonolignans—for example, silybin and silymarin and OH
acidified Claqueous extract of the dried fresh berries.O The Gl i loss on dry
pomegranate
(a 1,4-dioxan produced by the oxidative combination of taxifolin and HO O
pH=8.5
O Gl i
Cyanidin
coniferyl alcohol)—haveOH H properties,
antihepatotoxic Cornflowers,
and extractsred
of poppies, Rosa of the fresh berries is 80–90%.
+ C OH
plants containing them—for example, Silybum marianum spp., cocoamar-
(Carduus and cherries C.OH O
Frozen C fresh berries should be stored at or below −18°C. It
ianus), Compositae—are widely used in Germany for the treatment of Acido Base O H
Peonidin OCH3 H Peony (Ranunculaceae) important
OH
H
to inspect the dried drug for insect and mouldiness.
liver ailments. The fruits of S. marianum contain silybin, silydianin and
Delphinidin OH OH Delphinium and Viola spp. Cyanidin chloride HO O
silychristin. For further details and structure of silybin see Chapter 29.
Petunidin OH OCH3 Petunia spp. (Solanaceae)
Uses
Table 21.6 gives a few and actions.
examples Bilberry
of these numerous haswidely
and very many traditionalO Glmedicinal uses
Malvidin
Visnaga OCH3 OCH3 Malva spp., purple distributed
grades compounds. The most common anthocyanidin, cyanidin, i
number of which have been supported O Gl i by fairly extensive pH=11
pharm
The drug consists of the dried ripe fruits of Ammi visnaga occurs in about 80% of permanently pigmented leaves, 69% of fruits
(Umbelliferae), an annual plant about 1–1.5 m high. It grows in the and 50% of flowers. cological
Cyanidin is research. For detailed
followed in order references,
of frequency by the reader should c
Alejandro Martínez M.
tho- J. Ethnopharmacology, 1999, 68 , 71).
3. Pinosylvin, a natural stilbene of the heartwood of Pinus spp. is
METABOLISM
related to, and has similar antibacterial properties to, resveratrol. S. K.
PHENOLS AND PHENOLIC GLYCOSIDES: STILBENES
Lee et al., Fitoterapia, 2005, 76, 258.
Stilbenes are biosynthesized from hydroxycinnamic acids and
Two stilbenes of pharmacognostical interest are rhaponticin and resveratrol.
acetate.
eae)ResveratrolFor
is a further
constituentdiscussion, see Chapter
of species of Arachis, 32: The
Cassia, Eucalyptus, plant nutraceuticals.
Polygonum and Veratrum.
trib-
HO
ada.
oor-
itish CH CH R
with
ears HO
nish- Resveratrol, R = OH
lack Pinosylvin, R = H
METABOLISM
METABOLISM
METABOLISM
METABOLISM
TERPENOIDS: VOLATILE OILS
Volatile or essential oils, as their name implies, are volatile in steam.
They differ entirely in both chemical and physical properties from fixed oils.
They are secreted in oil cells, in secretion ducts or cavities or in glandular hairs
They are frequently associated with other substances such as gums and resins and themselves tend to resinify
on exposure to air.
Large quantities of volatile oil are produced annually; as examples, for lemon oil, eucalyptus oil, clove leaf oil
and peppermint oil world production annually runs into several thousand metric tons each.
METABOLISM
Volatile or essential oils, as their name implies, are volatile in steam.
They differ entirely in both chemical and physical properties from fixed oils.
They are secreted in oil cells, in secretion ducts or cavities or in glandular hairs
They are frequently associated with other substances such as gums and resins and themselves tend to resinify
on exposure to air.
Large quantities of volatile oil are produced annually; as examples, for lemon oil, eucalyptus oil, clove leaf oil
and peppermint oil world production annually runs into several thousand metric tons each.
xamples. Analyses show that these volatile oils. The classification is arbitrary, since an oil may contain a
noterpenoids, many in relatively number of compounds all about equally important but belonging to dif-
METABOLISM
ent of one oil may be a minor one ferent chemical classes. The substance used for classification is not nec-
essarily the one present in greatest amount. Thus, nutmeg is classified
+
?
+
+
IIIA Camphane IIB Menthane type I Linear type IIA Cyclocitral
+ +
tween
IIIC Fenchane IIIB Pinane IIID Carane type IIIE Thujane
xamples. Analyses show that these volatile oils. The classification is arbitrary, since an oil may contain a
noterpenoids, many in relatively number of compounds all about equally important but belonging to dif-
METABOLISM
ent of one oil may be a minor one ferent chemical classes. The substance used for classification is not nec-
essarily the one present in greatest amount. Thus, nutmeg is classified
+
?
+
+
IIIA Camphane IIB Menthane type I Linear type IIA Cyclocitral
+ +
tween
IIIC Fenchane IIIB Pinane IIID Carane type IIIE Thujane
METABOLISM
TERPENOIDS: VOLATILE OILS VOLATILE OILS AND RESIN
OH
CH2OH CHO
OH
OH
Geraniol Citral Nerol Citronellol Linalool
OH
OH
Citronellal -Myrcene Limonene -Phellandrene -Terpineol

OH
METABOLISM
Citronellal -Myrcene Limonene -Phellandrene -Terpineol
OH
OH O
Menthol Menthone Carvone -Pinene Borneol
O
OH
O
Camphor Cineole Thymol Sabinene Thujone

Cineole Thymol Sabinene T
METABOLISM
OCH3 OH
OCH3
CH CH CH2
CH CH CH
CHO CH3 CH2
Cinnamaldehyde Anethole Eugenol

METABOLISM
Table 22.1 Composition of volatile oils.
Name Botanical name Important constituents
Terpenes or sesquiterpenes
Tea-tree Melaleuca alternifolia Cyclic monoterpenes
Turpentine Pinus spp. Terpenes (pinenes, camphene)
22 Juniper Juniperus communis Terpenes (pinene, camphene); sesquiterpene
(cadinene); alcohols
Cade (Juniper Tar Oil) Juniperus oxycedrus Sesquiterpenes (cadinene); phenols
(guaiacol, cresol)
Alcohols
Coriander Coriandrum sativum Linalol (65–80% alcohols); terpenes
Otto of rose Rosa spp. Geraniol, citronellol (70–75% alcohols); esters
Geranium Pelargonium spp. Geraniol; citronellol; esters
Indian or Turkish geranium Cymbopogon spp. Geraniol (85–90%)
(Palmarosa)
Sandalwood Santalum album Santalols (sesquiterpene alcohols), esters,
aldehydes
Esters and alcohols
Bergamot Citrus bergamia Linalyl acetate, linalol
Lavender Lavandula officinalis Linalol; linalyl acetate (much); ethyl-pentyl ketone
Rosemary Rosmarinus officinalis Borneol and linalol (10–18%); bornyl acetate, etc.
(2–5%); terpenes; cineole
Pumilio pine Pinus mugo var. pumilio Bornyl acetate (about 10%); terpenes;
sesquiterpenes
Peppermint Mentha piperita Menthol (about 45%); menthyl acetate (4–9%)
Aldehydes
(Palmarosa)
Sandalwood Santalum album Santalols (sesquiterpene alcohols), esters,
METABOLISM
aldehydes
Esters and alcohols
266 PHARMACOPOEIAL AND RELATED DRUGS
Bergamot OF BIOLOGICAL ORIGIN
Citrus bergamia Linalyl acetate, linalol
Lavender Lavandula officinalis Linalol; linalyl acetate (much); ethyl-pentyl ketone
sesquiterpenes
Peppermint Mentha piperita Menthol (about 45%); menthyl acetate (4–9%)
Aldehydes
Cinnamon
Tea-tree bark Cinnamomum
Melaleuca verum Presl.
alternifolia Cinnamaic
Cyclicaldehyde
monoterpenes(60–75%); eugenol; terpenes
Cassia
Turpentine Cinnamomum
Pinus spp. cassia Cinnamic aldehyde
Terpenes (80%)camphene)
(pinenes,
22 Lemon
Juniper
Lemon grass
Citrus limon communis
Juniperus
Cymbopogon spp.
CitralTerpenes
(over 3.5%);
Citral and
limonene
(pinene, (about 90%)
camphene);
citronellalalcohols
(cadinene);
sesquiterpene
(75–85%); terpenes
‘Citron-scented’ eucalyptus Eucalyptus citriodora Citronellal (about 70%)
Cade (Juniper Tar Oil) Juniperus oxycedrus Sesquiterpenes (cadinene); phenols
Ketones (guaiacol, cresol)
Spearmint Mentha spicata and M. cardiaca Carvone (55–70%); limonene, esters
Alcohols
Caraway Carum carvi Carvone (60%); limonene, etc.
Coriander Coriandrum sativum Linalol (65–80% alcohols); terpenes
Dill Anethum graveolens Carvone (50%); limonene, etc.
Otto of rose Rosa spp. Geraniol, citronellol (70–75% alcohols); esters
Sage Salvia officinalis Thujone (about 50%); camphor; cineole etc.
Geranium Pelargonium spp. Geraniol; citronellol; esters
Wormwood Artemisia absinthium Thujone (up to 35%); thujyl alcohol; azulenes
Phenols
(Palmarosa)
Cinnamon
Sandalwoodleaf Cinnamomum verum Presl.
Santalum album Eugenol (up to 80%)
Santalols (sesquiterpene alcohols), esters,
Clove Syzygium aromaticum (L.) Eugenolaldehydes
(85–90%); acetyl eugenol, methylpentyl
Merr & L. M. Perry ketone, vanillin
Esters and alcohols
Thyme Thymus vulgaris Thymol (20–30%)
Bergamot
Horsemint Citrus bergamia
Monarda punctata Linalyl
Thymol acetate,
(about 60%) linalol
Lavender
Ajowan Lavandula officinalis
Trachyspermum ammi Linalol;
Thymol linalyl acetate (much); ethyl-pentyl ketone
(4–55%)
Ethers
Anise and Star-anise Pimpinella anisum and Illicium verum Anethole (80–90%); chavicol methyl ether, etc.
Caraway Carum carvi Carvone (60%); limonene, etc.
Dill Anethum graveolens Carvone (50%); limonene, etc.
Sage Salvia officinalis Thujone (about 50%); camphor; cineole etc.
METABOLISM
266
Wormwood
Phenols
Artemisia absinthium
PHARMACOPOEIAL AND RELATED DRUGS OF BIOLOGICAL ORIGIN
Cinnamon leaf Cinnamomum verum Presl.
Thujone (up to 35%); thujyl alcohol; azulenes
Eugenol (up to 80%)

TERPENOIDS:
Clove VOLATILE OILS Syzygium aromaticum (L.) Eugenol (85–90%); acetyl eugenol, methylpentyl
Merr & L. M. Perry ketone, vanillin
Thyme Thymus vulgaris Thymol (20–30%)
Horsemint Monarda punctata Thymol (about 60%)
Ajowan Trachyspermum ammi Thymol (4–55%)
Ethers
Anise and Star-anise
Tea-tree Pimpinella alternifolia
Melaleuca anisum and Illicium verum Anethole
Cyclic (80–90%); chavicol methyl ether, etc.
monoterpenes
Fennel
Turpentine Foeniculum
Pinus spp. vulgare Anethole(pinenes,
Terpenes (60%); fenchone,
camphene) a ketone (20%)
22 Eucalyptus
Juniper
Cajuput
Eucalyptuscommunis
Juniperus globulus
Melaleuca spp.
Cineole (over
Terpenes
Cineole
70%);
(pinene,
(50–60%);
(cadinene);
terpenes,sesquiterpene
camphene);
alcohols
etc.
terpenes, alcohols and esters
Camphor
Cade (Juniper Tar Oil) Cinnamomum
Juniperus camphora
oxycedrus After removal of
Sesquiterpenes the ketonephenols
(cadinene); camphor contains
(guaiacol, cresol) etc.
safrole; terpenes,
Parsley
Alcohols Petroselinum sativum Apiole (dimethoxysafrole)
Indian dill
Coriander Peucedanumsativum
Coriandrum soja Dill-apiole
Linalol (dimethoxysafrole)
(65–80% alcohols); terpenes
Nutmeg
Otto of rose Myristica
Rosa spp. fragrans Myristicincitronellol
Geraniol, (methoxysafrole)
(70–75% upalcohols);
to 4%; terpenes
esters
Geranium Pelargonium spp. (60–85%);
Geraniol; alcohols,
citronellol; phenols
esters
Indian or Turkish geranium
Peroxides Cymbopogon spp. Geraniol (85–90%)
(Palmarosa)
Chenopodium Chenopodium ambrosioides var. Ascaridole (60–77%), an unsaturated
Sandalwood Santalum album
anthelmintica Santalols
terpene(sesquiterpene
peroxide alcohols), esters,
aldehydes
Non-terpenoid and
Esters andfrom
derived alcohols
glycosides
Bergamot
Mustard Citrus bergamia
Brassica spp. Linalyl acetate, linalol
Glucosinolates
Lavender
Wintergreen Lavandula
Gaultheriaofficinalis
procumbens Linalol;
Methyl linalyl acetate (much); ethyl-pentyl ketone
salicylate
Rosemary
Bitter almond Rosmarinus officinalis
Prunus communis var. amara Borneol and linalol
Benzaldehyde and(10–18%);
HCN (frombornyl acetate, etc.
amygdalin)
sesquiterpenes
water-soluble glycosides and sugars of fennel fruit (Chem. Pharm. Bull.,
g. 1998, 46, 1587, 1591, 1599, 1603, 1643, 1738; 1999, 47 , 805, 988) have
ug Comm
METABOLISM
recorded alkyl-, erythro-anethol-, p-hydroxyphenylpropylene glycol-, OH
flower
er- fenchane-, menthane-, aromatic (phenylpropane etc)- and 1,8-cineole- diverse
type glycosides. It is of further interest that of the cineole-type glycosides ference
re TERPENOIDS: VOLATILE OILS 1992 p
refer to
m),
O CH2 which
he
re CH2
22 -Bisabolol Farnesene Yarr
in mos
er come l
H3 CO in othe
ic
mi- Fenchone Estragole Chara
H3CO O O
id (Methyl chavicol) corym
in diam
m. with fi
a Chamazulene Herniarin
florets
OCH3
m OH
ous ele
These
of HO H with an
l., OAc typical
COO
ds +
N H Consti
ee H3 CO
O H3C CH3 not les
as cham
CHO O
folium
trans-Anethole Anisaldehyde Achillicin Betonicine consid
Fig. 22.17 spread
% Fig. 22.8 guaian
Constituents of matricaria flowers.
nd Constituents of fennel oils. sesquit
METABOLISM

O OH
MeO
(CH2)nMe
22 H OH
HO
Zingiberene ar -Curcumene Zingiberol Gingerols
[6]-Gingerol, (n = 4)
OH OH O
MeO MeO OMe
HO HO OH
[6]-Gingerdiol Gingerenone A
(Acetylation of one or two of the three hydroxyls
gives rise to a further range of compounds)
CHO
O
CHO
O MeO
(CH2)nMe
HO
A dialdehyde Shogaols
[(E)-8 ,17-epoxylabd-12-ene-15,16-dial] [6]-Shogaol, (n = 4)
[8]-Shogaol, (n = 6)
[10]-Shogaol, (n = 4)
Fig. 22.14
Constituents of ginger.
ate cancer, and a 53% lowered risk of advanced
decline in protective effect of a range of tomato and leukotrienes. Disruption of its production by the action of delta-6-
shown to correspond to a decline in plasma lyco- desaturase on linoleic acid is thought to be responsible for a number of
METABOLISM
human disease states. Atopic eczema and premenstrual syndrome are
nary evidence suggests that lycopene intake, and two of the most popular applications. Metabolism of γ-linolenic acid to
els are associated with a reduced risk of developing DGLA in healthy individuals may reduce inflammation via competitive
y prostate and lung cancer. inhibition of leukotrienes and 2-series prostaglandins. Trials using 1.4
TERPENOIDS: CAROTENOIDS
utein concentration is believed to be inversely
or 2.8 g/daily of γ-linolenic acid for up to 12 months have shown
progressive improvements in symptoms of rheumatoid arthritis.
ease, and an inverse relationship has been reported
in levels and progression of intima-media thickness Policosanol/octacosanol
Policosanol is found in sugar cane waste and the leaves of alfalfa and
wheat, and is also present in wheat germ. The major component, octa-
A number of plant-derived carotenoids such as lycopene, lutein and zeaxanthin are currently commercially
xanthin have been implicated in maintenance of
selectively accumulate in the retina of mammals, cosanol is present at levels of 67% in material obtained from sugar
available as single entities and have wide-ranging activities
cula lutea its yellow colour, and makes up a screen- cane waste and wheat germ.
CH3 CH3 CH3 H3C

H3C
CH3
CH3 CH3 CH3 CH3 Table 32.1 Single-component nutraceuticals.
Lycopene Nutraceutical Antioxidant Plant sources Major application(s)
Lycopene √ Tomato (Lycopersicon esculentum), spinach Cardiovascular health and cancer

(Spinacea oleracea) prevention
H3C OH Lutein √ Tomato (Lycopersicon esculentum), butternut Cardiovascular and eye health
H3C CH3 CH3 CH3 32 Zeaxanthin √
squash (Cucurbita moschata)
Tomato (Lycopersicon esculentum), butternut Eye health
squash (Cucurbita moschata)
γ-Linolenic acid √ Evening primrose (Oenothera biennis), borage Skin, joint and women’s health
seed (Borago officinalis)
CH3 CH3 H3C CH3 Policosanol/octacosanol √ Sugar cane (Saccharum officinarum) Cardiovascular health
HO CH3 Resveratrol √ Grapes (Vitis vinifera), wine, cranberry juice Cardiovascular health and cancer
prevention
Lutein Sterols/stanols × Seed oils, e.g. tall oil Cardiovascular health
Theanine × Tea (Camellia sinensis) Cardiovascular health, relaxant and
memory enhancement
CH3 CH3 H 3C OH
H3C CH3
Table 32.2 Multi-component products.
Nutraceutical Antioxidant Source Typical constituents Major applications
CH3 CH3 H3C CH3

HO CH3 GSPE √ Grape Catechins and derivatives Cardiovascular health
Pycnogenol √ Maritime pine (Pinus pinaster) Procyanidins Cardiovascular and respiratory health
Soy isoflavones √ Soy (Glycine max) Isoflavones Cardiovascular, mental, women’s health,
Zeaxanthin cancer prevention
non-alcoholic beverages. cultivation of good-quality plants. Hardman in a review on steroids
Saponins have a high molecular weight and BIOGENESIS
a high polarity OF STEROIDAL
and their SAPONINS
(Planta Med., 1987, 53, 233) recorded that, annually, the American
METABOLISM
isolation in a state of purity presents some difficulties. Oftenarise
Steroidal saponins theyvia
occur
the mevalonic acid pathway; the pre- Chemical Abstracts contained some 3000 references pertinent to plant
as complex mixtures with the components liminarydiffering stages have been discussed in Chapter 18. A scheme for the steroids or related compounds. Some of the better-known examples
only slightly from
subsequent cyclization of squalene to give cholesterol is illustrated of steroidal sapogenins and their sources are given in Table 23.2.
one another in the nature of the sugars present, or23.1.
in Fig. in the structurethe
Cholesterol, ofwide
the distribution of which in plants has (For a review, tabulating over 200 sapogenins, see A. V. Patel et al.,
TERPENOIDS: SAPONINS,
aglycone. Various chromatographic techniques
only have CARDIOACTIVE
relatively
of C27 sapogenins
been
recentlyemployed DRUGS
been shown, can be incorporated
withouttoside-chain
AND
into a number OTHER
Fitoterapia, 1987, 58,STEROIDS
67.)
for their isolation. As glycosides they are hydrolysed by acids give cleavage (Fig. 23.2), although
it is not necessarily an obligatory precursor. Extensive investigations Dioscorea species
an aglycone (sapogenin) and various sugars and related uronic acids.
involving whole plants, homogenates and cell cultures have been per- Tubers of many of the dioscoreas (yams) have long been used for
According to the structure of the aglycone or sapogenin,
formed twodetailed
to elucidate these kindspathways, including the origin of the food, as they are rich in starch. In addition to starch, some species
Saponins
of saponin (Latin sapo,
are recognized—the soap)
steroidal which(e.g.
(commonly
25-epimers are characterized
tetracyclic
diosgenin yamogenin).by their property of
triter-
and producing
contain a frothing
steroidal saponins, aqueous
others alkaloids. From a suitable source the
penoids) and the pentacyclic triterpenoid types
solution. As early
(see asformulae
1947 Marker and Lopez had postulated that steroidal sapogenins are isolated by acid hydrolysis of the saponin. Previous
below).
Both of these have a glycosidal linkage atsaponinsC-3 exist in plants in a form where the side-chain is held open by fermentation of the material for some 4–10 days often gives a better
and have a common
glycoside formation. However, direct evidence for the natural occurrence yield. The water-insoluble sapogenin is then extracted with a suitable
biogenetic origin via mevalonic acid and isoprenoid units.
22
21 (29) (30)
20 23
18 26 H3C CH3
24
12 17 25 20
11 13 16 27
D 19 21
19 C 15 E
14 18 22 HO
1 9
+
H O H
2 10 8 13 17
A B D CH3
3 5 7 14 16
4 6 15 (28) Squalene Squalene-2,3-oxide Cycloartenol
CH3
(27)
Steroid skeleton Pentacyclic triterpenoid skeleton
A distinct subgroup of the steroidal saponins is that of the steroidal

alkaloids which characterize many members Fig.of the Solanaceae. They
23.1
HO HO HO
possess a heterocyclic nitrogen-containing ring, giving the compounds
Possible route for the H H
formation of cholesterol in
basic properties (as an example see solasodine, Fig. 23.5 ).
higher plants and algae. Cholesterol Zymosterol Lanosterol
METABOLISM
TERPENOIDS:
306 SAPONINS,
PHARMACOPOEIAL CARDIOACTIVE
AND RELATED DRUGS OF BIOLOGICAL ORIGIN DRUGS AND OTHER STEROIDS
O
23 HO
Diosgenin
HO
O
O
Dioscorea
HO
Kryptogenin
Lycopersicum O N
H
HO
Cholesterol
Solanum HO
H
Tomatidine
HO
Solanidine
HO
Solanidine
METABOLISM
Fig. 23.2
Some plant metabolites of cholesterol.
TERPENOIDS: SAPONINS, CARDIOACTIVE DRUGS AND OTHER STEROIDS

Cholesterol
Dioscorea floribunda
CH2O—D-Gluc.
OH
L−Rhamnose ∆5 -Furostene-3 β,22,26-triol

3 β-chacotrioside-26β-D-glucopyranoside
D-Gluc. O
L−Rhamnose Dioscorea floribunda

homogenate
L−Rhamnose
Dioscin
D-Gluc. O
Fig. 23.3
Formation and metabolism of an L−Rhamnose
open-chain saponin in Dioscorea. Diosgenin
CH3
OH OH CO
METABOLISM
TERPENOIDS: SAPONINS, CARDIOACTIVE DRUGS Testosterone
AND OTHER STEROIDS
O HO O
Oestradiol Progesterone
SEX HORMONES
CH3 CH2 O CO CH3 CH2 OH
OH OH CO CO
OH
CO
OH
O HO CH3
O O
Cortisone acetate Betamethasone
CORTICOIDS
O HO O O
C CH C CH
OH OH O
Testosterone Oestradiol Progesterone
SEX HORMONES 23
CH2 O CO CH3 CH2 OH O CH3O O S CO CH3
Fig. 23.4 Norethisterone Mestranol Spironolactone

CO Examples of structures of
CO
OH therapeutically active steroids.OH
O HO
ORAL CONTRACEPTIVES DIURETIC STEROID
CH3
F
F 22 25
O
E
OO OO
O O C D
Cortisone acetate Betamethasone 3 A B

HO 5 HO
CORTICOIDS 6
METABOLISM
O CH3O O S CO CH3
Fig. 23.4 Norethisterone Mestranol Spironolactone

Examples of structures of
therapeutically active steroids. ORAL CONTRACEPTIVES DIURETIC STEROID
TERPENOIDS: SAPONINS, CARDIOACTIVE DRUGS AND OTHER STEROIDS
F
22 25
O
E
OO OO
C D
3 A B
HO 5 HO
6
Diosgenin (∆5 25α-spirosten-3 β-ol) Hecogenin (Sisal spp.)
(various spp. of Dioscorea,
Fenugreek)
COOH
HO
ON
H
HO HO
Solasodine (Solanum spp.) Deoxycholic acid (ox-bile)
HO HO
Fig. 23.5
Some naturally occurring steroids. Stigmasterol (soya) Sitosterol (soya)
METABOLISM
TERPENOIDS: SAPONINS, CARDIOACTIVE DRUGS
PHARMACOPOEIAL AND RELATED DRUGS OF BIOLOGICAL ORIGIN AND OTHER STEROIDS
Table 23.2 Some steroidal sapogenins and their sources.
Sapogenin Species Location
Diosgenin Dioscorea sylvatica Transvaal and Natal

D. mexicana and D. composita Mexico and Central America
D. collettii, D. pathaica and D. nipponica China
3 D. floribunda
D. deltoidea and D. prazeri
Guatemala and cultivated in India
India
D. tokoro Japan
Costus speciosus India
Kallstroemia pubescens Tropical America; introduced into West Brazil
Trillium spp. North America
Trigonella foenum-graecum India, Egypt, Morocco
Hecogenin Agave sisalana Subtropical America and cultivated in Kenya
for sisal and saponin
A. rigida Mexico
Hechtia texensis Central America
Sarsapogenin Yucca spp., Smilax spp. Central America
Sarmentogenin Strophanthus spp. Africa
organic solvent. Both wild and cultivated plants are used. Cultivation and China. A number of new steroidal saponins have been isolated
22 23
O
22 23
METABOLISM
20
18
21 O
R1O 12 17 O 18
20 24
21
R2H2C 19
11
13 D
16 17 O
TERPENOIDS: CARDIOACTIVE 1 9
C
15 13 16
14 D
R1 R2 2 10 8 15
A B 14
3 7
α-Hederin Ara 2−1 Rha OH 5
SAPONINS, CARDIOACTIVE DRUGS AND OTHER STEROIDS 323
4 6
β-Hederin Ara 2−1 Rha H
Hederacolchiside A1 Ara [Glc 4−1] 2−1 Rha H Cardenolide Bufadienolide
Table 23.6 Genins of some cardioactive glycosides.

Substitution patterns for some typical genins are given in Table
Fig. 23.14 The sugar moieties, attached to the aglycone by a C-3,β-lin
Saponins of Ivy. Carbon ring numbering are composed of up to four sugar units which may include gluco
Genins 1 3 5 10 11 12 14 16
Cardenolides
Digitoxigenin
Gitoxigenin
OH
OH
CH3
CH3
OH
OH OH 23
Gitaloxigenin OH CH3 OH OCHO
Digoxigenin OH CH3 OH OH
Diginatigenin OH CH3 OH OH OH
Strophanthidin OH OH CHO OH
Ouabagenin OH OH OH CH2OH OH OH
Dienolides
Scillaridin A* OH CH3 OH
Scilliphaeosidin* OH CH3 OH OH
Hellebrigenin OH OH CHO OH
22 23
O
22 23
METABOLISM
20
18
21 O
R1O 12 17 O 18
20 24
21
R2H2C 19 13 D
11 16 17 O
TERPENOIDS: CARDIOACTIVE 1 OTHER
SAPONINS, CARDIOACTIVE DRUGS AND
C
9 STEROIDS 327
15 13 16
14 D
R1 R2 2 10 8 15
O O add 10 ml of water and 0.5 ml of strong solution
O O
A of leadBacetate; shake 14
3 7
α-Hederin Ara 2−1 Rha OHthe filtrate with 5 ml of chloroform,5 allow to separate,
and filter. Shake
pipette off the chloroform and remove the solvent 6 evaporation
4 by gentle
β-Hederin
H Ara 2−1 Rha H H
OH in a porcelain dish. Dissolve the cooled residue in 3 ml of glacial acetic
Cardenolide Bufadienolide
Hederacolchiside A1 Ara [Glc 164−1] 2−1 acid
Rhacontaining H two drops of 5% ferric chloride solution. Carefully
RMACOPOEIAL H AND RELATED DRUGS OF
H BIOLOGICAL ORIGIN
transfer this-solution to the surface Substitution patterns
of 2 ml of concentrated for some typical
sulphuric genins are given in Table
acid; a reddish-brown layer forms at the junction of the two liquids and
Fig. H
23.14 OH H OH The sugar moieties, attached to the aglycone by a C-3,β-lin
23units which
3
the upper layer slowly becomes bluish-green, darkening with standing.
her reading
HO
Saponins
H of Ivy.
HO
H
O ofOup to four sugar
are composed O O include gluco
may
on JK 1985 An account of the foxglove and its medical uses 1785–1985. Digitalis seeds. The seeds of D. purpurea contain different glyco-
ord UniversityDigitoxigenin
Press, Oxford Gitoxigenin OHextracted and standardized, they
sides from those of the leaves. When OH
(Series
1991A)A note on the use of (Series B) prior to William
s MJ, Bisset NG Digitalis are known as ‘Digitalin’ (Digitalinum PurumHGermanicum or amor- H
hering. Journal of Ethnopharmacology 35: 99–103 phous Digitalin). This consists of the physiologically active ‘digita- OH
O O linum verum’, with other water-soluble glycosides, including the
H H
saponins digitonin and gitonin.
TALIS LANATA LEAF H
O
H OH H OH
O C H Allied drugs. Digitalis thapsi is found in Spain and Italy. The leaves
lant, Digitalis lanata (Scrophulariaceae),
H
the leaves of whichhave
are a crenate
HO margin and decurrent lamina. The leavesHO are characterized
s a source of the glycosides digoxin and lanatoside C, is a perennial H
by the absence of non-glandular hairs, the presence of glandular hairs H of
H OH two types, some consisting of a bicellular gland and unicellular stalk, oth-
nnial herb about 1 m high, indigenous to central and south-eastern ers having a unicellular
Digoxigenin
gland and a three- to four-celled stalk, the
Diginatigenin
presence
HO
e. It is also cultivated in Holland,
H Ecuador and the USA. Some 1000 (Series
of a striated cuticle, pericyclic fibresC)and small prisms of calcium oxalate.(Series D)
s of plant material are required annually
Gitaloxigenin
to meet world demand. Fig.
The vein-islet 23.20
number is higher than the other Digitalis species, varying
from 8.5 to 16. D. lutea has
Aglycones of a potency similar
Digitalis lanata to cardioactive
those of D. purpurea and
glycosides. See Fig. 23.19
(Series E)
D. ferruginia and is cultivated in the former USSR. D. ferruginea ssp.
acters. The leaves are sessile, linear-lanceolate to oblong-
Fig. 23.19 for those also found in D. purpurea.
ferruginea is the most widespread of the nine Digitalis spp. which grow
late Aglycones
and up toofabout
Digitalis purpurea cardioactive glycosides.
30 cm long and 4 cm broad. The margin is entire, in Turkey. For a report on the isolation of phenylethanoid glycosides from
derivedorfrom
alkaloids’ mammalsamines.
biological include ones of indole and isoquinoline classes
Leguminosae, a few are found in both plants and animals. I, Mescaline II,1 Pyrrole
II. Heterocyclic or typical alkaloids, divided into 14 groups according
Apocynaceae, H
METABOLISM
to their ring structure. N
nvolvulaceae, PROPERTIES N N
mily Lobelio-
The nitrogen of alkaloids
Most alkaloids are well-defined crystalline substances which unite
ALKALOIDS
distribution,
with
Alkaloids, acids in
taken to form salts.
their In the plant
broadest theymay
sense, may exist
have inathenitrogen
free state,atom
salts or as N-oxides (see below). In addition to the elements carbon,
as II,1 Pyrrolidine II,2 Pyrrolizidine II,3 Pyridine
which is primary (mescaline), secondary (ephedrine), tertiary (atropine) H
omic signifi- hydrogen and nitrogen, most alkaloids contain oxygen. A few, such as
or quaternary
coniine(one
fromofhemlock
the N atoms
and of tubocurarine),
nicotine from and
tobacco, are this factor affects
oxygen-free and 1 2
regard to all N
Typical
nues to be a
the alkaloids
derivatives
are ofare
liquids.the derived
alkaloid
Although from
which
coloured canplant sources,
be prepared
alkaloids are they
andrare,
relatively the are
isolation
they are basic,
they contain7 oneNMeor more 3 nitrogen atoms
(usually in anot unknown; berberine,
heterocyclic
narine are copper-red.
for example,
ring) and is yellow
they and the salts
usually haveof sangui-
a marked physiological 6
action
5 4 on man or N other
es are known
animals. A knowledge of the solubility of alkaloids and their salts is of II,3 Piperidine II,4 Tropane II,5 Quinoline
toxins. They MeO
considerable pharmaceutical importance. Not only H are alkaloidal sub-
f the genus stances often administered in solution, but also the differences in
solubility between .
alkaloids .
and their salts N
provide methods for the
us substances MeO CH2 CH2 NH2
isolation of alkaloids from the plant and their separation from the non-
al. Alkaloids
alkaloidal substances also present. While the solubilities of different
noline classes MeO and salts show considerable variation, as might be expected
alkaloids
I, Mescaline II,1 Pyrrole N N Me N
from their extremely varied structure, it is true to say that the free bases
are frequently
H sparingly soluble in water but soluble in water but solu- II,6 Isoquinoline II,7 Aporphine II,8 Quinolizidine
ble in organic solvents; with salts the reverse is often
N the case, these
N
being usually soluble in waterN but sparingly soluble in organic sol-
vents. For example, strychnine hydrochloride is much more soluble in
which unite water than is strychnine base. It will soon be realized that there are N
free state, as many exceptions to the
II,1 Pyrrolidine II,2above generalizations,
Pyrrolizidine caffeine (base) being
II,3 Pyridine N
ments carbon, readily extracted from tea with water and colchicine being soluble in H
H neutral or alkaline water. Again, some alkaloidal salts are II,9 Indole II,10 Indolizidine
few, such as either acid,
ygen-free and sparingly soluble—for example,1 quinine
2 sulphate is only soluble to the
N N
extent of 1 part in 10007 parts of water, although 1 part quinine hydro-
are, they are chloride is soluble in less thanNMe
1 part of3 water. N NH
N
lts of sangui- 6
N
5 4 N N
H
STRUCTURE
II,3 PiperidineANDII,4
CLASSIFICATION
Tropane II,5 Quinoline II,11 Imidazole II,12 Purine
ir salts is of
METABOLISM
ALKALOIDS
Table 26.1 Types of alkaloid and their occurrence.
I. Non-heterocyclic alkaloids
Hordenine or N-methyltyramine In germinating barley, Hordeum distochon
Mescaline, related to tryptamine (see formula) Lophophora williamsii (Cactaceae)
Ephedrine Ephedra spp. (Ephedraceae)
Colchicine (tropolone nucleus with nitrogen in side-chain) Colchicum spp. and related genera (Liliaceae)
Erythromycin (an antibiotic) Streptomyces erythreus (Bacteriophyta, Actinomycetales)
Jurubin (steroid with 3-amino group) Solanum paniculatum (Solanaceae)
Pachysandrine A (steroid with N-containing C-17 side-chain) Pachysandra terminalis (Buxaceae)
Taxol (a modified diterpene pseudo alkaloid) Taxus brevifolia (Taxaceae)
II. Heterocyclic alkaloids
1. Pyrrole and pyrrolidine
Hygrines Coca spp. (Erythroxylaceae); often associated with tropane alk
Solanaceae
Stachydrine Stachys tuberifera (Labiatae), soya bean and other Leguminosa
2. Pyrrolizidine
Symphitine, echimidine Symphytum spp.
Senecionine, seneciphylline, etc. Senecio spp.
I. Non-heterocyclic alkaloids
Hordenine or N-methyltyramine In germinating barley, Hordeum distochon
Mescaline, related to tryptamine (see formula) Lophophora williamsii (Cactaceae)
METABOLISM
Ephedrine
Colchicine (tropolone nucleus with nitrogen in side-chain)
Ephedra spp. (Ephedraceae)
Colchicum spp. and related genera (Liliaceae)
Erythromycin (an antibiotic)
ALKALOIDS
Jurubin (steroid with 3-amino group)
Streptomyces erythreus (Bacteriophyta, Actinomycetales)
Solanum paniculatum (Solanaceae)
2
Pachysandrine A (steroid with N-containing C-17 side-chain) Pachysandra terminalis (Buxaceae)
Taxol (a modified diterpene pseudo alkaloid) Taxus brevifolia (Taxaceae)
II. Heterocyclic alkaloids
1. Pyrrole and pyrrolidine
Hygrines Coca spp. (Erythroxylaceae); often associated with tropane alkaloids of the
Solanaceae
Stachydrine Stachys tuberifera (Labiatae), soya bean and other Leguminosae
2. Pyrrolizidine
Symphitine, echimidine Symphytum spp.
Senecionine, seneciphylline, etc. Senecio spp.
3. Pyridine and piperidine
Trigonelline Fenugreek (Leguminosae), strophanthus (Apocynaceae), coffee (Rubiaceae)
Coniine Conium maculatum (Umbelliferae)
Arecoline Areca catechu (Palmae)
Lobeline Lobelia spp. (Lobeliaceae)
Pelletierine Punica granatum, the pomegranate (Punicaceae)
Nicotine (pyridine + pyrrolidine) Nicotiana tabacum and other spp. (Solanaceae)
Anabasine Nicotiana glauca; Anabasis aphylla (Chenopodiaceae)
Piperine Piper spp. (Piperaceae)
Ricinine Ricinus communis (Euphorbiaceae)
4. Tropane (piperidine/N-methyl-pyrrolidine)
Hyoscyamine, atropine, hyoscine, meteloidine, etc. Species of Atropa, Datura, Hyoscyamus, Duboisia, Mandragora and
Scopolia (Solanaceae)
Arecoline Areca catechu (Palmae)
Lobeline Lobelia spp. (Lobeliaceae)
METABOLISM
Pelletierine
Nicotine (pyridine + pyrrolidine)
Anabasine
Punica granatum, the pomegranate (Punicaceae)
Nicotiana tabacum and other spp. (Solanaceae)
Nicotiana glauca; Anabasis aphylla (Chenopodiaceae)
ALKALOIDS
Piperine Piper spp. (Piperaceae)
Ricinine Ricinus communis (Euphorbiaceae)
4. Tropane (piperidine/N-methyl-pyrrolidine)
Hyoscyamine, atropine, hyoscine, meteloidine, etc. Species of Atropa, Datura, Hyoscyamus, Duboisia, Mandragora and
Scopolia (Solanaceae)
Calystegines Convolvulus spp., Ipomoea polpha (Convolvulaceae), some solanaceous
spp., Morus spp. (Moraceae)
Cocaine Coca spp. (Erythroxylaceae)
Pesudo-pelletierine Punica granatum (Punicaceae)
5. Quinoline
Quinine, quinidine, cinchonine, cinchonidine Cinchona spp. (Rubiaceae), Remijia spp. (Rubiaceae)
Cusparine Angostura or cusparia bark, Galipea officinalis (Rutaceae)
6. Isoquinoline
Papaverine, narceine, narcotine Papaver somniferum (Papaveraceae)
Corydaline Corydalis and Dicentra spp. (Fumariaceae)
Hydrastine, berberine Numerous genera of the Berberidaceae, Ranunculaceae and Papaveraceae
Emetine, cephaeline Cephaelis spp. (Rubiaceae)
Tubocurarine Curare obtained from plants of Menispermaceae
Morphine, codeine Papaver somniferum (Papaveraceae)
Erythraline Erythrina spp. (Leguminosae)
Galanthamine Leucojum aestivum (Amaryllidaceae)
7. Aporphine (reduced isoquinoline/naphthalene)
Boldine Peumus boldus (Monimiaceae)
Corydaline Corydalis and Dicentra spp. (Fumariaceae)
Hydrastine, berberine Numerous genera of the Berberidaceae, Ranunculaceae and Papaveraceae
METABOLISM
Emetine, cephaeline Cephaelis spp. (Rubiaceae)
Tubocurarine Curare obtained from plants of Menispermaceae
Morphine, codeine Papaver somniferum (Papaveraceae)
ALKALOIDS
Erythraline Erythrina spp. (Leguminosae)
Galanthamine Leucojum aestivum (Amaryllidaceae)
7. Aporphine (reduced isoquinoline/naphthalene)
Boldine Peumus boldus (Monimiaceae)
8. Quinolizidine
Sparteine, cytisine, lupanine, laburnine Sometimes called ‘the lupin alkaloids’. Occur particularly in the
Leguminosae, subfamily Papilionaceae, e.g. broom. Cytisus scoparius;
dyer’s broom, Genista tinctoria; Laburnum and Lupinus spp.
9. Indole or benzopyrrole
Ergometrine, ergotamine Claviceps spp. (Hypocreaceae)
Lysergic acid amide, clavine alkaloids Rivea corymbosa, Ipomoea violacea (Convolvulaceae)
Physostigmine Physostigma venenosum (Leguminosae)
Ajmaline, serpentine, reserpine Rauwolfia spp. (Apocynaceae)
Yohimbine, aspidospermine Aspidosperma spp. (Apocynaceae)
Vinblastine, vincristine Catharanthus roseus (Apocynaceae)
Calabash curare alkaloids Strychnos spp. (Loganiaceae)
Strychnine, brucine Strychnos spp. (Loganiaceae)
(Continued)
PHARMACOPOEIAL AND RELATED DRUGS OF BIOLOGICAL ORIGIN
METABOLISM
ALKALOIDS
Table 26.1 Types of alkaloid and their occurrence. (Cont’d)
10. Indolizidine
Castanospermine Castanospermum australe (Leguminosae), Alexa spp. (Leguminosae)
Swainsonine Swainsona spp. (Leguminosae), Loco plants (Leguminosae)
11. Imidazole or glyoxaline
Pilocarpine Pilocarpus spp. (Rutaceae)
12. Purine (pyrimidine/imidazole)
Caffeine Tea (Ternstroemiaceae), coffee (Rubiaceae), maté (Aquifoliaceae), guarana
(Sapindaceae), cola nuts (Sterculiaceae)
Theobromine Cocoa (Sterculiaceae)
13. Steroidal (some combined as glycosides)
Solanidine (glycoside = solanine) Shoots of potato (Solanaceae), etc.
Veratrum alkamine esters and their glycosides Veratrum spp. and Schoenocaulon spp. (Liliaceae)
Conessine Holarrhena antidysenterica (Apocynaceae)
Funtumine Funtumia elastica (Apocynaceae)
14. Terpenoid
Aconitine, atisine, lyctonine, etc. Aconitum and Delphinium spp. (Ranunculaceae)
procedures. In the plant, alkaloids may exist in the free state, as salts or the developing fruits. Oxidation–reduction involving N-oxides and ter-
as amine or alkaloid N-oxides. tiary bases is a probability. It has been suggested that N-oxides may be
involved in demethylations and their participation in the biosynthesis
METABOLISM
ALKALOIDS: ORNITHINE-DERIVED ALKALOIDS
N
Me
N
Nicotine
(Nicotiana spp.)
26 +
N COO
e
M
Me Me
+
ci d
Stachydrine
ica
tin
co
Ni
N Me C O
Me
+ 2[Me ]
Hygrine
HOOC NH2 NH2
CH2 C CH2
Ornithine
N Me O Me N
MeCOCH2COOH + Me Cuscohygrine
HOOC N
H 1
H
Proline N Me C Hyoscyamine,
5 OH hyoscine, etc.
Tropine
Acetate
NH2 NH2
COOH
Putrescine OH
N Me C Cocaine, etc.
H
Ecgonine
OH
OH
OH
N H C
H
Calystegine A3
HOH2C
Senecio alkaloids
N
Fig. 26.2
Some ornithine-derived alkaloids. Necine
isolations from S. porrigens see O. Muñoz and S. Cortés, Pharm.
Senecio1998,
alkaloids
36, 162, and from S. hookeri see M. Jordan et al., Phytochem
METABOLISM N 2006, 67 , 570. Other tropane bases occur in the Erythroxyl
(see cocaine in coca leaves), Convolvulaceae, Dioscorea
ALKALOIDS: TROPANE ALKALOIDS
Necine Rhizophoraceae, Cruciferae and Euphorbiaceae.
CH3
N
CH3 HO
Me Me CH3 N
N N H3C O
O
O H
O
OCO Ph OCO Ph
O
O
CH2OH CH2OH O CH3
Hyoscyamine, Atropine Hyoscine (Scopolamine) Schizanthine Z a tropandiol mesaconic acid diester
Altogether
These three specific alkaloids are confined to the Solanaceae, in over 200 tropane alkaloids have now been reco
Semisynthetic derivatives, e.g. hyoscine butylbromide (Buscopan
hich some 40 different ester bases of the tropane type have now been
of medicinal importance.
covered; they constitute an interesting chemotaxonomic study
other genera has become more evident and Japanese workers in enzymes were separately purified and characterized. Furthermore,
particular have employed species of Hyoscyamus and Duboisia with cDNA clones coding for the two separate enzymes TR-I and TR-II
METABOLISM
considerable success. have been isolated and shown to involve polypeptides containing 272
ALKALOIDS: TROPANE ALKALOIDS
Table 26.2 Examples of ester components of tropane alkaloids of the Solanaceae.
Genera of pharmaceutical interest Atropa, Acnistus, Scopolia, Physochlaina, Przewalskia, Hyoscyamus, Physalis, Mandragora,
Datura, Solandra, Duboisia, Anthocercis
Tropanol components of esters
R2 N R1 N R1
N CH3
R3 O
H H
OH
OH OH
R1 = H or CH3 H
R2 = H or OH Scopine: R1 = CH3
-Tropine
R3 = H or OH Norscopine: R1 = H
(Esterified with tiglic
(Tropine: R1 = CH3, (Esterified with tropic
acid only)
R2 = R3 = H) or atropic acid only)
Esterifying acids Acetic, propionic, isobutyric, isovaleric, 2-methylbutyric, tiglic, nonanoic, tropic,
atropic, 2-hydroxy- 3-phenylpropionic, 2,3-dihydroxy-2-phenylpropanoic,
p-methoxyphenylacetic, anisic
an arc of pericyclic fibres, above and below which is a considerable diastereomers, see E. Leete et al., Phytochemistry, 1988
amount of collenchyma. A surface preparation of the lower epidermis
METABOLISM
shows the papillae as well-marked circles, and numerous stomata (see
Fig. 42.2J), each with four subsidiary cells, two of which have their
Manufacture of cocaine. The crude alkaloids may be
dilute sulphuric acid or by treatment with lime and petr
ALKALOIDS:
long TROPANE
axes parallel to the pore. ALKALOIDS organic solvents. Non-alkaloidal matter is roughly
CH3 CH3
N COOH H
N
COOCH3 COOCH3
H5C6 H H C6H5
OCO.C6H5 OCO.CH:CH.C6H5
H COOH
Cocaine Cinnamylcocaine -Truxillic acid
(acidic moiety of -truxilline)
CH2.CO.CH3 CH2.CH.CH3 CH2.CO.CH2

N N N N
OH
CH3 CH3 CH3 CH3
Hygrine Hygroline Cuscohygrine

Fig. 26.9
Constituents of coca.
METABOLISM
SOURCE MATERIALS
It is imperative that correct identification of the source material is made.
Adulteration may be accidental, particularly if collection is made from wild plants, or it may be deliberate.
For the isolation of specific constituents, the source can vary

METABOLISM
DISTRIBUTION OF TISSUES
Phloroglucinol and hydrochloric acid. Mount the section in a 1% solution of phloroglucinol in ethanol (90%)
and allow to stand for about 2 min
Hydrochloric acid is a powerful clearing agent and it must be remem- bered that it will dissolve many cell
contents, including calcium oxalate.
Chlor-zinc-iodine solution. The reagent, often somewhat slowly, stains cellulose walls blue or violet, lignified or
suberized walls yellow or brown, and starch grains blue.
Solution of chloral hydrate. This dissolves starch, proteins, chlorophyll, resins and volatile oils, and causes
shrunken cells to expand.
METABOLISM
DISTRIBUTION OF TISSUES
Solution of potash. Solutions of potassium hydroxide, both aqueous and alcoholic, up to a strength of 50% are used
for different purposes, but for use as a clearing agent a 5% aqueous solution is most generally useful.
A 0.3% solution of potash may be used to dissolve aleurone grains. A 5% solution is much more powerful, and
rapidly dissolves starch, protein, etc., causing the swelling of cell walls.
Ether–ethanol. A mixture of equal parts of ether and ethanol (96%) is useful for the removal of fixed oils, fats,
resins, volatile oils, tannins or chlorophyll.
Solution of sodium hypochlorite. This solution is useful for bleach- ing dark-coloured sections such as those of
many barks and for removing chlorophyll from leaves.
Prolonged contact with solution of chlorinated soda causes the removal of starch and lignin, which may not be
desirable.
METABOLISM
DISINTEGRATION AND ISOLATION OF TISSUES
The use of reagents for purposes of disintegration is based on their action on the cell wall,
Woody tissues are usually disintegrated by means of oxidizing agents, as these oxidize away the middle
lamella, which is composed mainly of lignin
Thus, dilute nitric acid has a marked disintegrating effect on wood, whereas dilute sulphuric acid has not
The middle lamella of cellulose cells is composed of pectic substances which are made soluble by dilute
acids or dilute alkalis
METABOLISM
Pure celluloses, however, are resistant to hydrolysing and oxidizing agents, and the stability of cellulose in
boiling 5% potash is made use of for the separation of cotton from wool.
Other materials such as mannans, galactans, pectin, hemicelluloses, gums and lichenin, which may occur in
the cell wall, are much more readily attacked by hydrolysing agents.
METABOLISM
Potassium chlorate and nitric acid. The strength of the reagent and the time it is allowed to act must be
varied according to the nature of the material. For woods (e.g. quassia) the material, in small pieces or
thick sections, is immersed in 50% nitric acid. Minute quantities of potassium chlorate are added at
intervals to maintain an evolution of gas.
Chromic acid and nitric or sulphuric acid. The reagent usually consists of a mixture of equal parts of
10% chromic acid and 10% nitric or sulphuric acid. It is frequently used for the disintegration of
sclerenchymatous tissues
METABOLISM
Solution of potash or soda. As mentioned above, alkalis are used both for clearing and disintegrating. The
material is usually digested with 5% potash on a water-bath until the more resistant cells can be teased out
of the more or less completely disintegrated parenchyma. Potash is also useful for the isolation of lignified
elements such as are found in the veins of leaves, in senna stalks and in many barks.
Preparation of a crude fibre

Mix about 2 g of the drug, in No. 60 powder, with 50 ml of 10% nitric acid in a casserole. Bring to the boil
and maintain at the boiling point for 30s. Dilute with water and strain through a fine filter cloth held over
the mouth of a filter funnel. Transfer the washed residue to the casserole and boil for a further 30 s with 50
ml of a 2.5% solution of sodium hydroxide.

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METABOLISM

Monohydric aliphatic alcohols

Carnauba Wax BP which contains myricyl cerotate.

METABOLISM CH2OH CHO OH

Lignin Structure, Properties, and Applications

Scheme 2 Examples of chemical structures of acidolysis lignin

Scheme 3 Examples of chemical structures of hydrogenolysis of lignin

follows: 4-n-propylguaiacol (28), dihydroconiferyl alcohol (29), 4-n-propylsyringol

Frontiers in Plant Science | www.frontiersin.org 3

ROSELLE - Hibiscus sabdariffa - Flor de Jamaica

Phenolic compounds include anthocyanins involving

ROSELLE - Hibiscus sabdariffa - Flor de Jamaica

Phenolic compounds include anthocyanins involving

Tamarind pulp - Tamarindus indica

Flavonoids include luteolin-7-B-D-glucoside and the 7-B-D-rutinoside. H H

ARTICHOKE LEAF - Cynara scolymus - Alcachofa

DRUGS CONTAINING ACIDS, ALCOHOLS AND ESTERS

TOLU BALSAM - Myroxylon balsamum - Ortiga

and about 8% of free benzoic acid OCH3

Cinnamaldehyde Anethole Eugenol

The largest group of plant secondary metabolites

Phenolic compounds in this group often also possess

Glycoside formation is common, and the widely

VANILLA AND VANILLIN

lkaline solution. A petroleum spirit extract has a blue OH OMe OH

Many tannins are glycosides.

Ellagitannins: pomegranate rind, pomegranate bark, HO

Australian kinos, chestnut (Castanea spp.) and oak bark. OH

On treatment with acids or enzymes condensed A dimeric procyanidin

known as phlobaphenes. A trimeric procyanidin

2. Roots and rhizomes: krameria (rhatany) and male

Condensed tannins (proanthocyanidins)

Compound Additional groupings Occurrence

of the anhydride of sedanonic acid, the lactone of sedanolic 6 acid

Archangelicin: R1 = R2 = angeloyl Visnadin

10 CH2OH Aloesol derivative

Type Compound Nature Occurrence

CALENDULA FLOWER: Calendula officinalis OH O OH O

OR Rutin; R = rhamno-glucosyl MeO

OR Rutin; R = rhamno-glucosyl MeO

powderAnthocyanidins are flavonoids

Volatile or essential oils, as their name implies, are volatile in steam.

Volatile or essential oils, as their name implies, are volatile in steam.

Geraniol Citral Nerol Citronellol Linalool

Citronellal -Myrcene Limonene -Phellandrene -Terpineol

Menthol Menthone Carvone -Pinene Borneol

Camphor Cineole Thymol Sabinene Thujone

Cinnamaldehyde Anethole Eugenol

Name Botanical name Important constituents

Eugenol (up to 80%)

TERPENOIDS: VOLATILE OILS

CH3 CH3 CH3 H3C

Lycopene Nutraceutical Antioxidant Plant sources Major application(s)

Lycopene √ Tomato (Lycopersicon esculentum), spinach Cardiovascular health and cancer

Nutraceutical Antioxidant Source Typical constituents Major applications

CH3 CH3 H3C CH3

Steroid skeleton Pentacyclic triterpenoid skeleton

A distinct subgroup of the steroidal saponins is that of the steroidal

TERPENOIDS: SAPONINS, CARDIOACTIVE DRUGS AND OTHER STEROIDS