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342
Pharmaceutical Chemistry of Natural Products
Modification in ring A
1. Contraction of ring A to norcortisol yields an inactive compound.
2. Ring A can be modifi ed isosterically to a heterocycle like 2-oxacortisol acetate, which has
25% activity of the cortisol.
3. The introduction of unsaturation (a double bond) at C-1 leads to enhanced anti-infl ammatory
activity (e.g. betamethasone), while the addition of –OH group makes the compound
inactive.
4. The introduction of a 2α-methyl group into cortisol leads to increase in activity. The C-2
bromo substituent is potent among the halogens.
5. The C-3 carbonyl group can be fused with a heterocyclic moiety to yield a soft drug. C-3-
spirofused thiazolidine derivative (1) was found to be active and this derivative considerably
reduced the thinning of the skin, a characteristic feature generally found in corticosteroids.
(1)
HO
N
OAc
O
OH
H
CH
52
CH
25
OOC
S
6. The Δ
4
double bond is important but not essential for anti-infl ammatory activity (e.g. 5-α-
pregnane-3-one is more active than cortisone).
O
CH OH
2
CO
OH
F
H
HO
O
O
CH
3
O
O
O
CH
3
CH
3
CH OP(OK)
22
O
Cortisone
5 -Pregnane-3-one␣
7. Ring A can be fused with a pyrazole ring. Compound (2) has 2000 times the potency of
cortisol, but lacks mineralocorticoid activity.
Steroids and Hormones
343
F
HO
N
OH
O
N
OH
(2)
Modification in ring B
1. Substitution of 6α-position with hydrophobic groups like alkyl or halogens (methyl, chloro
and fl uoro) leads to increase in activity.
2. Polar substituents such as –OH or =O at 6α-position decrease the activity.
3. 7α- and 7β-substituents decrease the anti-infl ammatory activity. Thus, 7α- and 7β- methyl
cortisol derivatives are less potent than cortisol.
4. Introduction of –OH group at both 6α- and 7α-position leads to decrease in activity.
5. 6α- and 7α-difl uoromethylene and 6β- and 7β-derivatives show enhanced activity.
6. Introduction of 8(9) double in prednisolone affords compound with lower anti-infl ammatory
activity.
O
HO
CH
2
OH
CO
OH
Prednisolone
7. Anti-infl ammatory potency of corticosteroids is drastically infl uenced by the substituents at
the C-9 position. The groups added include –F, –Cl, –Br, –I, –OH and –CH
3
. The activity of
the compounds increases with increasing hydrophobic bonding of the C-9α-substituents.
The function of the electron withdrawing group at C-9 was to increase the acidity of the
neighbouring 11β-hydroxy group which in turn leads to increase in corticoid activity.
8. Removal of the C-19 angular –CH
3
group reduces anti-infl ammatory activity.
9. The H at C-10 should be in β-confi guration for the optimal activity.
344
Pharmaceutical Chemistry of Natural Products
Modification in ring C
1. The C-11 oxygen group is not essential for anti-infl ammatory activity. It can be replaced by
groups such as –Cl, which can be converted to the hydroxyl group in vivo.
2. Ester substituents at C-12 have showed anti-infl ammatory activity and the potency is in the
following order: propionyl > butyl > isovaleryl.
Modification in ring D
1. Methyl group at C-15 with α-confi guration enhances anti-infl ammatory activity.
2. Placement of 16α-hydroxy and 17α-hydroxy groups yields potent compounds. These two
groups may also form acetonide derivatives, which are more potent than the corresponding
16,17-dihydroxy derivatives.
3. At C-16 position, introduction of chloro, methyl groups increases activity.
4. The 17α-OH group is not essential for activity. Ketals and esters yield compounds with
improved potency.
5. Introduction of –Cl, –Br, –F at C-17α position lowers the activity.
Modification in the side chain at C-17
1. Acetonide derivatives across the 17,20-diol arrangement resulted in more potent analogues
compared to free diols.
2. Hydroxyethanone side chain attached at C-17 in the classical corticosteroid is not essential
for activity. Tipredane, a 17-thioketal is a potent topical anti-infl ammatory drug.
O
Tipredane
HO
SCH
3
SC H
25
F
3. Retaining anti-infl ammatory activity of corticosteroids is observed upon ketalization of the
C-20 carbonyl group with ethylene glycol.
4. Replacement of the –OH group at C-21 by –Cl or –F enhances activity.
5. Replacement of the C-21 carbon by sulphur (fl uticasone) afforded 21 thioesters, which are
also useful clinically.
O
Fluticasone
O
F
F
FH CS
2
O—C—C H
25
O
CH
3
HO
Steroids and Hormones
345
6. Replacement of –CH
2
OH group with an aldehyde (3) leads to compound with some systemic
absorption.
O
O
HO
OHC
OCOC H
65
(3)
7. The C-21 –OH group can be esterifi ed to afford lipophilic compounds which are meant for
repository use.
8. Introduction of activating groups at C-21 and conversion of –CH
2
OH group to a –CH
3
group
(medrysone) yield clinically useful ophthalmic anti-infl ammatory compound with relatively
little effect on intraocular pressure.
O
O
CH
3
Medrysone
PROBABLE QUESTIONS
1. What are steroids? Enumerate the steroids of biological importance with their chemical structure and mention their
signifi cance.
2. Describe the important reactions used in the determination of the structure of cholesterol.
3. Describe the nomenclature of steroids with the suitable examples.
4. Write a note on stereochemistry of steroids.
5. What are steroids? Describe the relationship between sterols and bile acids.
6. Write a note on the chemistry of bile acids.
7. Classify progesterone derivatives used in pharmacy.
346
Pharmaceutical Chemistry of Natural Products
8. Sketch the following transformation:
a. Cholesterol and testosterone
b. Dehydroepiandrosterone to progesterone
c. Ergosterol to progesterone
9. Classify oestrogen derivatives used in pharmacy.
10. Write the interrelation between oestrone, oestriol and oestradiol.
11. Write a note on the chemistry of cortisone and outline its synthesis.
12. Outline the synthetic route leading to the formation of the following:
a. Oestradiol
b. Progesterone
c. Testosterone
d. Cortisone
e. Stilboestrol
13. What are hormones? Classify them with suitable examples and write the synthesis of testosterone.
14. Describe the structure–activity relationship of progesterones.
15. Write a brief note on the following:
a. Steroidal alkaloids
b. Cardiac glycosides
16. Write a note on synthetic anabolic androgenic steroids.
17. Outline the synthesis of androsterone.
18. How will you establish the structure of cholesterol by degradation?
19. Describe the structure–activity relationship of androgens.
20. Outline the following conversions:
a. Oestrone to oestriol
b. Anethole to diethylstilboestrol
c. Oestrone to oestradiol
d. Oestrone to 17α-ethinylestradiol
e. Diethylstilboestrol to dienoestrol
21. Outline the synthetic route leading to the synthesis of testosterone or progesterone.
22. Outline the following conversions:
a. Cholesterol to testosterone
b. Cholesterol to dehydroepiandrosterone
c. Cholesterol to aldosterone
23. Describe the structure–activity relationship of oestrogens.
24. Classify corticosteroids with suitable examples.
25. Outline the synthesis of cortisone.
Steroids and Hormones
347
SUGGESTED READINGS
Bhatnagar, A et al. (ed) (1997). Fourth International Anrnatase Conference. J Steroid Biochem Mol Biol 61: 107–426.
Block, JH and Beale, JM (2004). Wilson Gisvold’s Text book of Organic Medicinal and Pharmaceutical Chemistry, 11th Ed.
Lippincott Williams and Wilkins, New York.
British Pharmacopoeia Commission (2008). British Pharmacopoeia. Medicines and Healthcare Products Regulatory Agency,
London.
Brown, GD (1998). Biosynthesis of steroids and triterpenoids. Nat Prod Rep 15: 653–696.
Bruntan, LL, Lazo, JS and Parker, KL (2006). Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, 11th Ed.
McGraw-Hill Inc., New York.
Cook, JW (1953). Progress in Organic Chemistry, Vol 2. Academic Press, 212.
Fieser, Huang-Minlon, J Am Chem Soc 71: 1840.
Gennaro, AR (2006). Remington: The Science and Practice of Pharmacy, 21st Ed. Lippincott Williams and Wilkins, New
York.
Gilman, H (1943). Organic Chemistry: An Advanced Treatise, Vol 2. Wiley, New York, 1172 M.
Government of India (1996). Indian Pharmacopoeia. Ministry of Health and Family Welfare, New Delhi.
Guo, JZ, Hahn, DW and Wachter, MP (1995). Kirk–Othmer Encyclopedia of Chemical Technology, Vol 13, 4th Ed. Wiley, New
York, pp. 481–512.
Jarman, M et al. (1998). Inhibitors of enzymes of androgen biosynthesis, cytochrome P45017α and 5α-steroid reductase. Nat
Prod Rep 24: 495–512.
Klyne, W (1957). The Chemistry of Steroids. Methuen, London.
Lednicer, D and Mitscher, LA (1995). The Organic Chemistry of Drug Synthesis. John Wiley and Sons, New York.
Lemke, TL and William, DA (2008). Foye’s Principle of Medicinal Chemistry, 6th Ed. Lippincott Williams and Wilkins, New
York.
Litwack, G and Kritchevsky, D (1964). Actions of Hormones on Molecular Processes. John Wiley & Sons Inc., New York.
Petrow, V (1992). A History of Steroid Chemistry, Part I. Steroids 57: 354–418.
Petrow, V (1992). A History of Steroid Chemistry, Part II. Steroids 57: 578–657.
Pincus, G, Thimann, KV and Astwood, EB (eds) (1964). The Hormones, Vol 4. Academic Press, London and New York, 67.
Reynolds, EF (ed) (1997). Martindale the Extra Pharmacopoeia, 31st Ed. The Pharmaceutical Press, London.
Russell, DW and Setchell, KDR (1992). Bile acid biosynthesis. Biochemistry 31: 4737–4749.
Shoppee, CW (1958). Chemistry of the Steroids. Academic Press, New York.
Spitz, IM and Agranat, I (1995). Antiprogestins: modulators in reproduction. Chem Ind 3: 89–92.
Stewart, AW and Graham, H (1948). Recent Advances in Organic Chemistry, Vol 3. Longmans, Green and Co.
Wainwright, M (1998). The secret of success. Chem Brit 34 (1): 46–47 (prednisone and prednisolone).
West and Todd (1597). Text Book of Biochemistry, 80.
Wolff, ME (1995). Burger’s Medicinal Chemistry and Drug Discovery, 5th Ed. John Wiley & Sons Inc., New York.
Zeelen, FJ (1990). Medicinal Chemistry of Steroids. Elsevier, Amsterdam.
INTRODUCTION
The term ‘ terpene’ was derived from the German word terpentin and applied to a mixture of
isomeric hydrocarbons of the molecular formula C
10
H
16
occurring in turpentine and other essential
oils. The oxygenated derivatives of these hydrocarbons like alcohols, aldehydes, ketones were
called camphors. When terpenes are modifi ed chemically, the resulting compounds are known as
terpenoids.
To cover all the compounds of the empirical formula C
5
H
8
and their oxygenated derivatives
(called camphors of the earlier time), the term terpenoids is used now. Therefore, the term terpene
is only limited to a class of terpenoids called monoterpenes, which have the molecular formula of
(C
5
H
8
)
2
, while the term camphor is limited to an individual compound of terpenoid.
Thus, the term terpene represents only the hydrocarbons of the molecular formula (C
5
H
8
)
2
and
the term terpenoids represent the hydrocarbons of plant origin of the general formula (C
5
H
8
)
n
as
well as their oxygenated, hydrogenated and dehydrogenated derivatives.
Most terpenoids are optically active. Thermal decomposition of terpenoids yields isoprene as
one of the products. Terpenoids have one or more double bonds; hence they are easily oxidized
and undergo addition reaction with hydrogen, halogens, hydrogen halides, nitrosyl bromide, etc.
Some of the terpenoids having conjugated system of double bonds undergo Diels–Alder reaction.
Terpenes are actually derived from isoprene units which are linked in ‘head-to-tail’ fashion.
‘Head’ refers to the branched end of isoprene unit.
CCC C C C C C
Head Tail Head Tail
Isoprene unit Isoprene unit
C C
Terpenoids
7
CHAPTER
350
Pharmaceutical Chemistry of Natural Products
Terpenoids comprise the largest class of plant secondary metabolites and are colourless,
pleasant smelling liquids or solids, insoluble in water and readily volatile in steam. The biosynthetic
building blocks of terpenoids are derived from mevalonic acid, which is biosynthetically obtained
from acetyl-CoA. Geranyl pyrophosphate acts as a key intermediate in the biosynthesis of about
40 terpenoids. Biogenesis of terpenoids is depicted in Figure 7.1.
Acetyl CoA
Acetoacetyl CoA
HMG-CoA
Mevalonic acid
IPP
DMAPP
GPP
Monoterpenoids
(C compounds)
10
FPP
Sesquiterpenoids
(C compounds)
15
X C 0PP
23
Squalene
Sterols
GGPP
GFPP
Diterpenoids
(C compounds)
20
Carotenoids
(C compounds)
40
Polyterpenoids
(Containing more than
C or eight isoprene units)
40
Sesterpenoids
(C compounds)
25
IPP
DMAPP
GPP
FPP
GGPP
: Isopentenyl
pyrophosphate
: Dimethyl allyl
pyrophosphate
: Geranyl pyrophosphate
: Farnesyl pyrophosphate
: Geranyl geranyl
pyrophosphate
Figure 7.1 General metabolic pathway of isoprenoids
Terpenoids are sometimes called isoprenoids, as they are composed of isoprene units. Terpenoid
hydrocarbons are multiples of C
5
H
8
[(e.g. myrcene (C
10
H
16
)], having the carbon skeleton dividable
into two isoprene units.
Terpenoids
351
CH
2
C
HC
2
HC
2
CH
CH
2
CH
C
HC
3
CH
3
Myrcene
Due to their pleasant smell, terpenoids are used in pharmaceutical industries as fl avouring
agents, in pharmaceutical dosage forms, as well in perfumery and cosmetic industry as perfumes.
The biological activity of terpenoids includes antiseptic, insecticidal and anthelmintic properties,
and hence they are useful in pharmacy. Many of the plants containing terpenoids are used as
traditional remedies for the treatment of various ailments.
Nomenclature: Terpenoids are known by their trivial names and these trivial names are assigned
on the basis of their botanical source. For example, khusinol is an alcohol obtained from kush oil
(which in turn is obtained from vetiver oil).
Occurrence
The pleasant smell of the fruits is due to the presence of certain volatile oils known as essential
oils. These oils are complex mixtures of hydrocarbons and their oxygenated derivatives (e.g. oil of
bitter almond contains benzaldehyde and oil of wintergreen contains methyl salicylate). Among
Table 7.1 Important essential oils and their terpenoid constituents
Essential oil Constituent terpenoid
Caraway Limonene, carvone
Camphor Camphor
Sweet orange d-Limonene
Cardamom Terpineol
Clove Eugenol
Coriander
α-Pinene, linalool
Citronella Farnesol, citronellal, geraniol
Eucalyptus Cineole
Geranium Geraniol esters, citronellol
Ginger Zingiberene
Jasmine Linalool
Lavender Linalool
Lemon
d-Limonene, citral
Peppermint Menthol
Rose Geraniol, citronellol and farnesol