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STEROIDS

A PRESENTATION BYARGHA SEN

B.PHARM(3RD YEAR)ROLL NO.-19301910036REG. NO.-101930210006

DONE UNDER THE GUIDANCE OF Dr. JAYANTA CHATTERJEE

INTRODUCTION•Steroids are members of a large class of organic compounds occurring mostly in plants and animals.

•Steroids are characterized by the presence of 1,2 -cyclopentanophenanthrene nucleus in their structure.

Sources of SteroidsVitamin DBile acidsAdrenal Cortex and Sex HormonesCardioactive LactonesSapogeninsCertain alkaloids and antibiotics

Definition of SteroidsSteroids are compounds possessing the

skeleton of cyclopenta[α]phenanthrene or a skeleton derived there from by one or more bond scissions or ring expansions or contractions.

Steroids can also be defined as compounds which yields Diel’s hydrocarbon when distilled with Selenium 360 degree Celsius.

Definition of Steroids

CH3

Diel’s hydrocarbon

Properties of SteroidsThey have relatively flat and rigid

molecular framework.They have high crystalline properties.Enormous number of derivatives have

been produced.They are both hydrophobic and

lipophilic. They contain no fatty acidsCholesterol is the best known steroid,

occurs exclusively in animals.

Nomenclature of SteroidsGeneral Structure of Steroids is as follows:

Nomenclature of Steroids

There are four steroid skeletons present in the steroidal drugs; the gonane skeleton, the estrane skeleton, the androstane skeleton, and the pregnane skeleton.

The gonane skeleton is the simplest one. The C19 methyl group at C10 and the C18 methyl group at C13 are absent in this skeleton.

In estrane only the methyl group at C10 is missing.

In the androstane skeleton, both the methyl groups at the C10 and C13 positions are present.

In pregnane, an additional ethyl group in the β-position at C17 is present.

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1712

11

15

16

75

6

H

H1

4

2

3

H

H

H

H

13

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810

1712

11

15

16

75

6

CH318

CH319

1

4

2

3

H

H

H

H

13

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810

1712

11

15

16

75

6

H1

4

2

3

H

H

H

H

13

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810

1712

11

15

16

75

6

CH318

CH319

1

4

2

3

H

H

H

20 CH321

H

5-α- gonane

5-α- estrane

5-α- androstane

Pregnane

Stereochemistry of Steroids 8 dissimilar chiral centers. Number of possible isomers is 256. If the chiral center at C-20 was taken into

consideration then number of isomers would be 512.

Stereochemistry of Steroids

When the H-atom at C-5 is pointing towards the bottom side( i.e. it lies below the plane) it is indicated by 5α and it will be drawn by a hatched bond in the formula.

When the H-atom at C-5 is pointing towards the top side( i.e. it lies above the plane) it is indicated by 5β and it will be drawn by a thick wedge-shaped bond in the formula.

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17

12

11

15

16

75

6

20CH318

CH319

1

23

22

4

CH321

24

2

3

H

H

H

H25

CH327

CH326

H

13

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810

17

12

11

15

16

75

6

20CH318

CH319

1

23

22

4

CH321

24

2

3

H

H

H

H25

CH327

CH326

H

5β-cholestane

(Coprostane) 5α-cholestane

Stereochemistry of Steroids All naturally occurring steroids have either

‘cholestane’ or ‘coprostane’ configuration. In cholestane, the A and B rings, B & C rings , C & D

rings are in ‘trans’ configuration respectively. In coprostane, the A and B rings are in ‘cis’

configuration & B & C rings , C & D rings are in ‘trans’ configuration respectively.H

H

A B

H

HA B

Stereochemistry of Steroids Three dimensional structure of three most

common isomersCH3 H

HH

CH3

H

R

H

CH3 H

HH

CH3

H

R

H

trans-trans-transcis-trans-trans

CH3 H

HH

H

CH3R

H

cis-trans-cis

IDENTIFICATION OF STEROIDS

Steroids can be identified by one of the following methods:

1) Fourier transform Infrared spectroscopy(FT-IR), Gas Chromatography, Fourier transform Nuclear Magnetic Resonance (FT-NMR), TLC.

2) Four spot tests are performed: with sulphuric acid, napthol-sulphuric acid, Libermann & Buchard’s Test.

3) In Libermann and Buchard test steroid is reacted with acetic anhydride & H2SO4 which leads to the formation of a blue-green complex.

Steroid Hormones: Molecular Action

Biosynthesis of steroids

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17

1211

15

16

75

6

20CH318

CH319

1

22

4

2

3H

H

H

H

OH H OH

OHCH3

O

OH

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17

12

11

15

16

75

6

20CH318

CH319

1

23

22

4

24

2

3H

H

H

H25

CH327

CH326

OH

CH3

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17

12

11

15

16

75

6

20CH318

CH319

1

CH322

4

2

3H

H

H

H

OH

O

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810

17

12

11

15

16

75

6

20CH318

CH319

1

CH322

4

2

3H

H

H

H

O

O

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810

17

12

11

15

16

75

6

20CH318

CH319

1

22

4

2

3H

H

H

OH

O

O

OH

OH

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1712

11

15

16

75

6

OH20CH3

18

CH319

1

4

2

3H

H

H

O

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1712

11

15

16

75

6

OH20CH3

18

1

4

2

3H

H

H

OH

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1712

11

15

16

75

6

OH20CH3

18

1

4

2

3H

H

H

OH

OH

Aromatase

Pregnenolone

Cholesterol

Metabolism

Cholic Acid

Cortisol

Progesterone

Testosterone

Estradiol

16-α-hydroxylaseEstriol

Classification of SteroidsSTEROLS.GLUCOCORTICOIDS(GC’s):

Hydrocortisone, 11-Dehydrocorticosterone, Corticosterone.

MINERALOCOTICOIDS(MC’s): Aldeosterone, 11-Deoxy-corticosterone, 11-Deoxy-17-oxy-corticosterone.

CARDIAC GLYCOSIDES: Digitoxin, Digoxin. SEX HORMOMES:

1. MALE SEX HORMONES: Androsterone, Androstendion.

2. FEMALE SEX HORMONES: Oestrone, Progesterone.

Sterols Sterols are steroids carrying hydroxyl group at C-3

and most of the skeleton of cholestane. In most naturally occurring sterols the hydroxyl group at C-3 is in β-configuration(cis) i.e. it lies above the plane of the ring. E.g. cholesterol, ergosterol etc..

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17

12

11

15

16

75

6

20CH318

CH319

1

23

22

4

CH321

24

2

3H

H

H

H25

CH327

CH326

OH

H

HCholesterol

( cholest-5-en-3β-ol)

HORMONE SOURCE PHYSIOLOGICAL ACTION

THERAPEUTIC ACTION/USE

ANDROGENNATURAL:testosterone

Leydig cells of testis

Development and maitenance of masculine characteristics and secondary male sex characters

Parenteral:•testosterone•Testosterone propionate/ethanoate/cypionate

OTHER ANDROGENS

Oral:•Methyl testosterone•Danazole

Androsterone Byproduct of androgen breakdown, or derived from progesterone

Has some masculinising effects

Nandrolone

DHT(Dihydro-testosterone)

Metabolite of testosterone

More potent than testosterone as it binds more strongly to androgen receptors.

Androstanedione

Testis, adrenal cortex, ovaries

Metabolically converted to testosterone & other androgens.

BANNED BY IOC

Androstanediol

Steroidal metabolite

Main regulator of gonadotropin secretion

DHEA(dehydroepiandrosterone)

From Cholesterol in Adrenal cortex

Precursor of natural estrogens

Androgens( S.A.R.)

1)Esterification of 17-β hydroxyl group with carboxyl decreases polarity , and increases lipid solubility which in turn causes prolonged action.2)Alkylation of C-17 position (17-α) allows androgen to be effective orally as they are slowly catabolised by liver.

CH3

CH3

H

H

H

OH

O

C H 3M gB r

CH3

CH3

H

H

H

OH

OH

CH3

O p p an eu e r O x id a tion

CH3

CH3

H

H

H

O

OH

CH3

CH3

CH3

H

H

H

OH

OH

CH

O p p an eu e r O x id a tion

CH3

CH3

H

H

H

O

OH

CH

H C O O C 2H 5

C H 3O N a

CH3

CH3

H

H

H

O

OH

CHOH

N H 2O H

CH3

CH3

H

H

H

O

OH

CH

N

Dehydroepiandrostane

Lithium acetylide

17- Methyl Testosterone

DANAZOL

Synthesis of Various Synthetic Androgens



OESTROGEN Ovaries, follicles, Corpus leuteum, placenta

Found both in men and women.1)Development of secondary sexual characters in female

Oral contraceptives.Hormone receptor positive cancer(treated with estrogen receptor blocker)

NON-STEROIDAL(SYNTHETIC:Diethylstilbestrol

Secondary source: liver, adrenal glands

2) Regulate menstrual cycle

Ethinyl estradiol & Mestranol(prodrug)

Demethylation in liver

STEROIDAL

Oestrone Diethylstilbestrol

Oestriol

Oestradiol

Oestrogens( S.A.R.)

1)In 17-β oestradiol,oestrone,oestriol the ethynyl group at C-17 greatly increases oral potency.2)Esters get absorbed more slowly.

Synthesis of DiethylstilbestrolO CH3

O

O CH3

O CH3

O

O CH3

CH3

O CH3

O CH3

CH3 OHCH3

OH

OH

CH3

CH3

1,2-bis(4-methoxyphenyl)ethanoate

Ketone

Carbinol

Diethylstilbestrol(trans-α,β-Diethyl-4,4’-stilbendiol)

C2H5IC2H5ONa

C2H5MgBr

p-toluenesulphonic acidKOH



PROGESTERONE(C-21) STEROID HORMONE.

Ovary, adrenal gland, corpus luteum, placenta

Involved in menstrual cycle, pregnancy(supports gestation),prepares uterus for implantation

Used in Hormone receptor positive cancer.Used as Oral Contraceptives.

Normal menstrual bleeding is a Progesterone withdrawal

bleeding

To control ovulatory bleeding

S.A.R. of Progesterone.

1)Progesterone receptor favors a ∆4-3-one A ring in an inverted 1β,2α configuration.2)17-α hydroxyprogesterone is itself inactive but 17-α hydroxyprogesterone caproate is active.3)17-esters at C-6 of the B-ring yields orally active compounds.(medroxyprogesterone acetate, megestrol acetate).4) 19-Nor Compounds: ethynyl substituent at C-17 decreases hepatic metabolism and yields 19-nor testosterone analouges( norethindrone & norethynodrel) which are orally active.


THERAPEUTIC ACTION /USE

S.A.R

Glucocorticoid Adrenal cortex

1)Stimulates gluconeogenesis

1)Potent anti-inflammatory and immunosuppressive activity.

1)4-5 double bond & 3 keto group of ring A are essential for activity.

Mineralocorticoid/ Aldosterone

2) Stimulates fat breakdown in

adipose tissues.

2) Short – medium acting: hydrocortisone, prednisone, prednisolone.

2)11-β hydroxy group is required for GC and not for MC activity

3)Inhibits glucose uptake in muscles &

adipose tissue.

Intermediate acting: triamcinolone,fluprednisolone

3) A hydroxy group at C-21 is essential for MC & not for GC activity.

4)Maintains normal concentration of

glucose.

Long acting:Betamethasone, dexamethasone.

3) As Bronchodialator

4) Used in shock.

QUIZ ON STEROIDS1.Which of the following is not a parenteral androgen?

(A) testosterone (B) testosterone propionate (C) testosterone ethantate (D) methyl testosterone.

Answer:- (D) methyl testosterone. (oral)

2.Example of an aromatic ring containing steroid– estradiol

3)Drugs used in doping and banned by IOC- androstanedione, nandrolol, stanozol, methyl testosterone.

4)Which of the following is not a naturally occurring female hormone?

(a) oestradiol (b) oestriol (c) mestranol (d) oestrone

Ans:- (c) mestranol.

5) Oestrogen is synthesized from- Androstendione.

6) Structural feature important for both glucocorticoids and mineralo corticoids:- 3-keto group on Ring A.

7)The inactive derivative of progesterone is :- 17α-hydroxy progesterone.

8) The steroid metabolite that acts as main regulator of gonadotropin secretion is:- Androstendiol.

9) An orally active progestrine:- norethindrone.

10) The reagent for conversion of hydrocoetisone to cortisone acetate is:- Cr2O3

11)Example of aromatic ring containing steroid:- estradiol, estriol

12) 19 carbon atoms containing sex steroidal hormone:- Androgen

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