STRUCTURE AND SYSTEMATIC NOMENCLATURE OF STEROIDS

Steroids are derivatives of the perhydrocyclopentanophenanthrene ring system

Male Sex Hormone Female Sex Hormone Congested Heart Symptoms Examples of Steroid-based Drugs in Use Today Male Sex Hormone Female Sex Hormone Congested Heart Symptoms Anti-inflammatory Agent

Fusion points between rings Configurational Isomers of Steroids Fusion points between rings A B A B trans- configuration cis- configuration

Fusion points between rings Configurational Isomers of Steroids Fusion points between rings A B C D 3 fusion points  23 isomers = 8

α substituents: groups that lie on the bottom. In most steroids the B, C and C, D ring junctions are trans. The A, B ring junction may be either cis or trans. Angular methyl groups: The methyl groups that are attached at points of ring junction β substituents: other groups that lie on the same general side of the Molecule as the angular methyl groups. α substituents: groups that lie on the bottom.

When α and β designation are applied to the hydrogen atom at position 5,the ring system in which the A, B ring junction is trans become the 5 α series; and the ring system in which the A, B ring junction is cis becomes the 5 β series. In systematic nomenclature of the R group at position 17 determines the base name of an individual steroid.

Three dimensional structure of three most common isomers Configurational Isomers of Steroids Three dimensional structure of three most common isomers trans-trans-trans cis-trans-trans trans-trans-trans cis-trans-trans cis-trans-cis cis-trans-cis

Number of Nuclear Positions and Steroid Classification Nomenclature of Steroids Number of Nuclear Positions and Steroid Classification C-27 skeleton … Cholestanes C-24 skeleton … Cholanes C-21 skeleton … Pregnanes C-19 skeleton … Androstanes C-18 skeleton … Estranes

Usage of ‘Nor’ terminology Nomenclature of Steroids Usage of ‘Nor’ terminology C-27 skeleton … Cholestanes 18-Nor C-27 skeleton … 18-nor cholestane C-19 skeleton … Androstanes 19-Nor C-19 skeleton … 19-nor androstane

The absolute stereochemistry of the molecule and any substituents is shown with solid (β) and dashed (α) bonds Most carbons have one bond and one bond, with the bond lying closer to the “top” or C18 and C19 methyl side of the molecule. Both -α andβ -substituent's may be axial or equatorial.

The stereochemistry of the H at C5 is always indicated in the name The stereochemistry of the H at C5 is always indicated in the name. The stereochemistry of the other H atoms is not indicated, unless it differs from 5-cholestane All hydrogen's along the backbone should be drawn. When the stereochemistry is not known, a wavy line is used in the drawing. Methyl's are explicitly indicated as CH3.

The terms cis and trans are occasionally used in steroid nomenclature to indicate the backbone stereochemistry among rings. For example, 5 α steroids are A/B trans, and 5- β steroids are A/B cis. The terms syn and anti are used analogously to trans and cis for indicating stereochemistry in bonds connecting rings (e.g., the C9:C10 bond that connects rings A and C).

Double bonds from C8 may go toward C9 or C14, and those from C20 may go toward C21 or C22. In such cases, both carbons are indicated in the name if the double bond is not between sequentially numbered carbons (e.g., 5-androst-8(14)-ene or 5-8(14) androstene

The symbol often is used to designate a carbon–carbon double bond (C==C) in a steroid. If the C==C is between positions 4 and 5, the compound is referred to as a C4-steroid. If the C==C is between positions 5 and 10, the compound is designated a C5(10)-steroid.

STEROID BIOSYNTHESIS Steroid hormones in mammals are biosynthesized from cholesterol, which in turn is made in vivo from acetyl-coenzyme A (acetyl-CoA) via the mevalonate pathway. Conversion of cholesterol to pregnenolone is the ratelimiting step in steroid hormone biosynthesis. It is not the enzymatic transformation itself that is rate limiting; however, the translocation of cholesterol to the inner mitochondrial membrane of steroid-synthesizing cells is rate limiting

HSD =hydroxysteroid dehydrogenase

CLASSIFICATION five categories depending solely on the type of substituent group at C-17, i.e., group R.

(i) Sterols—where R is an aliphatic side chain (i) Sterols—where R is an aliphatic side chain. They contain usually one or more hydroxyl groups attached in alicyclic linkage. (ii) Sex Hormones—where R bears a ketonic or hydroxyl group and mostly possesses a twocarbon side chain. (iii) Cardiac Glycosides—where R is a lactone ring. The glycosides also contain sugars linked through oxygen in other parts of the molecule. Normally on hydrolysis it yields this sugar together with the cardiac aglycone.

(iv) Bile Acids—where R is essentially a five-carbon side chain ending with a carboxylic acid moiety. (v) Sapogenins—where R contains an oxacyclic (ethereal) ring system.

Sex hormones

Functional Classification of Steroids Anabolic Steroids - Interact with androgen receptor; enhance muscle mass/athlete’s performance; male sex hormones Glucocorticoids - regulate metabolism and immune function; anti-inflammatory activity Mineralocorticoids - maintain blood volume and renal excretion Progestins - Development of female sex organs and characteristics Phytosteroids - Plant steroids Ergosteroids - Steroids of the fungi; vitamin D related

Adrenocorticoids Or Cortocosteroids

corticosteroids refers to steroid hormones secreted by the adrenal cortex Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

Glucocorticoids, are endogenous compoundswhich regulate carbohydrate, lipid, and protein metabolism Mineralocorticoids, are endogenous compounds which influence salt balance and water retention Adrenal androgens, which have weak androgenic activity in men and women and can serve as precursors to the sex hormones, estrogens and androgens.

Glucocordicoids : The various salient features are (1) Affect all cells, but not all to the same extent and manner. (2) Prime activity rests upon their anti-inflammatory and immunosupressant effects. (3) Mainly check and prevent release of the host of ‘lytic enzymes’ which cause tissue damage during all inflammation and eventually give rise to leukotactic substances (4) Minimise phagocytosis by macrophages. (5) Decrease lipid eicosanoid and prostaglandin (PG) generation by inhibiting the production of cytokines which specifically induce cycloxygenase-II in inflammatory cells.

Mineralocorticoids : The cardinal salient features are They especially exert their action upon the distal tubules and collecting ducts of the kidney to enhance specifically the expression of genes which help in encoding the proteins that increase reabsorption of Na+ from the tubular fluids.

Overall effect upon the electrolytes are intimately linked with an appreciable increment in the number of Na+ and K+ channels strategically located in the luminal membrane tubular cells ; and hence, they in turn enhance distinctly the activity of the basolateral membrane Na+/K+-activated ATPase. The ultimate result being a region of Na+ to the systemic circulation in exchange for K+.

‘electrolyte effects’ are duly promoted by the mineralocorticoids in a host of other tissues viz., colon, salivary glands, and sweat glands. primary effects of mineralocorticoids’ are adequately observed upon the cortical collecting tubule cells strategically positioned in the kidneys to enhance substantially sodium reabsorption vis-a-vis potassium secretion.

This eventually leads to an elevated aldosterone titer values that actually governs, controls, and monitors effectively sodium retention and potassium depletion thereby giving rise to volume expansion and weight gain, metabolic alkalosis, and hypertension.

All corticosteroids are derivatives of cyclopentanophenanthrene with keto-groups at C3 and C20 and an unsaturated bond between C4 and C5 (indicated as Δ4), and the presence of an axial β-CO-CH2OH side chain at C17, which is absolutely necessary. They differ from one another in the presence of a keto- or β-hydroxyl group at C11, as well as on C17 and/or C18. These differences determine the major pharmacological properties of these drugs and their precursors.

Structure Activity Relationship of Corticosteroids

Why SAR of Corticosteroids? Chemical modifications leads to generation of derivatives with Greater separation of glucocorticoid & mineralocorticoid activity Different potency & duration of action

Cyclopentanoperhydrophenanthrene nucleus

Structural features All contain 21 carbon atoms. Steroid nucleus α,β substitution

All require 3 keto group and 4,5 unsaturation

Glucocorticoid activity requires 11 β hydroxyl(OH) group

Mineralocorticoid activity requires Hydroxyl group at C21 on ring D

Natural Glucocorticoids Cortisone and Hydrocortisone (cortisol), which are biochemically interconvertible

Changes that glucocorticoid activity Additional double bond b/w 1 & 2 carbon atoms Alpha methylation at 6th position Alpha fluorination at 9th position Substitution at 16th position

Additional unsaturation of Ring A Slow metabolism increase in GC activity Enhance antiinflammatory effect glucocorticoid/ mineralocorticoid potency ratio Salt retaining activity

Additional unsaturation of Ring A

6 α substitution on Ring B Increase GC activity Unpredictable effects 6 α methyl cortisol - GC & MC activity 6 α methyl prednisolone - GC & MC

9 α fluorination of Ring B Enhances GC & MC activity

Fluorination at 9 and substituent at 17 Resistant to local destruction

6α-Fluorination Fluocinolide 6α-fluoro has less salt retention properties than 9α-fluoro. Fluocinolide

9α-chlorination 9α-chloro derivative of betamethasone Beclomethasone dipropionate Increase stabilization Increase lipophilicity Increase bronchial tissue absorption Increase duration of action.

Substitution at C16 on ring D More GC activity & anti inflammatory activity Eliminates MC activity

17 α hydroxyl group on ring D IMPORTANT FOR GC ACTIVITY

17 α ether or ester Enhance anti inflammatory potency and glucocorticoid receptor affinity Triamcinolone acetonide more potent

Lipophilicity & topical/systemic potency ratio Acetonide b/w OH groups at C16 & C17 Esterification of OH groups with Valerate at C17 Esterification of OH groups with propionate at C17 & C21 Substitution of OH group at C21 with Chlorine

Acetonide b/w OH groups at C16 & C17

Relative potencies & equivalent doses Compound Anti-inflammatory potency Na+ retaining potency DOA Equivalent dose Cortisol 1 S(‹12 hr) 20 Prednisolone 4 0.8 I(12-36h) 5 6α -methyl prednisolone 0.5 I Triamcinolone Betamethasone 25 L(›36hr) 0.75 dexamethasone L Fludrocortisone 10 125

21 hydroxylation is essential for MC

changes that alters mineralocorticoid activity Aldehyde group in the C18 Fluorination at the 9α position on ring B 6α substitution on ring B Substitution at C16 on ring D

Aldehyde group in the C18

Fluorination at the 9α position on ring B Increases MC activity Ex: Fludrocortisone 6α substitution on ring B Unpredictable effects 6α methyl cortisol – increase MC activity 6α methyl prednisolone – decrease MC activity

Substitution at C16 on ring D Eliminates MC activity Ex: betamethasone , dexamethasone

Summary Essential features for superior GC activity: - C=O at C3 - a double bond bet. C4 &C5 11 β hydroxyl group on ring C Additional double bond b/w 1 & 2 carbon atoms Alpha methylation at 6th position Alpha fluorination at 9th position Substitution at 16th position

Summary Aldehyde group in the C18 changes that alters mineralocorticoid activity Aldehyde group in the C18 Fluorination at the 9α position on ring B 6α substitution on ring B Substitution at C16 on ring D