1. STRUCTURE AND SYSTEMATIC NOMENCLATURE OF STEROIDS

2. Steroids are derivatives of the perhydrocyclopentanophenanthrene ring system

3. 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

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

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

6. 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.

7. 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.

8. 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

9. 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

11. 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

15. 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.

16. 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.

17. 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).

18. 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

19. 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.

20. 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

22. HSD =hydroxysteroid
dehydrogenase

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

24. (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.

25. (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.

26. Sex hormones

27. 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

28. Adrenocorticoids Or Cortocosteroids

29. 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.

30. 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.

31. 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.

32. 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.

33. 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+.

34. ‘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.

35. 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.

36. 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.

37. Structure Activity Relationship of Corticosteroids

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

39. Cyclopentanoperhydrophenanthrene nucleus

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

41. All require 3 keto group and 4,5 unsaturation

42. Glucocorticoid activity requires
11 β hydroxyl(OH) group

43. Mineralocorticoid activity requires
Hydroxyl group at C21 on ring D

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

46. 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

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

48. Additional unsaturation of Ring A

49. 6 α substitution on Ring B
Increase GC activity
Unpredictable effects
6 α methyl cortisol GC & MC activity
6 α methyl prednisolone - GC & MC

50. 9 α fluorination of Ring B
Enhances GC & MC activity

51. Fluorination at 9 and substituent at 17
Resistant to local destruction

52. 6α-Fluorination Fluocinolide
6α-fluoro has less salt retention properties than 9α-fluoro.
Fluocinolide

53. 9α-chlorination 9α-chloro derivative of betamethasone
Beclomethasone dipropionate
Increase stabilization
Increase lipophilicity
Increase bronchial tissue absorption
Increase duration of action.

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

55. 17 α hydroxyl group on ring D
IMPORTANT FOR GC ACTIVITY

56. 17 α ether or ester
Enhance anti inflammatory potency and glucocorticoid receptor affinity
Triamcinolone acetonide
more potent

57. 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

58. Acetonide b/w OH groups at C16 & C17

59. 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

60. 21 hydroxylation is essential for MC

61. 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

62. Aldehyde group in the C18

63. 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

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

65. 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

66. 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