Medicinal Chemistry of Steroidal Harmons Classification of Steroidal Harmons Medicinal Uses Biosynthesis of Steroidal Harmons Mechanism of action of Steroidal Harmons Natural and Synthetic derivatives of Steroidal Harmons and their Inhibitors

1. Steroidal
Harmons
DR. NAGA PRASHANT KOPPURAVURI, M.PHARM, PH.D, FAGE.,
ASSISTANT PROFESSOR,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

2. Your best quote that reflects your
approach… “It’s one small step for
man, one giant leap for mankind.”
- NEIL ARMSTRONG

3. Cyclo pentane

4. cyclopentanoperhydrophenanthrene

5. • Steroids consist of four fused rings (A, B, C, and D) .
• Steroids are hydrocarbons with a cyclopentane (D) ring attached to a
saturated phenanthrene.
• Note that the angular methyl groups are numbered 18 (attached to C13)
and 19 (attached to C10).
• The steroid structure has two planes: the top or β surface which points
upward and the bottom or α surface pointing downward

6. • Steroid hormones: produced in the adrenal cortex, testis, ovary, and some
peripheral tissues (adipose tissue, the brain!)
• All steroid hormones share a typical (but not identical) ring structure.
• Despite similarities, each class of steroids demonstrates unique and
distinctively different biologic activities.
• Steroids are considered rigid ring structures

7. Functions of Steroid Hormones
• Steroid hormones play important roles in:
‐ carbohydrate regulation (glucocorticoids)
‐ mineral balance (mineralocorticoids)
‐ reproductive functions (gonadal steroids)
• Steroids also play roles in inflammatory responses, stress
responses, bone metabolism, cardiovascular fitness, behavior,
cognition, and mood.

8. 5α - Gonane

11. Sites of Steroid Synthesis

12. DHEA= Dehydroepiandrosterone
DHEAS= DHEA sulphate
Bio-Synthesis of Steroidal hormones from Cholesterol

13. (a) adrenodoxin reductase, (b) 17αhydroxylase, (c) 5-ene-3β-hydroxysteroid dehydrogenase, (d) 3-oxosteroid-4,5-isomerase, (e)
17β-hydroxysteroid dehydrogenase type 5, (f) aromatase, and (g) estradiol dehydrogenase.

14. Progestrone
17αhydroxylase
Progesterone
Dehydroepiandrostero
ne

16. • Estrogens; including estradiol and estrone
• Glucocorticoids; cortisol is the major representative in most mammals
• Mineralocorticoids; aldosterone being most prominent
• Androgens; such as testosterone
• Progestogens; (also known a progestins) such as progesterone

17. Estrogens
• The active endogenous estrogens are estradiol, estrone, and estriol.
• Estradiol provides the greatest estrogenic activity, with less activity for
estrone, and the least activity with estriol.
• The estrogens are synthesized by the action of the enzyme aromatase
on androstenedione or testosterone.
• They are normally produced in relatively large quantities in the ovaries
and the placenta, in lower amounts in the adrenal glands, and in trace
quantities in the testes.

18. • In postmenopausal women, most estrogens are synthesized in adipose
tissue and other nonovarian sites. About 50 to 350 g/d of estradiol are
produced by the ovaries (especially the corpus luteum) during the
menstrual cycle.
• During the first months of pregnancy, the corpus luteum produces
larger amounts of estradiol and other estrogens; the placenta produces
most of the circulating hormone in late pregnancy.
• During pregnancy, the estrogen blood levels are up to 1,000 times
higher than during the menstrual cycle.

24. THERAPEUTIC USES OF
ESTROGENS
Birth Control
Hormone Replacement Therapy.
Treatment of Estrogen Deficiency from Ovarian Failure or after
Oophorectomy.
Cancer

25. Selective estrogen receptor modulators (SERMs) and antiestrogens.

28. Compounds that can antagonize the ER have been of great interest for
the treatment of estrogen dependent breast cancers. Tumor biopsies
have shown ER to be present in about 60% of primary breast cancers,
and most are responsive to estrogen blockade. Unfortunately, most of
these ER-related breast cancers also develop resistance to antiestrogen
therapy within 5 years.

29. Aromatase
inhibitors

30. Aromatase is a cytochrome P450 enzyme complex that catalyzes
the conversion of androstenedione to estrone and testosterone
to estradiol. In premenopausal women, aromatase is primarily
found in ovaries, but in postmenopausal women, aromatase is
largely in muscle and adipose tissue.

31. • The key endogenous steroid hormone that acts at the PRs is progesterone. All
other endogenous steroids lack significant progestational action.
• Progesterone is produced in the ovaries, testes, and adrenal glands. Much of the
progesterone that is synthesized from pregnenolone is immediately converted to
other hormonal intermediates and is not secreted.
• The corpus luteum secretes the most progesterone, 20 to 30 mg/d during the last
or “luteal” stage of the menstrual cycle. Normal men secrete about 1 to 5 mg of
progesterone daily.
• Progesterone has a half-life of only about 5 minutes when taken orally, because of
rapid metabolism.
Progestins

32. THERAPEUTIC USES OF PROGESTINS
• Birth Control.
• Reduction of the Risk of Endometrial Cancer from Postmenopausal Estrogens
• Primary and Secondary Amenorrhea and Functional Uterine Bleeding Caused by
Insufficient Progesterone Production or Estrogen–Progesterone Imbalance
• Breast or Endometrial Carcinoma
Progestin therapy may cause menstrual irregularities, such as spotting or amenorrhea.
Weight gain and acne have been associated with testosterone and 19-nortestosterone
analog, in part because of their slight androgenic effects.

34. Natural and synthetic progestins

38. Progesterone receptor antagonists

39. Ovulation Inhibitors and Related Hormonal Contraceptives

44. Endogenous Androgens
• Testosterone and its more potent reduction product 5-DHT are produced in
significantly greater amounts in males than in females, but females also produce low
amounts of these “male” sex hormones.
• These endogenous compounds have two important activities:
• androgenic activity (promoting male sex characteristics) and
• anabolic activity (muscle building).
• Testosterone and DHT cause pronounced masculinizing effects, even in the male
fetus.
• They induce the development of the prostate, penis, and related sexual tissues.
• At puberty, the secretion of testosterone by the testes increases greatly, leading to
an increase in facial and body hair, deepening of the voice, increased protein
anabolic activity and muscle mass, rapid growth of long bones, and loss of some
subcutaneous fat.

45. Testosterone and synthetic anabolic androgenic steroids.

47. Androgens and Sports
• The use of androgens for their anabolic effects (hence the term anabolic steroids) by
athletes began in the late 1940s and has, at times, been widespread.
• Prior to urine testing requirements, it was estimated that up to 80% of competitive
weight lifters and about 75% of professional football players used these drugs, along with
various other athletes.
• Despite the growing awareness of the dangers of anabolic steroid use over the past 20
years, abuse of steroids is still a problem in many competitive sports.

48. Some of the specific risks associated with the use/abuse are
In both sexes
• Increased risk of coronary heart disease, stroke, or obstructed blood vessels
Increased aggression and antisocial behavior (known as “steroid rage”) Liver tumors,
peliosis hepatis (blood-filled cysts), and jaundice (for 17-alkylated androgens only)
In men
• Testicular atrophy with consequent sterility or decreased sperm count and abnormal
motility and morphology Impotence Enlarged prostate Breast enlargement (for
androgens that can be converted to estrogens)
In women
• Clitoral enlargement Facial and body hair growth Baldness Deepened voice Breast
diminution

49. Antiandrogens

50. 5-DHT is important for maintaining prostate function in men. The formation of DHT is mediated by 5-
reductase
Inhibition of 5-Reductase

51. Endogenous Corticosteroids
The adrenal glands (which lie just above the kidneys) secrete over 50 different steroids,
including precursors for other steroid hormones. The most important hormonal steroids
produced by the adrenal cortex, however, are aldosterone and hydrocortisone.
Aldosterone is the primary MC in humans (i.e., it causes significant salt retention).
Hydrocortisone is the primary GC in humans (i.e., it has its primary effects on
intermediary metabolism). The GCs have become very important in modern medicine,
especially for their anti-inflammatory effects. Aldosterone and, to a lesser extent, other
MCs maintain a constant electrolyte balance and blood volume. The GCs have key roles in
controlling carbohydrate, protein, and lipid metabolism.
The adrenocortical steroids permit the body to adjust to environmental changes, to
stress, and to changes in the diet. Aldosterone and, to a lesser extent, other MCs
maintain a constant electrolyte balance and blood volume, and the GCs have key roles in
controlling carbohydrate, protein, and lipid metabolism.

52. Natural and synthetic corticosteroids.

57. Ophthalmic glucocorticoids.

58. Glucocorticoids used to treat asthma and allergic rhinitis (some are also used topically).

60. Aldosterone receptor antagonists.