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Nomenclature of Steroids Number of Nuclear Positions and Steroid Classification C-27 skeleton … Cholestanes C-24 skeleton … Cholanes C-21 skeleton … Pregnanes.

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Presentation on theme: "Nomenclature of Steroids Number of Nuclear Positions and Steroid Classification C-27 skeleton … Cholestanes C-24 skeleton … Cholanes C-21 skeleton … Pregnanes."— Presentation transcript:

1 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

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

3 Female Sex Hormones (Estrogens and Progestins)  Control:  Follicle –Stimulating Hormone (FSH) stimulate the production of Estrogens.  Luteinizing Hormone (LH) stimulate the production of Progestins.

4 Estrogens Natural Estrogens: Excreted by human ovary Excreted by human ovary. It has 1/3 the effect of estradiol. It is the metabolite by oxidation of estradiol.

5 Physiological Effects Uses Birth control pills. Failure of ovarian development. Menstrual disturbances. Suppress lactation after birth. Postmenopausal osteoporosis. Prostate cancer. Side Effects Nausea, vomiting and diarrhea. Sodium and water retention. Inhibition of ovulation in large doses.

6 – Aromatic ring with C-3-OH is essential for activity. – Steroidal structures is not essential for activity. – Alkylation of the aromatic ring decrease the activity. – The 17  -hydroxyl with constant distance from 3-OH is essential for activity. – The group between the two hydroxyl must be hydrophobic. – Unsaturation of ring B decreases the activity. – 17  - and 16 position when modified enhance the activity. SAR

7 Steroidal Estrogenic Drugs Estradiol: – Most active natural estrogen. – Very short duration of action due to first pass metabolism. – Mainly used for local effect on the uterus. Ethinyl estradiol  ( 17-α-ethynylestradiol). – more potent than estradiol orally. Estra-1,3,5(10)triene-3,17-diol

8 Nonsteroidal Estrogens 1. Diethylstilbesterol: – The trans form is the active one. – Advantages: As active as Estradiol. Longer duration of action. Orally active Cheap. – Disadvantages: Increase the risk of uterine cancer. – Uses: Treatment of prostate cancer. Trans -diethylstilbene-4,4'-diol.

9 2.Chlortrianisene: Tris(p-anisyl)chloroethene. Active orally Nonsteroidal Estrogens

10 Xenoestrogens (Enviromental Estrogens) Estrogenic compounds with weak activity present in food and drinks. Isoflavones and coumestrol (Coumestan derivatives) present in family Leguminosae are examples of xenoestrogens.

11 Estrogen Antagonists Triphenylethylene antagonists: – They are related to stilbene in structure. – Antagonist bind strongly to the receptors. Aromatase inhibitors: – Steroidal or nonsteroidal. – Block conversion of androgens to estrogens. Uses: Treatment of estrogen dependent cancers.

12 12 1.Clomiphene (clomid) R = Cl It acts as ovulation stimulant by increasing gonadotrophin hormone (GRH). 50 mg dose for 5 days starting from 5 th day of menstruation If ovulation dose not occur, the dose is increased to 100 mg. 2. Tamoxifen (Nolvadex): R = CH 3 CH 2 -. Used in treament of early & advanced breast cancer in postmenopausal women. Antiestrogens Triphenylethylene antagonists

13 Progestins Progesterone is the major natural progestin. Secretion: By the ovary mainly the corpus luteum during the second half of the menstrual cycle. Physiological Effects: – Development of the endometrium. – Development of the mammary gland during pregnancy. – Milk secretion starts when its level decrease with birth. – Thermogenic action. Preg-4-ene-3,20-dione.

14 – Steroidal nucleus essential for activity. – Have some androgenic activity. – Removal of the 19 CH 3 increase activity. – Unsaturation of ring B or C increase the activity. – Removal of the keto function remove androgenic activity. SAR

15 Progestrogenic Drugs 1. Lynestrenol: – Semisynthetic progestin with pure progestrogenic activity.

16 Uses: Contraceptive pills. Uterine bleeding. Prevention of abortion. Amenorrhea, dysmenorrhea, endometriosis. Suppression of lactation. Endometrial, renal and breast carcinoma. Enhance respiration (for Hypoventilation). Side Effects: Nausea, vomiting, irregular bleeding, edema, weight gain, breakthrough bleeding, breast discomfort.

17 17 2. Medroxyprogestrone (provera) 17-α-acetoxy-6-α-methylpreg-4-ene-3,20-dione. Uses: Oral contercetptive. Progestrogenic Drugs

18 Progestin Antagonists 1. Mifepristone: – Compete with the progestin receptors. – Uses: Contraceptive. Abortifacient. 11-β-(p-dimethylaminophenyl)- 17-β-hydroxy-17-α-(1-propynyl)- estra-4,9-diene-3-one.

19 Male Sex Hormones (Androgens)  Control:  Luteinizing Hormone (LH) or Interstatial Cell-Stimulating Hormones (ICSH) stimulate the production of Androgens.

20 20 Androgenic Steroids – Physiological Activities Androgenic Activity Growth and development of male sex organs Important for male sex drive and performance Development of secondary sexual characteristics Important role in spermatogenesis Primarily two activities – Androgenic and Anabolic Anabolic Activity Development of muscle mass Reverse catabolic or tissue-depleting processes Side Effects: Sodium and water retention leads to edema. Masculinization of women. Hepatic dysfunction.

21 Natural Androgens:

22 22 Structure Activity Relationships in Androgens Generalizations Steroid skeleton is necessary An electronegative (may not be oxygen) at 3 position is required A/B ring fusion should be either trans or presence of a double bond at 4 position Alkyl group (CH 3 ) at 17-position is necessary for anabolic activity Alkyl group at 17- confers oral activity

23 23 1.Testosterone: 17-β-hydroxy-androst-4-ene-3-one In male: FSH stimulates sperm production LH stimulates secretion of testosterone. Medical Uses: 1.Treatment of hypogonadism {decreased functional activity of the gonads, thus resulting in lower amounts of testosterone}. 2.Androgens possess anabolic activity. 3.Treament of breast cancer in menopausal women. 4.Dysmenorrhea but of no advantage over Progestins & estrogens. Androgens & anabolic agents

24 Adverse effects of testosterone Virilization (female) Feminizing side effects (male) Precocious puberty (i.e early puberty) & stunted growth (reduced growth rate). Cholestatic jaundice Enlargement of prostate Atherosclerosis Hepatic carcinoma Oedema

25 Androgenic Drugs  -methyltestosterone: (17-β-hydroxy-17-α-methyl-androst-4-ene-3-one) – Orally active. – Prolonged action. – Androgenic and anabolic effects. * 3. Fluoxymestrone: 10 times more potent than testosterone.

26 Anabolic Steroids Class of steroid hormones related to the male hormone – testosterone Increase protein synthesis within cells which results in growth of muscle Also have androgenic properties which include the development and maintenance of males characteristics Have both medical and sport performance uses

27 Anabolic Steroids Anabolic Effects Two different, but overlapping effects Anabolic – promote cell growth. Increased protein synthesis, appetite, bone remodeling and growth, and production of red blood cells Increase the size of muscle fibers (hypertrophy) leading to increase in muscle mass and strength Decrease the amount of fat in muscle

28 Anabolic Steroids Androgenic Effects Androgenic (virilizing) - development and maintenance of male characteristics: Increased growth of pubic, beard, chest and limb hair Enlargement of vocal cords Suppression of natural sex hormones

29 Anabolic Steroids Adverse Effects Most side effects are dose dependent Elevated blood pressure (most common) Increase LDL cholesterol and decrease HDL Increase risk of CV disease and coronary artery disease, arrhythmias, and heart attacks (chronic use)

30 Anabolic Steroids Adverse Effects Accelerate the rate of premature baldness (male and female) Acne – stimulates the sebaceous glands Liver damage (cancer) – increased demand on liver as oral steroids are changed (increase bioavailability and stability)

31 Anabolic Steroids Adverse Effects Tendon rupture has been linked to AS Stiffer and less elastic tendon Probably tendon does not adapt as fast. Gynecomastia – development of breast tissue in males Conversion of testosterone to estrogen by an aromatase enzyme Temporary infertility (decreased production of sperm) Testicular atrophy (caused by decrease levels in natural testosterone)

32 Anabolic Steroids Behavioral Effects Controversial Mood swings Aggression (roid rage) Mania Depression Withdrawal Dependence

33 Anabolic Steroids Medical Uses Bone marrow stimulation – aplastic anemia Growth stimulation – use GH now Appetite stimulate – AIDS, cancer Induction of male puberty – extreme delay Reversible male contraceptive - future Hormone replacement therapy (men) Gender dysmorphia - psyciatric

34 Oral Anabolic Steroids 17-alpha methyl testosterone (Android) 17-alpha ethyl testosterone (Maxibolin) 1-methyl testosterone (Primobolan) Androstenediol (“Andro” food supplements) Androstenedione Dihydroepiandrosterone (DHEA)

35 Injectable Anabolic Steroids 19-nortesterone ester derivitives (Durabolin) Testosterone ester derivatives (Oreton) Testosterone cypionate derivatives (Virilon) Boldenone Stanozolol (Winstrol) oral form as well

36 36 Synthetic Anabolic Steroids: 1. Norethandrolone Orally active. Anabolic effects. C-10 CH 3 group removed eliminate androgenic effect. Stanozolol 2. Stanozolol Orally active. Anabolic effects.

37 37 3. Oxymetholone: 17-β-hydroxy-17-α-methyl-2-(hydroxy- methylene)androstan-3-one. Anabolic agents 4. Oxandrolone: 17-β-hydroxy-17-α-methyloxandrostan-3-one 5. Nandrolone: (nortestosterone) Used as ester (decanoate or phenylpropionate)

38 38 Structure Activity Relationships in Androgens Anabolic Androgenic Testosterone 1 1 (injectable) Testosterone 1 1 esters (injectable) R = COCH 2 CH 3 propionate = CO(CH 2 ) 5 CH 3 enanthate = COCH 2 CH 2 (C 5 H 9 ) cypionate

39 39 Structure Activity Relationships in Androgens Anabolic Androgenic 17-methyl Testosterone 1 1 (oral) Fluoxymesterone 1 1 (oral)

40 40 Structure Activity Relationships in Androgens Anabolic Androgenic Nandrolone (injectable) Oxymetholone (oral)

41 41 Structure Activity Relationships in Androgens Anabolic Androgenic Stanozolol 3 1 (oral) Dromostanolone 4 1 (oral)

42 Androgen Antagonists Androgen Receptor Antagonists: 1. Danazol * Weak androgenic, anabolic, progestational & glucocorticoid action 2. Cyproterone acetate: Has antiandrogenic and progestrogenic activity. Used for treatment of acne, hirsutism, prostate hypertrophy, prostate cancer and precocious puberty. 3. Flutamide: Non steroidal antiandrogen. Used for treatment of hirsutism and prostate cancer 4. 5  -Reductase inhibitors: – They prevent conversion of testosterone into dihydrotestosterone. – Used for treatment of Benign Prostatic Hyperplasia (BPH).

43 43 Androgens Antagonists Danazol (endometriosis) Finesteride ( 5  reductase inhibitors) (baldness) Cyproterone acetate (prostate cancer) Flutamide (prostate cancer)

44 Male Contraceptives Gossypol: – Is a phenolic compound present in cotton seed oil. – Decrease number of sperms and impairs their motility. – Its effect is reversible. – Side Effects: Hypokalemia, weakness, diarrhea and edema.

45 1,25-Dihydroxy Vitamin D3  1,25-dihydroxy Vitamin D3 is also derived from cholesterol and is lipid soluble  Not really a “vitamin” as it can be synthesized de novo  Acts as a true hormone

46 HO Vitamin D 3 Diet HO OH 25(OH) D 3 Liver 25-OHase OH HO OH 1,25(OH) 2 D 3 (active hormone form) Kidney 1-OHase HO 7 Provitamin D 3 (7-dehydrocholesterol: Intermediate in cholesterol synthesis) UV from sunlight Skin Photobiosynthesis of vitamin D 3 and its metabolism Specific receptors in intestine, bone, kidney Ca: Intestinal absorption Renal reabsorption PO 4 : Intestinal absorption Renal reabsorption OHase = hydroxylase

47 The hormonal interactions controlling bone mineral homeostasis

48 Actions of Vitamin D on Gut, Bone, and Kidney Vitamin D IntestineIncreased calcium and phosphate absorption by 1,25 (OH) 2 D KidneyCalcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH) 2 D 1 BoneIncreased calcium and phosphate resorption by 1,25(OH) 2 D; bone formation may be increased by 1,25(OH) 2 D and 24,25(OH) 2 D Net effect on serum levels Serum calcium and phosphate both increased

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