nomenclature of steroids number of nuclear positions and steroid classification c-27 skeleton …...
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Nomenclature of Steroids
Number of Nuclear Positions and Steroid Classification
CH3
CH3
C-27 skeleton… Cholestanes
CH3
CH3
C-24 skeleton… Cholanes
CH3
CH3
C-21 skeleton… Pregnanes
CH3
CH3
C-19 skeleton… Androstanes
CH3
C-18 skeleton… Estranes
Nomenclature of Steroids
Usage of ‘Nor’ terminology
CH3
CH3
C-27 skeleton… Cholestanes
CH3
CH3
C-19 skeleton… Androstanes
CH3
18-Nor C-27 skeleton… 18-nor cholestane
CH3
19-Nor C-19 skeleton… 19-nor androstane
Female Sex Hormones(Estrogens and Progestins)
Control: Follicle –Stimulating Hormone (FSH) stimulate the production of Estrogens.
Luteinizing Hormone (LH) stimulate the production of Progestins.
Estrogens• Natural Estrogens:
HO
OH
OH
HO
O
HO
OH
17-estradiol Estrone Estriol
CH3OH
OH
12
3
4 5 67
8
910
1112
13
1415
1617
18
Excreted by human ovaryExcreted by human ovary.It has 1/3 the effect of estradiol.It is the metabolite by oxidationof estradiol.
Physiological EffectsUses• 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.
– 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 17b-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.– 17a- and 16 position when modified enhance the activity.
SARCH3OH
OH
12
3
4 5 67
8
910
1112
13
1415
1617
18
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).– 15- 20 more potent than estradiol orally.
HO
OHC CH
HO
OH
17-estradiol Ethinyl estradiol(Stertoidal Semisynthetic estrogen)Estra-1,3,5(10)triene-3,17-diol
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.
OH
HO
OH
OH
CH3OH
OH
4.5A
4.5A
Trans -diethylstilbene-4,4'-diol.
Cl
OMe
OMe
MeO
2.Chlortrianisene:Tris(p-anisyl)chloroethene.Active orally
Nonsteroidal Estrogens
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.
O
OH
OH
HO
O
Genisten
O
OHO
O
Coumesterol
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.
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1.Clomiphene (clomid)R = ClIt acts as ovulation stimulant by increasing gonadotrophin hormone (GRH).50 mg dose for 5 days starting from 5th day of menstruationIf ovulation dose not occur, the dose is increased to 100 mg.
2. Tamoxifen (Nolvadex):R = CH3CH2-.Used in treament of early & advanced breast cancer in postmenopausal women.
R
O CH2
CH2
N
CH2CH3
CH2CH3
AntiestrogensTriphenylethylene antagonists
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.
O
O
Preg-4-ene-3,20-dione.
– Steroidal nucleus essential for activity.– Have some androgenic activity.– Removal of the 19 CH3 increase activity.– Unsaturation of ring B or C increase the activity.– Removal of the keto function remove androgenic
activity.
SARO
O
Progestrogenic Drugs• 1. Lynestrenol:
– Semisynthetic progestin with pure progestrogenic activity.
O
O
Progesterone(Natural)
OH
Lynestrenol(Synthetic)
C CH
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.
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2. Medroxyprogestrone (provera)17-α-acetoxy-6-α-methylpreg-4-ene-3,20-dione.
Uses: Oral contercetptive.
CH3
CH3
CH3
O
O
OCOCH3
CH3
Progestrogenic Drugs
Progestin Antagonists
• 1. Mifepristone:– Compete with the progestin receptors.– Uses:
• Contraceptive.• Abortifacient.
CH3OH
O
N
CH3
CH3CH3
11-β-(p-dimethylaminophenyl)-
17-β-hydroxy-17-α-(1-propynyl)-
estra-4,9-diene-3-one.
Male Sex Hormones(Androgens)
Control:
Luteinizing Hormone (LH) or Interstatial Cell-Stimulating Hormones (ICSH) stimulate the production of Androgens.
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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.
• Natural Androgens:
O
OH
Testosterone(Natural)
O
OH
Dihydrotestosterone(Natural)
H
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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 (CH3) at 17a-position is necessary for anabolic
activity• Alkyl group at 17a- confers oral activity
CH3
OH
O
CH3
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1.Testosterone: 17-β-hydroxy-androst-4-ene-3-one
In male:FSH stimulates sperm productionLH 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
CH3
CH3
OH
O
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
Androgenic Drugs• 2. 17 a-methyltestosterone: (17-β-hydroxy-17-α-methyl-androst-4-ene-3-one)
– Orally active.– Prolonged action.– Androgenic and anabolic effects.
O
OH
17-Methyltestosterone(Semisythetic)
CH3
CH3
CH3
OH
O
CH3
F
OH
* 3. Fluoxymestrone: 10 times more potent than testosterone.
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
Anabolic SteroidsAnabolic 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
Anabolic SteroidsAndrogenic 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
Anabolic SteroidsAdverse 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)
Anabolic SteroidsAdverse 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)
Anabolic SteroidsAdverse 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)
Anabolic SteroidsBehavioral Effects
• Controversial• Mood swings• Aggression (roid rage)• Mania• Depression• Withdrawal• Dependence
Anabolic SteroidsMedical 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
Oral Anabolic Steroids
• 17-alpha methyl testosterone (Android)
• 17-alpha ethyl testosterone (Maxibolin)
• 1-methyl testosterone (Primobolan)• Androstenediol (“Andro” food
supplements)• Androstenedione• Dihydroepiandrosterone (DHEA)
Injectable Anabolic Steroids• 19-nortesterone ester derivitives (Durabolin)• Testosterone ester derivatives (Oreton)• Testosterone cypionate derivatives (Virilon)• Boldenone• Stanozolol (Winstrol) oral form as well
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O
OH
Norethandrolone(Sythetic-Pure anabolic)
C2H5
Synthetic Anabolic Steroids:1. Norethandrolone
Orally active.Anabolic effects.C-10 CH3 group removed eliminate androgenic effect.
CH3
OH
O
CH3
Stanozolol
2. Stanozolol Orally active.Anabolic effects.
CH3
OH
N
CH3CH3
NH
H
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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)
CH3OH
O
O
CH3
CH3
OH
O
CH3
CH3
CH3
OH
O
CH3
CH
OH
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Structure Activity Relationships in Androgens
CH3
OH
O
CH3
Anabolic Androgenic
Testosterone 1 1(injectable)
CH3
OR
O
CH3
Testosterone 1 1esters (injectable)
R = COCH2CH3 propionate
= CO(CH2)5CH3 enanthate
= COCH2CH2(C5H9) cypionate
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Structure Activity Relationships in Androgens
CH3
OH
O
CH3CH3
Anabolic Androgenic
17a-methylTestosterone 1 1(oral)
CH3
OH
O
CH3OH
FFluoxymesterone 1 1(oral)
CH3
OH
O
CH3
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Structure Activity Relationships in Androgens
Anabolic Androgenic
Nandrolone 2.5 1(injectable)
H
OH
O
CH3
CH3
OH
O
CH3CH3
OH
H
Oxymetholone 2.5 1(oral)
CH3
OH
O
CH3
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Structure Activity Relationships in Androgens
Anabolic Androgenic
Stanozolol 3 1(oral)
Dromostanolone 4 1(oral)
CH3
OH
N
CH3CH3
NH
H
CH3
OH
O
CH3
H
CH3
CH3
CH3
OH
O
CH3
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. 5a-Reductase inhibitors:– They prevent conversion of testosterone into dihydrotestosterone.– Used for treatment of Benign Prostatic Hyperplasia (BPH).
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Androgens Antagonists
NH
CF3
O
CH3
NO2
CH3
O
CH3
CH3OH
CH
N
CH3
CH3
NH
O
O
NH
CH3CH3
CH3
HDanazol
(endometriosis)Finesteride (5 reductase inhibitors)
(baldness)
Cyproterone acetate(prostate cancer)
Flutamide(prostate cancer)
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.
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
HO Vitamin
D3
Diet
HO
OH
25(OH) D3
Liver
25-OHase
OHHO
OH
1,25(OH)2 D3
(active hormone form)
Kidney1-OHase
HO
7
Provitamin D3
(7-dehydrocholesterol: Intermediate in cholesterol synthesis)
UV fromsunlight
Skin
Photobiosynthesis of vitamin D3 and its metabolism
Specific receptors in intestine, bone, kidney
Ca:Intestinal absorptionRenal reabsorption
PO4:Intestinal absorption Renal reabsorption
OHase = hydroxylase
The hormonal interactions controllingbone mineral homeostasis
Actions of Vitamin D on Gut, Bone, and Kidney Vitamin D Intestine Increased calcium and phosphate absorption by 1,25
(OH)2D
Kidney Calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D1
Bone Increased calcium and phosphate resorption by 1,25(OH)2D; bone formation may be increased by 1,25(OH)2D and 24,25(OH)2D
Net effect on serum levels
Serum calcium and phosphate both increased