Exam 2: Lecture X, Medical Chemistry of Steroid Hormones I & II Flashcards
Glucocorticoids regulate
carb, lipid and protein metabolism
Mineralocorticoids regulate
salt balance and water balance
5a-cholestane is..
trans-trans-trans
5b-cholestane is…
cis-trans-trans
1,2-diaxial or 1,2-diequatorial is
trans
1,2-equatorial-axial. is…
cis
pregnenolone formation
cholesterol converted in adrenal gland by enzymatic cleave into pregnenolone
this is precursor of adrenocorticoids
this done by complex of enzymes…CYP11A1, Adrenodoxin and Adrenodoxin reductase
Hydroxylation of pregnenolone at position 17 by the enzyme
17A-hydroxylase
Oxidation of 17A-hydroxypregnenolone to the 3-keto intermediate by
3b-hydroxy steroid dehydrogenase followed by isomerization of double bond by enzyme 3-oxo steroid-4,5 isomerase
The final step in the biosynthesis catalyzed by the enzyme
11B-hydroxylase leads to formation of hydrocortisone, the most potent endogenous glucocorticoid secreted by the adrenal cortex.
Cortisone, the inactive metabolite is formed by the oxidation of
11B-hydroxy group of hydrocortisone by 11-hydroxy steroid dehydrogenase .
Hydrocortisone and cortisone are biochemically interconvertible by the
11B-hydroxysteroid dehydrogenase, with the reaction equilibrium towards hydrocortisone.
Functionalities important for superior glucocorticoid activity:
Carbonyl group at C-3.
C=C between C-4 and C-5.
C=O or b-OH at C-11.
b-ketol side chain at C-17.
Glucocorticoid activity is inversely proportional to the size of halogen at
C-9
9a-F (Fludrocortisone) is approximately 11 times more potent (for treatment of rheumatoid arthritis) than cortisone acetate. but also 300-800 times increase mineralocorticoid activity
Methhylprednisolone
More potent than predinisolone.
Has improved glucocorticoid activity
and reduced mineralocorticoid activity.
Note: 6a-F group also increases gluco-
coritcoid activity, but it has less minera-
ocorticoid activity than 9a-F function.
Prednisone
Increase in potency related to change in geometry of ring A
possesses more potent antirheumatic and anti-allergic activity than hydrocortisone and produces fewer undesirable side effects.
Triamcinolone
Inserting 16a-hydroxy group into 9a-fluoroprednisolone
Resulted in glucocorticoid activity equivalent to prednisolone but with decreased mineralocorticoid activity.
9F - improve anti inflammatory, prevent oxidation 11-OH
Hydroxy group in any position reduce sodium retention
All trans (B/C and C/D) ring fusion is required
activity
The 17b ketol (-COCH2OH) side chain and 4 -3 ketone function are found in
clinically used adrenocorticoids and these groups do contribute to the potency.
Insertion of a double bond between 1 and 2 in hydrocortisone increases
glucocorticoid activity and longer half-life
The 9a-F group increases
glucocorticoid activity and nearly prevents metabolic oxidation of the 11b-OH group to a ketone.
The 6a-F also increases glucocorticoid activity, but it has less effect than the 9a-F on
sodium retention
Highly active naturally occurring mineralocorticoids have no
OH function in position 11/17
Conversion of 17a-hydroxy to either a 17a-ester or an ether with 16a, 17a- isopropylidenedioxy (acetonide) greatly enhances the
anti-inflammatory potency
Cortisle induce production of….
lipocortin
LH induces….
luteinization which leads to formation of corpus luteum which is responsible for the biosynthesis and secretion of progesterone.
Estradiol has…
phenol at 3, OH at 17
Progesterone has…
double bond O at 3, ketone at 17
Testosterone has….
Double bond O at 3, OH at 17
Estrone:Estradiol Premenopausaul women
1:2
Estrone:Estradiol Postmenopausal women
2:1
Placenta primary location of estrogen biosynthesis during…
pregnancy
Estrogen biosynthesize in maturing….
dominant follicle and corpus lute in premenopausal women
Estradiol key role in…
development of secondary sex characteristics
stimulation of mammary glands during pregnancy
thermoregulatory capacity
Estradiol admin orally….
conjugated and oxidatively metabolized in liver = poor bioavail and therapeutic effectiveness
Enterohepatic recycling Ethinyl Estradiol
bacteria in GI track hydrolyze the glucuronide and sulfate conjugates, permitting reabsorption of EE….main reason for antibacterial agents to have adverse effects on oral contraceptive efficacy
SAR Estradiol
Aromatic Ring A and Hydroxyl group at C-3 essential for estrogenic activity
Enlargement of ring D greatly reduces estrogenic activity
Introduction of unsaturation into ring B boosts estrogenic potency
modification of 17a/16 position can lead to enhanced activity
adding hydroxyl group at 6/7/11 reduces activity
removal of oxygen function from 3/17 or epimerization 17b-OH = decrease activity
distance between 2 OH groups, 17B-OH group important for full estrogenic activity
11b sub well tolerated, 11b-methoxy/ethyl analog sig greater activity for receptor
Impeded estrogens
interact with ER in target tissue but dissociate from receptor too rapidly to produce any strong estrogenic effect
classical impeded estrogen is estriol
Antiestrogens
Triphenylethylene analogs exhibit strong and persistent binding to the estrogen receptor, producing antiestrogen-receptor complex which is unable to produce an estrogenic response.
Clomiphene citrate
has both esterogenic and antiesterogenic properties (partial agonist) and is used to induce ovulation for the treatment of infertility.
Tamoxifen
is an estrogen agonist-antagonist (partial agonist) that is used in the treatment of estrogen-dependent breast cancer. Metabolism of tamoxifen produces active metabolite 4-hydroxytamoxifen
Inhibitors of aromatase will….
block the conversion of androgens to estrogens and thus have therapeutic potential in the control of reproductive functions and in the treatment of estrogen dependent cancers such as breast cancer.
competitive inhibitors of aromatase will….
selectively inhibit the conversion of testosterone to estrogens in all tissues.
Anastrazole and other triazoles inhibit the aromatase enzyme by binding of the
N-4 nitrogen of the triazole ring with the heme iron atom of the CYP19 enzyme complex.
Anastrazole and letrozole are used for the treatment of advanced breast cancer in postmenopausal woman with disease progression following tamoxifen therapy.
Progesterone Metabolism
rapidly metabolized by liver and mainly excreted as glucuronide and sulfate conjugates of 5b-pregnanediol.
also 6a-hydroxylation (CYP3A4)
and reduction of 20-ketone to alcohol by dehydrogenase
premature drop of what may be a warning of possible miscarriage
glucuronide conjugate of 5b-preganediol
Substituents at what position hinder 6-hydroxylation of progestins, increase their lipohilicity and result in enhanced biologic effect?
C6
further enhanced when double bond introduced between position 6-7
Removal of what group on steroids results in activity equal to or greater than that of parenterally admin progesterone
C19 methyl
antiprogestin
is a compound that antagonizes the actions of progesterone by competing for its receptor, would be an important agent for interfering with the early phases of pregnancy.
Mefepristone
