Transcript Estrogenic Steroids

Estrogenic Steroids
Overall Organization of the Topic
 Structure and nomenclature of natural estrogens
- Estradiol, estrone, and estriol
 Biosynthesis and metabolism of estradiol
 Synthetic estrogens
- Schuler’s hypothesis
 Estrogen antagonists
- clomiphene and tamoxifen
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Estrogenic Steroids
Structure and Nomenclature of Natural Estrogens
CH3 OH
CH3 O
CH3 OH
OH
HO
HO
Estradiol
intramuscular
100%
estr-1,3,5-triene3,17b-diol
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HO
Estrone
intramuscular
33%
3-hydroxy-estr-1,3,5
-triene-17-one
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Estriol
oral
1.6%
estr-1,3,5-triene3,16a,17b-triol
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Estrogenic Steroids
Physiological Activity of Natural Estrogens
•
•
•
Reproduction and development of female sex organs
Role in ovulation and pregnancy
Role in bone density modulation
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Biosynthesis and Metabolism of Estradiol
H3C
CH3
H3C
CH3
CH3
CH3
O
CH3
CH3
CH3
O
HO
HO
cholesterol
CH3 OH
pregnenolone
testosterone
CH3 OH
CH3 O
CH3 OH
OH
HO
HO
estriol
HO
estrone
estradiol
conjugation to glucuronides, sulfates, etc….
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Synthetic Estrogenic
Estradiol look-alikes
CH3 OH
HO
CH3 OH
O
HO
HO
HO
H3C
CH3 OH
CH3 OH
CH3 OH
CH3 OH
CH3
HO
OH
HO
HO
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CH3 OH
HO
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HO
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Synthetic Estrogenic
Diethyl-Stilbestrols (DES)
CH3 OH
C
H2C
CH
HO
RO
Ethinyl-estradiol R = H
Mestranol R = CH3
Cl
MeO
OH
CH2
Diethylstilbestrol
OMe
H3C CH
HO
OMe
Chlorotrianisene
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H3C
CH3
OH
C CH
3
H
Dienestrol
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Synthetic Estrogenic
Schuler’s Hypothesis for Synthetic Estrogens
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Synthetic Estrogenic
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Estrogen Antagonists
Triphenylethylene Derivatives – Partial Agonists
Cl
Cl
OCH2CH2 N(CH2CH3)2
CH3
R
OCH2CH2N(CH2CH3)2
OCH2CH2 N(CH2CH3)2
Zuclomiphene
Enclomiphene
Tamoxiphen
R=H
4-Hydroxy tamoxiphen R = OH
OMe
Cl
MeO
OMe
Chlorotrianisene
(estrogenic)
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Estrogen Antagonists
Estrogen Derivatives
CH3 OH
CH3 OH
HO
(CH2)10CON(CH3)(CH2)3CH3
HO
(CH2)9SO(CH2)3CF2CF3
ICI 182,780
ICI 164,384
Selective Estrogen Receptor Modulators (SERM) – tissue specific activity
O
O
N
N
O
OH
HO
S
HO
Nafoxidine
Raloxifene
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