Molecular interactions of progesterone derivatives with 5 alpha-reductase types 1 and 2 and androgen receptors.
The aim of this study was to ascertain the inhibitory effect of several progesterone derivatives for 5 alpha-reductase types 1 and 2 isozymes and to determine the binding to the androgen receptor. The 3,20-dioxopregna-4-ene-17 alpha-yl acetate 4 containing an acetoxy group in C-17 and steroid 17 alpha-hydroxypregn-4-ene-3,20-dione 5 having a hydroxyl group in the same position inhibited both isozymes. On the other hand, 17 alpha-hydroxy-4,5-epoxypregnan-3,20-dione 6 with an epoxy function at C-4, inhibited only the type 1 enzyme. Steroid 4-chloro-17 alpha-hydroxypregn-4-ene-3,20-dione 7a and 4-bromo-17 alpha-hydroxypregn-4-ene-3,20-dione 7b having the C-4 conjugated system and a chlorine or a bromine atom at C-4 respectively, inhibited both types of 5 alpha-reductase. These results indicate that an increase in the electronegativity of ring A produces a major inhibitory activity for 5 alpha-reductase type 1; however this increase was not observed for type 2 enzyme. When the free hydroxyl group of 7a or 7b was esterified, compounds 3,20-dioxo-4-chloropregn-4-ene-17 alpha yl-4-ethylbenzoate 8a and 3,20-dioxo-4-bromopregn-4-ene-17 alpha yl-4-ethylbenzoate 8b were obtained; these steroids inhibited only the 5 alpha-reductase type 2 enzyme. Finasteride and steroids 4, 5, 7b, 8a showed a comparable in vivo pharmacological activity, however the IC(50) values of these compounds were higher as compared to that of finasteride. These results indicated also that steroids 4, 5, 7a, and 7b bind to the androgen receptor whereas compounds 6, 8a and 8b failed to do so. The overall data from this study showed that steroids 5 and 7b bind to the AR and decreased of the growth of prostate and seminal vesicles. Moreover, 4 decreased also the growth of seminal vesicles.
Bratoeff
Eugene
E
Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico, D.F., Mexico.
García
Perla
P
Heuze
Yvonne
Y
Soriano
Juan
J
Mejía
Adriana
A
Labastida
Ana María
AM
Valencia
Norma
N
Cabeza
Marisa
M
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001667:Binding, Competitive; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D011374:Progesterone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D012669:Seminal Vesicles / Q000187:drug effects / Q000254:growth & development
D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011944:Receptors, Androgen; D011374:Progesterone; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase