Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico, D.F., Mexico.
Steroids. 2010 Jul;75(7):499-505. doi: 10.1016/j.steroids.2010.03.006. Epub 2010 Mar 30.
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.
本研究的目的是确定几种孕激素衍生物对 5α-还原酶 1 型和 2 型同工酶的抑制作用，并确定其与雄激素受体的结合。在 C-17 位含有乙酰氧基的 3,20-二氧孕甾-4-烯-17α-基乙酸酯 4 和在相同位置含有羟基的甾体 17α-羟孕甾-4-烯-3,20-二酮 5 抑制了两种同工酶。另一方面，在 C-4 位具有环氧功能的 17α-羟基-4,5-环氧孕甾-3,20-二酮 6 仅抑制 1 型酶。在 C-4 位具有共轭系统和 C-4 位上的氯或溴原子的甾体 4-氯-17α-羟孕甾-4-烯-3,20-二酮 7a 和 4-溴-17α-羟孕甾-4-烯-3,20-二酮 7b 抑制了两种 5α-还原酶。这些结果表明，A 环的电负性增加会产生对 5α-还原酶 1 型的主要抑制活性；然而，这种增加在 2 型酶中并未观察到。当 7a 或 7b 的游离羟基酯化时，得到 3,20-二氧-4-氯孕甾-4-烯-17α-基-4-乙基苯甲酸酯 8a 和 3,20-二氧-4-溴孕甾-4-烯-17α-基-4-乙基苯甲酸酯 8b；这些甾体仅抑制 5α-还原酶 2 型酶。非那雄胺和甾体 4、5、7b、8a 表现出相当的体内药理学活性，然而这些化合物的 IC50 值比非那雄胺高。这些结果还表明，甾体 4、5、7a 和 7b 与雄激素受体结合，而化合物 6、8a 和 8b 未能与雄激素受体结合。本研究的总体数据表明，甾体 5 和 7b 与 AR 结合并减少前列腺和精囊的生长。此外，4 还减少了精囊的生长。
