Numazawa M, Oshibe M
Tohoku College of Pharmacy, Sendai, Japan.
Steroids. 1995 Aug;60(8):506-11. doi: 10.1016/0039-128x(95)00058-x.
To gain further insight on the relationship between 6-alkylandrost-4-ene-3,17-diones and their aromatase inhibition activity, a series of alkyl steroids with long alkyl chains (n-pentyl, n-hexyl, or n-octyl) at C-6 alpha and 6 beta were synthesized. All of the steroids studied inhibited human placental aromatase in a competitive manner with apparent Ki values ranging from 2.8 to 80 nM. The 6 beta-pentyl analog 4a (Ki = 2.8 nM) was the most potent inhibitor. The inhibitory activities of the 6 beta-alkyl steroids 4 were more powerful than those of the corresponding 6 alpha-isomers 5. The addition of one methylene unit to the 6 alpha- and 6 beta-n-butyl moieties of androst-4-ene-3,17-dione markedly increased the affinity to aromatase, whereas further elongation of the n-pentyl group decreased affinity in relation to the carbon number of the alkyl chain. These results, along with molecular modeling with the PM3 method, suggest that the increased affinities of the pentyl steroids 4a and 5a may essentially depend on the formation of thermodynamically stable enzyme-inhibitor complex in the hydrophobic binding pocket.
为了进一步深入了解6-烷基雄甾-4-烯-3,17-二酮与其芳香化酶抑制活性之间的关系，合成了一系列在C-6α和6β位带有长烷基链（正戊基、正己基或正辛基）的烷基甾体。所有研究的甾体均以竞争性方式抑制人胎盘芳香化酶，表观Ki值范围为2.8至80 nM。6β-戊基类似物4a（Ki = 2.8 nM）是最有效的抑制剂。6β-烷基甾体4的抑制活性比相应的6α-异构体5更强。在雄甾-4-烯-3,17-二酮的6α-和6β-正丁基部分添加一个亚甲基单元显著增加了对芳香化酶的亲和力，而正戊基的进一步延长则相对于烷基链的碳原子数降低了亲和力。这些结果，连同用PM3方法进行的分子建模，表明戊基甾体4a和5a亲和力的增加可能主要取决于在疏水结合口袋中形成热力学稳定的酶-抑制剂复合物。
