Numazawa M, Yamaguchi S
Tohoku College of Pharmacy, Aobaku, Sendai, Japan.
J Steroid Biochem Mol Biol. 1998 Oct;67(1):41-8. doi: 10.1016/s0960-0760(98)00066-1.
Two series of 6alpha- and 6beta-phenylaliphatic-substituted androst-4-ene-3,17-diones (3 and 5) were synthesized as aromatase inhibitors to gain insights of structure-activity relationships of varying the n-alkyl moiety (C2 to C5) of the 6-phenylaliphatic substituents to the inhibitory activity. All of the inhibitors synthesized inhibited human placental aromatase in a competitive manner with apparent Ki values ranging from 16 to 115 nM. The 6alpha-phenethyl analog 3a and the 6beta-phenbutyl analog 5c (Ki=16 nM for the two inhibitors, respectively) were the most potent inhibitors in each series. The inhibitory activities of the 6beta-substituted steroids 5 except for the phenethyl compound 5a were more powerful than those of the corresponding 6alpha-isomers 3. Elongation of the alkyl moiety of the 6-substituent of the 6alpha-phenethyl steroid 3a up to five methylene units decreased affinity to aromatase in all cases, whereas the addition of two more methylene units to the 6-side chain of the 6beta-phenethyl analog 5a increased the affinity in relation to carbon number of the 6-substituent. These results along with molecular modelling with the PM3 method, would give a new information about the formation of thermodynamically stable enzyme-inhibitor complex in a hydrophobic binding pocket in the active site of aromatase.
合成了两个系列的6α-和6β-苯基脂肪族取代的雄甾-4-烯-3,17-二酮（3和5）作为芳香酶抑制剂，以深入了解6-苯基脂肪族取代基的正烷基部分（C2至C5）变化对抑制活性的构效关系。所合成的所有抑制剂均以竞争性方式抑制人胎盘芳香酶，表观Ki值范围为16至115 nM。6α-苯乙基类似物3a和6β-苯丁基类似物5c（两种抑制剂的Ki分别为16 nM）是每个系列中最有效的抑制剂。除苯乙基化合物5a外，6β-取代甾体5的抑制活性比相应的6α-异构体3更强。在所有情况下，将6α-苯乙基甾体3a的6-取代基的烷基部分延长至五个亚甲基单元会降低对芳香酶的亲和力，而在6β-苯乙基类似物5a的6-侧链上再添加两个亚甲基单元会增加与6-取代基碳原子数相关的亲和力。这些结果以及用PM3方法进行的分子建模，将为芳香酶活性位点疏水结合口袋中热力学稳定的酶-抑制剂复合物的形成提供新信息。
