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Study on aromatase reaction mechanism using the inhibitors as probes

以抑制剂为探针的芳香酶反应机理研究

基本信息

批准号：
15590066
负责人：
NUMAZAWA Mitsuteru
金额：
$ 1.98万
依托单位：
Tohoku Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

In order to gain insight into the aromatase reaction mechanisms, we explored aromatase reactions of the powerful aromatase inhibitors 3-deoxyandrogens, 3-deoxyandrostenedione (1)and 3-deoxydehydroepiandrosterone (2), in relation to the stereomechanisms of the 19-oxygenation and the C(10)-C(19)bond cleavage reaction.1.Treatment of the 19-oxo derivatives of compounds 1 and 2, steroids 5 and 6, with NaB^2H_4 or NaB^3H_4 produced the corresponding [19,19^<-2>H_2] 19-ols 3 and 4 or [19R^<-3>H]-ols 3 and 4 as well as their [19S^<-3>H] isomers.2.Incubation of [19, 19^<-2>H_4] 3 and 4 with human placental microsomes in the presence of NADPH produced the 19-oxo metabolites 5 and 6, respectively, where the deuterium isotope effect was not observed in each case.3.[19R^<-3>H]- and [19S^<-3>H] 3 and 4 were also incubated with the microsomes described above, and ^3H_2O and ^3HCOOH released into the incubation mixtures were analyzed. The results indicate that a 19-pro-R hydrogen in stereospecifically eliminated in the conversion of Steroid 4 into the 19-oxo steroid 6 whereas a selectivity of 75 : 25 for pro-R : pro-S is observed in the case of steroid 3. In both cases, the C(10)-C(19) bond cleavage reaction, yielding ^3HCOOH, was established.4.Structure-activity relationships of 4-substituted derivatives of inhibitor 1,2α-substituted ADs as well as 2, 4, or 6-substituted estrogens as aromatase inhibitors were also studied in relation to elucidate the spatial nature of the active site of aromatase.

为了深入了解芳香酶反应的机理，我们探索了强大的芳香酶抑制剂3-脱氧雄烯二酮(1)和3-脱氧雄烯二酮(2)与19-加氧和C(10)-C(19)键裂解反应的立体机理。1.化合物1和2的19-氧代衍生物5和6与NaB^2H_4或NaB^3H_4处理得到相应的[19，19^&lt；-2&GT；H_2]19-醇3和4或[19R^&lt；-3&GT；2.在NADPH存在下，[19，19^&lt；-2&gt；H_4]3和4与人胎盘微生物体孵育，分别产生19-氧代谢物5和6，其中没有在每种情况下观察到氢同位素效应。H]3和4也与上述微粒体孵育，并分析了孵育混合物中释放出的^3H2O和^3HCOOH。结果表明，在甾体4转化为19-氧代甾体6的过程中，19-PRO-R氢被立体特异性地消除，而在甾体3中，PRO-R：PRO-S的选择性为75：25。在这两种情况下，都建立了C(10)-C(19)键断裂反应，生成^3HCOOH。4.还研究了4-取代的1，2-α取代的ADS以及2，4或6-取代的雌激素作为芳香酶抑制剂的构效关系。