17β-（环丙氨基）-雄甾-5-烯-3β-醇，一种基于机制的细胞色素P450（17α）（甾体17α-羟化酶/C17-20裂解酶）选择性抑制剂。

17 beta-(cyclopropylamino)-androst-5-en-3 beta-ol, a selective mechanism-based inhibitor of cytochrome P450(17 alpha) (steroid 17 alpha-hydroxylase/C17-20 lyase).

作者信息

Angelastro M R, Laughlin M E, Schatzman G L, Bey P, Blohm T R

机构信息

Merrell Dow Research Institute, Cincinnati, OH 45215.

出版信息

Biochem Biophys Res Commun. 1989 Aug 15;162(3):1571-7. doi: 10.1016/0006-291x(89)90854-1.

DOI:10.1016/0006-291x(89)90854-1

PMID:2788415

Abstract

A new compound, 17 beta-(cyclopropylamino)-androst-5-en-3 beta-ol, MDL 27,302, has been designed and synthesized as a mechanism-based inhibitor of cytochrome P450(17 alpha). The time-dependent inactivation of human testicular P450(17 alpha) is irreversible by dialysis and requires the cofactor, NADPH; Kiapp. 90 nM (determined on cynomolgous monkey testis enzyme). Inactivation was not affected by the nucleophile DTT, suggesting retention of the inhibitor in the enzyme active site during the inactivation process. Inhibition is specific to the cyclopropylamino compound, since the isopropylamino- and cyclobutylamino-analogs were not inhibitory. Enzymatic specificity of MDL 27,302 for P450(17 alpha) was demonstrated by its failure to inhibit steroid 21-hydroxylase and the cholesterol side chain cleavage enzyme (P450scc). Both the 17 alpha-hydroxylase and C17-20 lyase activities of cytochrome P450(17 alpha) of human testis microsomes were inhibited by MDL 27,302.

摘要

一种新的化合物，17β-（环丙氨基）-雄甾-5-烯-3β-醇，MDL 27302，已被设计并合成，作为一种基于机制的细胞色素P450（17α）抑制剂。人睾丸P450（17α）的时间依赖性失活经透析后不可逆，且需要辅因子NADPH；表观抑制常数Kiapp为90 nM（根据食蟹猴睾丸酶测定）。失活不受亲核试剂二硫苏糖醇（DTT）的影响，这表明在失活过程中抑制剂保留在酶活性位点。抑制作用对环丙氨基化合物具有特异性，因为异丙氨基和环丁氨基类似物没有抑制作用。MDL 27302对P450（17α）的酶促特异性通过其对类固醇21-羟化酶和胆固醇侧链裂解酶（P450scc）无抑制作用得以证明。人睾丸微粒体细胞色素P450（17α）的17α-羟化酶和C17-20裂解酶活性均被MDL 27302抑制。