3-(2-丙烯基)-和3-(2-丙炔基)吡咯烷-2,5-二酮衍生物作为潜在芳香酶抑制剂的合成及生物学评价

Synthesis and biological evaluation of 3-(prop-2-enyl)- and 3-(prop-2-ynyl)pyrrolidine-2,5-dione derivatives as potential aromatase inhibitors.

作者信息

Barrell K J, Woo W L, Ahmadi M, Smith H J, Nicholls P J

机构信息

Welsh School of Pharmacy, University of Wales, Cardiff, UK.

出版信息

J Pharm Pharmacol. 1996 Feb;48(2):154-9. doi: 10.1111/j.2042-7158.1996.tb07115.x.

DOI:10.1111/j.2042-7158.1996.tb07115.x

PMID:8935164

Abstract

3-(4'-Aminophenyl)pyrrolidine-2,5-dione (WSP3), a known reversible inhibitor of P450 aromatase, was modified using molecular graphics and our model of reversible inhibitor and substrate binding to resemble 10 beta-prop-2-ynylestr-4-ene-3,17-dione (PED), a mechanism-based inactivator of the enzyme. The analogues prepared were 3-substituted 3-(prop-2-enyl) or 3-(prop-2-ynyl) pyrrolidine-2,5-diones and their N-alkyl derivatives. The reported compounds demonstrated no irreversible (time-dependent) inhibition of the human placental P450 aromatase enzyme. However, some reversible activity was seen in several of the 3-(prop-2-ynyl) compounds.

摘要

3-(4'-氨基苯基)吡咯烷-2,5-二酮（WSP3）是一种已知的细胞色素P450芳香酶可逆抑制剂，利用分子图形学以及我们的可逆抑制剂与底物结合模型对其进行修饰，使其类似于10β-丙-2-炔基雌甾-4-烯-3,17-二酮（PED），后者是该酶的一种基于机制的失活剂。所制备的类似物为3-取代的3-(2-丙烯基)或3-(2-丙炔基)吡咯烷-2,5-二酮及其N-烷基衍生物。所报道的化合物对人胎盘细胞色素P450芳香酶无不可逆（时间依赖性）抑制作用。然而，在几种3-(2-丙炔基)化合物中观察到了一些可逆活性。