去硫锥虫硫醇及其类似物对锥虫硫醇还原酶的合成与抑制活性
The synthesis and inhibitory activity of dethiotrypanothione and analogues against trypanothione reductase.
作者信息
Czechowicz Josephine A, Wilhelm April K, Spalding Maroya D, Larson Anna M, Engel Linnea K, Alberg David G
机构信息
Department of Chemistry, Carleton College, Northfield, Minnesota 55057, USA.
出版信息
J Org Chem. 2007 May 11;72(10):3689-93. doi: 10.1021/jo062597s. Epub 2007 Apr 17.
Abstract
Trypanothione reductase (TR) catalyzes the NADPH-dependent reduction of trypanothione disulfide (1). TR plays a central role in the trypanosomatid parasite's defense against oxidative stress and has emerged as a promising target for antitrypanosomal drugs. We describe the synthesis and activity of dethiotrypanothione and analogues (2-4) as inhibitors of Trypanosoma cruzi TR. The syntheses of these macrocycles feature ring-closing olefin metathesis (RCM) reactions catalyzed by ruthenium catalyst 17. Derivative 4 is our most potent inhibitor with a Ki=16 microM.
摘要
锥虫硫醇还原酶（TR）催化依赖于NADPH的锥虫硫醚二硫化物的还原反应（1）。TR在锥虫寄生虫抵御氧化应激的过程中起着核心作用，并已成为抗锥虫药物的一个有前景的靶点。我们描述了去硫锥虫硫醇及其类似物（2 - 4）作为克氏锥虫TR抑制剂的合成与活性。这些大环化合物的合成以钌催化剂17催化的闭环烯烃复分解（RCM）反应为特征。衍生物4是我们最有效的抑制剂，其抑制常数Ki = 16微摩尔。
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