Synthesis, conformation, and biological activity of teleocidin mimics, benzolactams. A clarification of the conformational flexibility problem in structure-activity studies of teleocidins
Synthesis, conformation, and biological activity of teleocidin mimics, benzolactams. A clarification of the conformational flexibility problem in structure-activity studies of teleocidins
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DOI：
10.1021/ja953578v
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发表时间：
1996-02-28
影响因子：
15
通讯作者：
Shudo, K
中科院分区：
文献类型：
--
作者：
Endo, Y;Ohno, M;Shudo, K
已知肿瘤促进剂teleocidin及其活性同源物（吲哚内酰胺）在溶液中以至少两种构象状态（扭曲和沙发形式）之间的平衡存在，这是由于酰胺键的顺反异构化和九元内酰胺环上取代基的空间效应。设计并合成了苯并内酰胺-Vs，其中吲哚内酰胺的吲哚环被苯环取代，试图再现teleocidin的活性构象。在这些苯并内酰胺中，八元内酰胺（苯并内酰胺-V8）只能以扭曲形式存在，而9元和10元内酰胺（苯并内酰胺-V9和-V10）在溶液中仅以沙发形式存在。benzolactam-V-8-310的生物活性强于indolactam-V（IL-V），而benzolactam-V-9-310对HL-60的诱导分化活性无影响，这表明其扭曲构型更接近于动环肽的活性构象。
Tumor-promoter teleocidins and their active congeners (indolactams) are known to exist in an equilibrium between at least two conformational states in solution, the twist and sofa form, due to cis-trans isomerization of the amide bond and the steric effects of substituents on the nine-membered lactam ring. Benzolactam-Vs, in which the indole ring of indolactams is replaced with a benzene ring, were designed and synthesized in an attempt to reproduce the active conformation of teleocidins. Among these benzolactams, eight-membered lactams (benzolactam-V8) can only exist in the twist form, and 9- and 10-membered lactams (benzolactam-V9 and -V10) exist exclusively in the sofa form in solution. The stronger biological activity of benzolactam-V-8-310 than that of indolactam-V (IL-V) and the inactivity of benzolactam-V-9-310 for differentiation inducing activity of HL-60 clearly indicated that the twist form is close to the active conformation of teleocidins.