7-(咪唑-4-烷基酰胺基)-1,3-二氢-1-羧基烷基-5-苯基-2H-1,4-苯并二氮杂-2-酮一类新的法呢基蛋白转移酶抑制剂

7-IMIDAZOLYLALKANAMIDO-1-CARBOXYLALKYLBENZO-DIAZEPINE, A NOVEL SERIES OF FARNESYLTRANSFERASE INHIBITORS

摘要: 目的设计并合成新结构类型的法呢基蛋白转移酶抑制剂。方法本文结合法呢基蛋白转移酶(FTase)的作用机理和已有FTase抑制剂结构特征,设计了一类以苯并二氮杂为分子骨架,一端连接有可与锌离子配位结合的咪唑基,另一端连接不同长度的末端含羧基的侧链的化合物。此类化合物模拟了FTase配体之一CAAX四肽片段,共合成10个此类新化合物(6～12,16～18),并对其进行体外生物活性测定。结果所有新目的化合物均经1HNMR和HRMS方法确证结构。结论对FTase抑制活性测定结果表明其中5个化合物(9,10,16～18)有较强的抑制活性。

Abstract: AIMDesign, synthesis and evaluation of a series of 7-imidazolylalkanamido-1-carboxylalkylbenzodiazepine farnesyltransferase (FTase) inhibitors. METHODS and RESULTSCoupling of imidazolylalkylcarboxylic acids and 1-substituted 7-aminobenzodiazepines (5a～5c) yielded 10 new compounds (6～12, 16～18) which were biologically tested against FTase using scintillation proximity assay method. CONCLUSIONFive target compounds were found to be potential farnesyltransferase inhibitors.