抗伊马替尼耐药的Bcr-Abl抑制剂的设计、合成与评价  

Design,synthesis and screen of Bcr-Abl inhibitors overriding imatinib resistance

作　　者：周丽[1,2] 肖军海[2] 

机构地区：[1]中南大学药学院,长沙410013 [2]军事医学科学院毒物药物研究所,北京100850

出　　处：《国际药学研究杂志》2013年第4期453-459,共7页Journal of International Pharmaceutical Research

摘　　要：目的针对慢性粒细胞白血病,以Bcr-Abl酪氨酸激酶为靶点,进行抗伊马替尼耐药作用的Bcr-Abl抑制剂的研究。方法基于STI-571与BMS-354825的结构设计了一系列以2-甲基-5-羰基-1,3-硒唑为母核的硒唑甲酰胺类化合物。并对目标化合物进行了STI-571耐药细胞株K562的筛选。结果与结论本研究共设计合成目标化合物16个,结构均经1H NMR、MS确证。生物活性评价结果表明,化合物Ⅰ7和Ⅰ10对K562/R抑制活性与阳性化合物较为接近,化合物Ⅰ11抑制作用最强,并对K562/R表现出选择性。Objective In order to fight against chronic myeloid leukemia,we took Bcr-Abl tyrosine kinase as the target and studied the inhibitors against imatinib-resistant mutants.Methods Based on the structure of STI-571 and BMS-354825,we designed a series of selenazole carboxamide derivatives based on the matrix structure of the 2 methyl 5-carbol-1,3-selenazole and screened these target compounds with STI-571-resistant cell lines K562.Results and Conclusion In the study,16 compounds were synthesized which were identified by 1H NMR and MS.The results of the activity test showed that the inhibitory activity of compounds Ⅰ7,Ⅰ10and Ⅰ11 against K562 / R were closed to or overmatch that of the control compound.Compound Ⅰ11 was the optimum and put up the selectivity for K562 / R.

关 键 词：慢性粒细胞白血病 Bcr-Abl酪氨酸激酶 抗耐药 硒唑甲酰胺 

分 类 号：R914[医药卫生—药物化学]