双二酮酸结构HIV-1整合酶抑制剂的合成及活性研究  

Anti HIV-1 integrase activity of the compounds containing bis-diketo acid

作　　者：武燕彬[1] 金洁[1] 王瑞贞[2] 刘浚[1] 王翀[2] 陈晓芳[1] 

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所有机化学室,北京100050 [2]山东新华制药股份有限公司,淄博255086

出　　处：《中国医药生物技术》2015年第5期411-415,共5页Chinese Medicinal Biotechnology

基　　金：科技部国际科技合作项目(2009DFA31140)

摘　　要：目的设计合成双二酮酸类化合物,并探讨此类化合物抑制HIV-1整合酶活性的构效关系。方法以甲基取代苯乙酮为起始原料,经溴代后与羟基取代苯乙酮反应生成乙酰基苄氧苯乙酮,然后在氢化钠作用下,脱去α氢后进攻草酸二乙酯生成双二酮酸酯,水解脱去酯基生成双二酮酸;经1H-NMR、IR和MS验证化合物结构。ELISA法测定目标化合物对HIV-1整合酶的抑制活性;采用高通量荧光法测定目标化合物对HIV-1整合酶3'加工过程的抑制活性;测定目标化合物对HIV假病毒的细胞活性。结果合成了6个全新结构的二酮酸类化合物;体外整合酶活性评价结果表明,6个目标化合物对HIV-1整合酶的活性IC50≤20μg/ml,双二酮酸之间距离稍短的5a、5c、5d对3'加工过程有一定的活性,IC50约为40μg/ml。结论 6个新化合物对HIV-1的活性主要表现在链转移过程。Objective To explore the relationship of structure and activity of these compounds with anti HIV-1 integrase through designing and synthesizing a series of novel bis-diketo acid compounds. Methods Title compounds were synthesized through bromination, substitution and hydrolyzation. 6 target compounds were obtained. All structures were confirmed by XH-NMR, IR and MS. Anti HIV-1 integrase activities in vitro of the target compounds were tested by ELISA, high-throughput fluorescence method was used to anti HIV-1 integrase 3P activities, and HIV-1 pseudovirus was applied to determine the infection rate of cells inhibited by the compounds. Results 6 novel compounds were synthesized. The title compounds exhibited moderate anti-integrase activity with IC50≤20μg/ml Three target compounds exhibited 3P activity with IC50≈40μg/ml. Conclusion 6 novel compounds exihibit mainly ST activity. The study will help to understand the relationship of structure and activity of compounds with anti HIV-1 activities.

关 键 词：HIV整合酶抑制剂 构效关系 双二酮酸类化合物 

分 类 号：R914.5[医药卫生—药物化学]