Structure-activity Relationship of Phenothiazines for Inhibition of Protein Kinase C and Reversal of Multidrug Resistance  

吩噻嗪类化合物抑制肿瘤细胞多药耐药及蛋白激酶C活性的三维构效关系研究(英文)

作　　者：彭晖[1] 杨纯正[1] 齐静[1] 梁巍[1] 黄牛[2] 郭宗儒[2] 

机构地区：[1]中国医学科学院中国协和医科大学血液学研究所,实验血液学国家重点实验室,天津300020 [2]中国医学科学院中国协和医科大学药物研究所,北京100050

出　　处：《Journal of Chinese Pharmaceutical Sciences》2002年第2期11-18,共8页中国药学（英文版）

基　　金：ThisworkwassupportedbygrantsfromNSFCGeneralProject,GrantNo .394 70 816andNo .3990 0 186

摘　　要：Studies on structure-activity relationship of phenothiazines (PTZs) forinhibition of protein kinase C (PKC) and reversal of multidrug resistance (MDR) has been made invitro. The results showed that the order of potency of reversal effect of PTZs on MDR is as follows:2-COC_3 H_7 > 2-CF_3 > 2-COCH_3 > H. The type of piperazinyl substitution also significantlyaffected potency against MDR. The results show the order: CH_3 > COOC_2 H_5 > C_2 H_4 OH. Inaddition, PKC plays a marked role in diverse cellular process including MDR. Some derivatives of PTZwas tested for inhibition of PKC, of which PTZ11 showed the highest inhibitory effect of MDR andPKC, implying a potential reversal agent of MDR for tumor therapy in the future. We also tried toexplore the possible binding model of PTZs to PKC. Our molecular-modeling study preliminarilysuggests how these PTZs bind to PKC and provides a structural basis for the design of high affinityPKC-modulator. The infor-mation may be used in the rational design of more effective drugs.体外条件下吩噻嗪类衍生物 (PTZs)逆转多药耐药 (MDR)活性的实验结果表明 ,2位取代各种基团逆转MDR作用强度依次为 :COC3 H7>CF3 >COCH3 >H。边链哌嗪环 4’位取代基作用强度为 :CH3 >COOC2 H5>C2 H4OH。选出代表性化合物测定对鼠脑蛋白激酶C(PKC)的抑制活性 ,进行PTZs抑制PKC活性的初步三维构效关系研究 ,利用计算化学和分子图形学手段探讨PKC抑制剂与PKC蛋白分子间可能的相互作用模式。本研究为进一步探索PTZs。

关 键 词：PHENOTHIAZINES multidrug resistance molecular modeling protein kinase C 

分 类 号：R73-36[医药卫生—肿瘤]