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

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

彭晖, 杨纯正^*, 齐静, 梁巍, 黄牛, 郭宗儒

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

收稿日期:2001-11-20 修回日期:2002-01-17 出版日期:2002-06-15 发布日期:2002-06-15
通讯作者: 杨纯正*

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

Peng Hui, Yang Chunzheng^*, Qi Jing, Liang Wei, Huang Niu, Guo Zongru

1. State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020;
2. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050

Received:2001-11-20 Revised:2002-01-17 Online:2002-06-15 Published:2002-06-15
Contact: Yang Chunzheng*

摘要/Abstract

摘要： 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:COC3H7>CF3>COCH3>H.边链哌嗪环4'位取代基作用强度为:CH3>COOC2H5>C3H4OH.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、PKC和MDR三者间的内在机制和设计有效PKC抑制剂或多药耐药逆转剂提供了新的途径.

关键词: 吩噻嗪类衍生物, 多药耐药, 分子模型, 蛋白激酶C

Abstract: Studies on structure-activity relationship of phenothiazines (PTZs) for inhibition of protein kinase C (PKC)and reversal of multidrug resistance (MDR) has been made in vitro. The results showedthat the order of potency of reversaleffect of PTZs on MDR is as follows: 2-COC3H7>2-CF3>2-COCH3>H. The type of piperazinyl substitution also signifi-cantly affected potency against MDR. The results show the order: CH3>COOC2H5>C3H4OH. In addition, PKC plays amarked role in diverse cellular process including MDR. Some derivatives of PTZ was tested for inhibition of PKC, of whichPTZ11 showed the highest inhibitory effect of MDR and PKC, implying a potential reversal agent of MDR for tumor therapy inthe future. We also tried to explore 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 affinity PKC-modulator. The infor-mation may be used in the rational design of more effective drugs.

Key words: Phenothiazines, Phenothiazines, Multidrug resistance, Multidrug resistance, Molecular modeling, Molecular modeling, Protein kinase C, Protein kinase C

Supporting: ^*First published in Chinese in Acta Pharmaceutica Sinica, 1999, 34 (2):114.
Corresponding author. Tel/Fax:86-022-27230740; E-mail: czyang@public.tpt.tj.cn

彭晖, 杨纯正^*, 齐静, 梁巍, 黄牛, 郭宗儒. 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[J]. .

Peng Hui, Yang Chunzheng^*, Qi Jing, Liang Wei, Huang Niu, Guo Zongru . Structure-activity Relationship of Phenothiazines for Inhibition of Protein Kinase C and Reversal of Multidrug Resistance[J]. .

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