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

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位取代各种基因逆转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＞C2H4OH，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PTZ s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。

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

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 showed that the order of potency of reversal effect of PTZs on MDR is as follows: 2-COC 3H 7> 2-CF 3>2-COCH 3>H. The type of piperazinyl substitution also significantly affected potency against MDR. The results show the order: CH 3>COOC 2H 5>C 2H 4OH. In addition, PKC plays a marked role in diverse cellular process including MDR. Some derivatives of PTZ was tested for inhibition of PKC, of which PTZ11 showed the highest inhibitory effect of MDR and PKC, implying a potential reversal agent of MDR for tumor therapy in the future. We also tried to explore the possible binding model of PTZs to PKC. Our molecular-modeling study preliminarily suggests how these PTZs bind to PKC and provides a structural basis for the design of high affinity PKC-modulator. The information may be used in the rational design of more effective drugs.