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

STRUCTURE ACTIVITY RELATIONSHIP OF PHENOTHIAZINES FOR INHIBITION OF PROTEIN KINASE C AND REVERSAL OF MULTIDRUG RESISTANCE

目的：利用本室诱导建立的耐药细胞株Ｋ５６２／Ａ０２，研究在体外条件下吩噻嗪类衍生物（ＰＴＺｓ）逆转多药耐药（ＭＤＲ）活性的构效关系。方法与结果：利用已知ＰＫＣＣｙｓ２功能区晶体结构，结合计算化学和分子图形学手段对ＰＫＣ抑制剂与ＰＫＣ蛋白分子间可能的相互作用模式进行探讨。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＞Ｃ２Ｈ４ＯＨ。结论：选出代表性化合物测定对鼠脑的抑制活性，初步三维构效关系研究表明，ＰＴＺｓ抑制ＰＫＣ活性确实与特定的立体结构特征有关。本研究为进一步探索ＰＴＺｓ。

AIM: To study the structure activity relationship of phenothiazines(PTZs) for inhibition of protein kinase C (PKC) and reversal of multidrug resistance (MDR) in vitro . METHODS and RESULTS: The possible binding model of PTZs to PKC based upon the X ray structure of PMA(phorbol myristic acetate) in complex with PKC Cys 2 with DOCK program was explored. 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 result showed the order: CH 3>COOC 2H 5>C 2H 4OH. CONCLUSION: Some derivatives of PTZ was tested for inhibition of PKC. The observation indicates that PTZs inhibit PKC in a manner related to specific structural feature. Our molecular modeling study suggests preliminarily how these PTZs bind to PKC and provide a structural basis for the design of high affinity PKC modulator. Our structure activity studies offer a way to understand which molecular structure affects activity, and this information may be used in the rational design of more effective drugs.