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应用MTT法研究了几个吩噻嗪类衍生物 (PTZ6,PTZ7及PTZ11)对多药耐药的逆转作用 ,同时检测了PTZ对PKC活性的抑制作用 .结果表明 ,PTZ6,PTZ7及PTZ11在K562 /AO2细胞中对阿霉素耐药作用的逆转倍数分别为 2 .4 9,3 6.58和 75.78倍 ,表明PTZ11具有较高的逆转MDR的活性 ;在PTZ存在时 ,PKC的活性分析表明 ,PTZ6及PTZ11以剂量依赖性方式抑制PKC活性 ,其IC5 0 值分别为 (4 89.77± 3 1.4 )和 (113 .0 0± 9.64 ) μmol/L ,而PTZ7对PKC活性无抑制作用 ;在PMA存在时 ,PTZ11对PKC的抑制作用减弱 ,表明PTZ11可能与PMA竞争PKC的结合部位 .为阐明PTZ抑制PKC活性的分子机制 ,进一步应用计算机软件系统模拟PTZ6和PTZ11与PKC结合的分子图象 ,发现PMA通过氢键与PKC结合 ,而PTZ6及PTZ11通过疏水力及静电作用与PKC结合 ,且PTZ11与PKC结合的疏水力大于PTZ6,从而在三维分子构象水平阐明了PTZ抑制PKC活性的机制 ,并为设计新的PKC抑制剂或多药耐药逆转剂提供了崭新的资料
The reversal effect of several phenothiazine derivatives (PTZ6, PTZ7 and PTZ11) on multidrug resistance was studied by MTT assay. The inhibitory effect of PTZ on PKC activity was also tested. The results showed that PTZ6, PTZ7 and PTZ11 were in K562. The reversal multiple of adriamycin resistance in /AO2 cells was 2.43, 3.58, and 75.78 fold, respectively, indicating that PTZ11 has a higher reversal of MDR activity; in the presence of PTZ, the activity analysis of PKC showed that PTZ6 PTZ11 inhibited the activity of PKC in a dose-dependent manner. The IC50 values were (4 89.77± 31.4) and (113.0± 9.64) μmol/L, respectively, while PTZ7 had no inhibitory effect on PKC activity; The inhibitory effect of PTZ11 on PKC weakened, suggesting that PTZ11 may compete with PMA for the binding site of PKC. To elucidate the molecular mechanism of PTZ inhibiting PKC activity, further computer software system was used to simulate the molecular images of PTZ6 and PTZ11 combined with PKC and found that PMA passed Hydrogen bonds bind to PKC, while PTZ6 and PTZ11 bind to PKC through hydrophobic forces and electrostatic interactions, and PTZ11 binds PKC with a greater hydrophobic force than PTZ6, thus elucidating the mechanism of PTZ inhibition of PKC activity at the three-dimensional molecular conformation level and designing new ones. PKC inhibitors or multi-drugs Drug reversal agent provides new information