N Replace The Derivatives Of Phenothiazine Multidrug Resistance Reversal Activity

The Multidrug Resistance (MDR) is defined as a cross-resistance to a wide range of structurally and mechanistically diverse anticancer agents, which remains a major cause of chemotherapy failure in cancer treatment. The mechanisms of MDR involved are complex , such as: MDR related proteins (P-gp, MRP, LRP); DNA topoisomerase II (Topo II); protein kinase C (PKC); glutathione (GSH) and glutathione-S-transferase (GST), etc. Among them, P-gp mediated MDR is one of the most intensively studied, which acts as a drug efflux pump resulting in a decrease of drug accumulation in the cells. Till now, a large number of drugs and compounds have been found to be capable of reversing MDR phenotype. According to the structure-activity relationship of MDR reversal agents: MS-209 and phenthiazine derivatives, we have designed and synthesized 24 new compounds. Their structures were confirmed by MS, -JNMR and EA. Sodium methyl sulfinyl methide, generated in situ by sodium hydride and dry dimethyl sulfoxide as a strong nucleophilic agent was used to synthesize I O-(2,3- epoxypropyl) phenothiazine in high yield and mild condition. By carefully controlling ratio of reactants and in acetonitrile, monosubstituted N4- diarylmethyl-piperazine can be obtained with high selectivity. Ring-opening reaction of epoxide and N1-alkylation of N4-diarylmethyl-piperazine can be catalyzed by silica gel with a high rate and yield. By using L1210/DOX and L1210/VCR in vitro test and Verapamil as control compound, 22 new compounds were evaluated their MDR reverse ability. The results showed that compound 1-D. 1-M had relatively high reverse activity (Resistance Modify Index, RMI: 31.48, 28.99 respectively), but lower than that of Verapamil 89. Using the comparative molecular field analysis (C0MFA), we have studied the 3D- QSAR of this class of phenothiazine derivatives, and come up with a good CoMFA model. The result provides valuable information on further study.