Design, Synthesis And Activity Evaluation Of Methylated EGCG Derivatives As Anti-MDR Activity

Chemotherapy is an important therapy for cancer, but the Emergence ofmulti-drug resistance of tumor cells makes chemotherapy face serious challenges,Even lead to the failure of chemotherapy. MDR refers to the tumor cells resistant to ananticancer drug, at the same time, they would come into being Cross Resistnce toother drugs which they have not contact, with different structure and mechanism.There are a variety of MDR mechanisms, including ABC (ATP binding cassette)transporter protein family which was deeply-researched. There are three kinds of ABCacross membrane transporters related to MDR: breast cancer resistance protein(BCRP) and multidrug resistance associated protein (MRP) and P glycoprotein (P-gp).P-gp, BCRP and MRP have similar structures, but efflux of different drugs. Amongthe three transporter proteins, the mechanism P-gp was most deeply-researched.According to drug selectivity, development time and activities, P-gp inhibitor can bedivided into three generations: Ca2+channel inhibitors represented by verapamil asthe first generation of P-gp inhibitor and it’s shortcomings mainly lie in poorselectivity and side effects; The second generation is derivative to the first generation,including the PSC833, dexverapamil, etc, the advantage of the second generation of P-gp lie in it’s high combining ability, but it effect on P-450, interfere with the drugmetabolism, these shortcomings restrict its application; the third generation of P-gpinhibitors mainly include Zosuquidar (LY335979), Tariquidar (XR9576) and so on,has good selectivity, low toxicity, and good development prospects. Currently, thereare a variety of clinical trials of the third generation.High efficiency, high specificity of MDR reversal agents have become the hottopics in the study of people. Although the third-generation P-gp inhibitor’s selectivityis better, they have a series of problems such as the test result is not ideal in the body, so the high specificity, high efficiency, low metabolic enzymes influence and lowpharmacokinetic effect of P-gp inhibitors Inhibitors are still in urgent need of researchand development. Our group dedicated to the research of cancer MDR over the yearsand we have made some achievements, designed and synthesized a series ofmethylation analogues of Marine alkaloids Ningalin B, quercetin and EGCG. Thesynthesized compounds were evaluated MDR reversal activity.EGCG is the main active ingredient in tea polyphenols. In the early, our groupmethylated EGCG and MDR reversal activity was significantly enhanced, then wedesigned and synthesised a series of methylation analogues of EGCG, including avariety of compounds potentiated paclitaxel cytotoxicity on P-gp overexpressedLCC6MDR cell and reversal factor of compound5can reach43.8. These compoundshave non-toxic side effects and significantly better than the control drug verapamil(RF=3.8). This paper is on the basis of existing research results of our laboratory andP-gp mediated mechanism of MDR, we designed and synthesized22newmethylation EGCG analogues, then the structure of the synthesized compounds wereconfirmed and P-gp as target of MDR reversal activity test, in which active test of15compounds has been completed. The results show that1μM compound34can reversehuman breast cancer cell lines LCC6resistance of paclitaxel, the RF can reach53.6,significantly higher than the control drug verapamil (RF=3.8). Cytotoxic test showsthat the synthesized six compounds have no significant cytotoxicity, so they ate lowtoxicity and efficient for cancer MDR reversal agents, and on this basis we getstructure-activity relationship of methylation analogues of EGCG, and we hope toprovide reference for the research of cancer MDR.