Design, Synthesis And Activity Evaluation Of Marine Alkaloid Ningalin B Analogues As P-gp Inhibitors

Multidrug resistance (MDR) has been a major challenge for successful cancer chemotherapy. An important mechanism for MDR of cancer cells is the enhanced cellular efflux of anticancer agents due to over-expression of ATP-binding cassette (ABC) transporter proteins. P-glycoprotein (P-gp), one of ABC transporters, has been shown to be associated with MDR and found to be over-expressive in a variety of drug-resistant tumor cells and efflux most of the anticancer drugs. Considerable effort has been laid to develop P-gp inhibitors and three generations have been discovered. However, only a few non-toxic and specific P-gp inhibitors have been found and none of these inhibitors can be used clinically. Therefore, searching for novel P-gp inhibitors with low toxicity and high potency has become an important task to reverse clinical multidrug resistance.In our previous study, a series of pyrrole-2,5-dione compounds, which mimic permethylated derivatives of marine natural product ningalin B, were synthesized and evaluated. Several nontoxic and potent P-gp inhibitors specifically modulating P-gp were developed. Further modification of these inhibitors and investigation of their inhibiting mechanism against P-gp may develop nontoxic, potent, and P-gp-specific lead compounds, which is very important to overcome the MDR of cancer cells and improve the efficacy of cancer chemotherapy.Based on the previous structure-acitvity relationship, we selected compounds 1-4 as the hit compounds. In this study, the function of B-rings and C-rings and their methoxy substituents and Ningalin B dimers were studied through synthesis of 29 pyrroledione derivatives. All compounds were confirmed by 1HNMR,13CNMR and HRMS.P-gp transfected breast cancer cell line (MDA435/LCC6MDR) and its parent (MDA435/LCC6) were employed to study P-gp modulating activity of permethyl ningain B analogues. All of these derivates have been tested for their P-gp modulating activity. Compounds 10,12,18,23, and 31 with a concentration of 1 μM can sensitize LCC6MDR cells towards paclitaxel by 11.8-fold,13.2-fold,13.1-fold,22.7-fold, and 47.1-fold respectively, much higher than verapamil (RF=3.8 fold).In this thesis, we studied the structure-activity relationship and P-gp inhibition mechanism of Permethyl Ningalin B, hopefully developing non-toxic, high efficient, P-gp-specific inhibitors to overcome multidrug resistance of tumor and improving the efficacy of cancer chemotherapy.