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

Multidrug resistance (MDR) in cancer has been a major obstacle to successful cancer chemotherapy. An important mechanism for MDR is the enhanced cellular efflux of anticancer agents due to over-expression of ATP-binding cassette (ABC) transporter proteins. Among the 48 ABC transporters identified so far, P-glycoprotein (P-gp, ABCB1), multidrug resistance-related protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2) are three main efflux transporters that have been shown to be associated with MDR. Considerable effort has been laid to develop P-gp inhibitors and three generations have been discovered. However, only a few non-toxic and P-gp-specific 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 methylated epigallocatechin derivatives were synthesized and evaluated. The EC50 of 8 hit compounds inhibiting P-gp is 140.0 to 280.0 nM. Several nontoxic and potent P-gp inhibitors specifically modulating P-gp were developed. Further modification of these inhibitors and investigation of their inhibiting mechanism aganist 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.In this thesis, methoxys on B ring and configuration of C-2 and C-3, and the linker of a piperidine connected C ring and D ring were studied. Four (2R,3R)-epicatechin derivatives, one (2R,3S)-catechin derivatives, three (2R,3R)-epigallocatechin derivatives, and four (2R,3S)-gallocatechin derivatives were designed and synthesised; In order to improve the water-solubility and improve the lipid-water partition coefficient, other 12 catechin and gallocatechin derivatives with the linker of a piperidine were designed and synthesized. All 24 new compounds were confirmed by 1HNMR,13CNMR.P-gp transfected breast cancer cell line (MDA435/LCC6MDR) and its parent (MDA435/LCC6) were employed to study P-gp modulating activity of methylated catechin derivatives. Compounds 2,3,4,6,7,8, and 11 with a concentration of 1 μM can sensitize LCC6MDR cells towards paclitaxel by 12.3-fold,10.9-fold,62.9-fold, 26.1-fold, and 47.4-fold,12.8-fold,32.5-fold respectively, much higher than verapamil (3.8-fold). EC50 of 4,7, and 11 are 83.3,140, and 181.0 nM respectively, which suggests that these compounds are effective P-gp inhibitors.