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

The development of multidrug resistance (MDR) in the course of chemotherapyhas been considered as a major obstacle in cancer treatment. Several cellularmechanisms can be responsible for MDR such as advanced DNA damage repairmechanisms and altered drug metabolism. Howerver, the most important factorcontributing to MDR is the over-expression of drug efflux pump, the ATP-bindingcassette (ABC) superfamily membrane proteins, which transport anti-cancer drugs outof the cells and result in chemotherapy ineffectiveness. P-glycoprotein (P-gp,ABCB1), multidrug resistance-related protein1(MRP1, ABCC1) and breast cancerresistance protein (BCRP, ABCG2) are three main ABC transporters that have beenshown to be associated with MDR. P-gp was the first human ABC drug transporteridentified and has been studied extensively among these three transmembranetransporters. Although different inhibitors or modulators of ABC multidrug effluxpumps have been identified either by serendipitous discovery, combinatorialchemistry and rational drug design or based on the known structure of thesetransporters, none of these inhibitors has been used clinically due to theirunacceptable toxicity and unpredictable pharmacokinetics interactions with theanticancer drugs. Tariquidar, belongs to the3rdgenerations inhibitors, have beenreported to be one of the most potent P-gp inhibitors and been in phase III trial inbreast cancer.Despite tremendous efforts to develop inhibitors and to discover natural productsmodulators of ABC drug transporters have been made, there are still no inhibitorscurrently used in clinical treatment. Consequently, searching for MDR reversal agentswhich has low toxicity, high efficiency, specificity and can be applicable to clinicaloncotherapy has been one of hotspots in anticancer research field. In order to find the most potent inhibitors, several series of natural products such as EGCG, quercetin anddihydromyricetin have been modificated of structure by our group and the results ofbioactivity are very promosing. In addition to the above-mentioned compounds, wehave been reported that synthetic permethyl ningalin B analogues exhibited apromising P-gp modulating activity at a low concentration (1μM) such as Compound6which can cause about18.2-fold resensitization of LCC6MDR toward paclitaxeland were found to become more effective than other traditional modulators likeverapamil.Based on the mechanism of P-gp mediated MDR and the previous researchachievements of our group-the structure-acitvity relationship of some presentderivatives,22new methylated Ningalin B analogues are designed and synthesized.All of these derivates have been tested for their P-gp modulating activity. Compounds17,18,20,35,36,37and38with a concentration of1μM can sensitize LCC6MDRcells towards paclitaxel by18.0-fold,13.2-fold,12.7-fold,42.7-fold,10.4-fold,42.7-fold, and16.8-fold respectively, much higher than verapamil.