Design, Synthesis And Primary Evaluation Of Quinoxalinone Derivatives As Potent Modulators Of Multidrug Resistance

Multidrugs resistance (MDR) phenotype often occurs when tumor cells are treated with a chemical therapeutically agent and eventually develop resistance to diverse structurally and mechanically unrelated anticancer drugs. The MDR has been implicated as a major obstacle in effective chemotherapy of cancer.Investigations have proved that the MDR phenomenon is often associated with over-expression of P-glycoprotein (P-gp), the product of the ABCBl gene. Great efforts have been focused on studies on the structure and function of the complex protein in the past thirty years. It has now been recognized that the" P-glycoprotein, an ATP-driven transmembrane transporter that capable of effluxing a wide variety of structurally diverse and functionally unrelated hydrophobic compounds out of the cell resulting in a decrease of anticancer drug concentration in cells to sub-lethal level, is the most frequent event causing the troublesome problem. Proportionate modulation of P-glycoprotein activity and/or expression might, therefore, benefit for chemotherapeutics. Inhibition of P-gp has been acknowledged as a viable means of reversing MDR and has been extensively studied for more than three decades. So far there have been three generations of P-glycoprotein inhibitors reported with a mechanism of increased accumulation of anti-tumor agents in MDR cells. However, unfortunately, none of them are clinically useful mainly due to their low potency, intrinsic cell toxicity, poor specificity or poor pharmacokinetics in vivo.An optimal P-gp pharmacophore model has been phrased as consisting of hydrophobic domain with at least two coplanar aromatic rings, a basic center at physiological pH environment, some proper hydrogen bond acceptors and/or donors.In our present study, in an attempt to develop novel and more potent P-gp inhibitors, we selected quinoxalinone scaffold according to the described pharmacophore model and synthesized two series of quinoxalinone derivatives, in which some natural L-amino acid residues were introduced with an expectation of decreasing in cytotoxicity. We also examined the anti-proliferative effect and MDR reversal activities of these compounds on human chronic myeloid leukemia cell line K562/AO2, which is a well known of over-expression of P-glycoprotein with multidrug resistance phenotype. Meanwhile their structure-activity relationships (SAR) were also investigated. Amongst them, compound 3,15,16 showed higher MDR reversal activities than verapamil, the positive control, without any significant cell cytotoxicity. Our study suggested that compound 3,15,16 deserved more consideration and might be candidate leads for further modification.