摘要：ATP-binding cassette (ABC) transporters form the largest family of transmembrane proteins. They play a vital physiological role in preventing xeno- toxic substances from entering the body, thereby shielding it from potentially harmful substances. Among these, ABCB1 is a multidrug resistance ABC transporter which plays a major role in absorption, distribution, metabolism and elimination (ADME) of drugs. ABCB1 have also been found associated with resistance of tumors towards anticancer drugs. Recently available crystal structure of human-mouse chimeric P-gp showed the presence of aromatic residues in zosuquidar binding pocket. The present study explored the role of two aromatic residues Y307 and Y310 in making interactions with benzophenone sulfonamide type of ligands which is a new class of compounds to be evaluated against P-gp. Both tyrosines were mutated individually to arginines to assess the alteration in the transport and inhibition properties of ABCB1by using benzophenone sulfonamide derivatives. As a control, transport and inhibition of best known substrate and inhibitor of P-gp including rhodamine123, verapamil and propafenone were also evaluated using Y307R and Y310R mutants. Results revealed that both arginine mutants showed a decrease in transport of rhoda- mine123 by 82-87%, which clearly demonstrated the importance of intact tyrosines at position 307 and 310 for transport activity of human P-gp for its renowned substrate rhodamine123. When the inhibition studies were performed both Y307R and Y310R showed lower IC_(50) values for verapamil (0.81 nM ±0.002, 1.08 nM ± 0.003), propafenone analogue GPV31 (3.64nM ± 0.004, 6.98nM ± 0.001) and three most active benzophenone sulfonamide derivatives 11, 13 and 14 (2.205 nM± 0.007, 6.75 nM ± 0.005 and 3.09 nM ± 0.004) (1.64 nM± 0.013, 7.109 nM ±0.013 and 2.53 nM ± 0.004), respectively. The data clearly indicated that these novel ligands can be used as anticancer compounds by targeting P-gp. These inhibitors are worth to investigate for the purpose of not only discovery of anticancer drugs, but also elucidation of chemical diversity of P-gp ligands to improve pharmacokinetics of drugs This would significantly contribute towards the pharmaceutical industry in developing anticancer drug.
