A Potent and Selective P-gp Modulator for Altering Multidrug Resistance Due to Pump Overexpression

P-glycoprotein (P-gp) is a membrane protein responsible for the active transport of several endogenous and exogenous substances. It constitutes a defense mechanism and, at the same time, it severely compromises the success rate of antitumor chemotherapy. In this study a small library of alkyl/oxyalkyl derivatives of MC70 [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], a well-known P-gp inhibitor, was synthesized through straightforward functionalization of the phenolic group present in the structure of MC70. All compounds were characterized for their effect on P-gp, proving capable of blocking P-gp-mediated calcein-AM efflux with micromolar potency, following their ability to act as high-affinity substrates of this transporter. Excitingly, compound 4 [6,7-dimethoxy-2-((4′-butoxybiphen-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline] exhibited low nanomolar potency (5.2 nm) and had a peculiar activity profile, acting both as a positive allosteric modulator and as a substrate of the transporter. A new and more efficient synthesis of MC70 is also described. Simple chemical modification of MC70, a well-known but rather nonselective P-glycoprotein (P-gp) inhibitor, led to a very potent and selective P-gp ligand (EC50=5.2 nm). The derivative displayed an intriguing double-faced mechanism of action, acting as both substrate and modulator. The synthesis of MC70 was also greatly improved, using a straightforward and protecting-group-free Suzuki-Miyaura coupling of halophenol.