A new class of 1-aryl-5,6-dihydropyrrolo[2,1-a]isoquinoline derivatives as reversers of P-glycoprotein-mediated multidrug resistance in tumor cells

A number of aza-heterocyclic compounds, which share with members of the lamellarin alkaloids' family the 5,6-dihydropyrrolo[2,1-a]isoquinoline (DHPIQ) scaffold, were synthesized and evaluated for their ability to reverse in vitro multidrug resistance (MDR) in cancer cells, through inhibition of P-glycoprotein (P-gp) and/or multidrug-resistance-associated protein-1 (MRP-1). Most of the investigated DHPIQs proved to be selective P-gp modulators, and the most potent ones, which are 2-carbaldehydes (3 and 4) or a thiosemicarbazone derivative (10), attained submicromolar inhibition potencies (average IC50s of 0.24, 0.19 and 0.24 µM, respectively). Schiff bases prepared by condensation of some 1-aryl-DHPIQ aldehydes with p-aminophenol also proved to be of some interest, compound 15 displaying IC50 of 1.01 µM. In drug combination assays in multidrug-resistant cells, some DHPIQ compounds, at non-toxic doses, significantly increased the cytotoxicity of doxorubicin in a concentration-dependent manner. Structure-activity relationship studies and investigation of the chemical stability of the Schiff bases provided physicochemical information useful for molecular optimization of lamellarin-like cytotoxic drugs active toward chemoresistant tumors as well as non-toxic reversers of P-gp-mediated MDR in tumor cells.