6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

摘要

Aiming to deepen the structure–activity relationships of the two P-glycoprotein (P-gp) modulators elacridarand tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl1,2,3,4-tetrahydroisoquinolinescaffold linked to different methoxy-substituted aryl moieties were synthesised.The obtained compounds were evaluated for their P-gp interaction profile and selectivity towardsthe two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistanceprotein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the bestP-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancercell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemicalstability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable inboth models while some ester compounds were hydrolysed in human plasma. This study allowed us toidentify two chemosensitizers that behave as non-transported substrates and are characterised by differentselectivity profiles.