STRUCTURE-ACTIVITY RELATIONSHIP OF NEWLY SYNTHESIZED QUINOLINE DERIVATIVES FOR REVERSAL OF MULTIDRUG-RESISTANCE IN CANCER

The effect of 24 newly synthesized quinoline derivatives on tumor cell multidrug resistance (MDR) was examined in vitro. At low concentratio ns, these compounds enhanced the accumulation of [H-3]vincristine in K 562/ADM cells and reversed tumor cell MDR. The results of the structur e-activity relationship analysis indicate that in highly active compou nds the two aryl rings in the hydrophobic moiety deviate from a common plane, so they are capable of interacting with hydrogen bond donors o f P-170 glycoprotein (P-gp) via pi-hydrogen-pi interactions. Other maj or structural features which influence the MDR-reversing activities of these compounds are a quinoline nitrogen atom and a basic nitrogen at om in piperazine. Furthermore, in highly active compounds, the distanc e between the hydrophobic moiety and the basic nitrogen atom (an atom connected to 2-hydroxypropoxyquinoline) must be at least 5 Angstrom. S everal compounds were found to reverse vincristine resistance in K562/ ADM cells in vitro, and compound 16 (MS-209) was selected for clinical studies.