BISBENZYLISOQUINOLINES AS MODULATORS OF CHLOROQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM AND MULTIDRUG-RESISTANCE IN TUMOR-CELLS

Ten naturally occurring bisbenzylisoquinolines (BBIQ) and two dihydro derivatives belonging to five BBIQ subgroups were evaluated in vitro f or their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance to chloroquine of strain FcB1. The same alkaloids were also assessed in vitro for their potentiating activity against vinblastine with the multidrug-resistant clone CCRF-C EM/VLB, established from lymphoblastic acute leukemia, Three of the BB IQ tested had 50% inhibitory concentrations of less than 1 mu M. The m ost potent antimalarial agent was cocsoline (50% inhibitory concentrat ion, 0.22 mu M). Regarding the chloroquine-potentiating effect, fangch inoline exhibited the highest biological activity whereas the remainin g compounds displayed either antagonistic or slight synergistic effect s, Against the multidrug-resistant cancer cell line, fangchinoline was also by far the most active compound, Although there were clear diffe rences between the activities of tested alkaloids, no relevant structu re-activity relationship could be established, Nevertheless, fangchino line appears to be a new biochemical tool able to help in the comprehe nsion of the mechanism of both chloroquine resistance in P, falciparum and multidrug resistance in tumor cells.