STRUCTURE-ACTIVITY-RELATIONSHIPS OF DIAMINES, DICARBOXAMIDES, AND DISULFONAMIDES ON VINBLASTINE ACCUMULATION IN P388 ADR CELLS

Diamines, dicarboxamides, and disulfonamides that have terminal benzen e, methyl- or chloro-substituted benzene rings were synthesized and ev aluated for the activity of [H-3]vinblastine accumulation in multidrug -resistant P388/ADR cells. The efficacy of these compounds was general ly in the order of dicarboxamides < diamines < disulfonamides. N-Methy lated diamine and disulfonamide compounds having terminal methyl- or c hloro-substituted benzene rings in their structure also showed rather potent efficacy. From these findings, we synthesized a novel disulfona mide compound, ydro-2,5-bis(p-toluenesulfonyl)benzo[2,5]diazocine (22) . Compound 22 suppressed the efflux of vinblastine from P388/ADR cells and increased its intracellular accumulation, while it barely increas ed the vinblastine accumulation in sensitive cells (P388/S). Compound 22 significantly potentiated the growth-inhibitory effects of vinblast ine, vincristine, colchicine and Adriamycin against P388/ADR cells in vitro.