NOVEL INHIBITORS FOR MULTIDRUG-RESISTANCE - 1,3,5-TRIAZACYCLOHEPTANES

1,3,5-Triazacycloheptanes were synthesized and examined for reversal o f the multidrug resistance dependent on P-glycoprotein. Most of these compounds increased the intracellular uptake of vinblastine in multidr ug-resistant mouse leukemia P388/ADR cells without influence upon the vinblastine accumulation in P388/S cells. The efficacy of 1,5-dibenzyl -1,3,5-triazacycloheptanes in increasing the vinblastine accumulation was in the order of 2,4-dithioxo (5) > 2-oxo-4-thioxo (4) approximate to 4-(methylthio)-2-oxo (6) > 2,4-dioxo (2). The efficacy was further increased when the benzyl group was converted to a chlorobenzyl group. Among these compounds, 6c terahydro-4-(methylthio)-2H-1,3,5-triazepin -2-one] potentiated the in vitro cell growth-inhibitory effect of vinb lastine, adriamycin, and mitomycin C on P388/ADR cells and prolonged t he life span of P388/ADR-bearing mice in combined therapy with vinblas tine more than vinblastine alone.