Structure-activity relationships of diamines, dicarboxamides, and disulfonamides on vinblastine accumulation in P388/ADR cells.
Diamines, dicarboxamides, and disulfonamides that have terminal benzene, methyl- or chloro-substituted benzene rings were synthesized and evaluated for the activity of [3H]vinblastine accumulation in multidrug-resistant P388/ADR cells. The efficacy of these compounds was generally in the order of dicarboxamides < diamines < disulfonamides. N-Methylated diamine and disulfonamide compounds having terminal methyl- or chloro-substituted benzene rings in their structure also showed rather potent efficacy. From these findings, we synthesized a novel disulfonamide compound, 1,2,3,4,5,6-hexahydro-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 increased the vinblastine accumulation in sensitive cells (P388/S). Compound 22 significantly potentiated the growth-inhibitory effects of vinblastine, vincristine, colchicine and Adriamycin against P388/ADR cells in vitro.
Sawanishi
H
H
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Wakusawa
S
S
Murakami
R
R
Miyamoto
K
K
Tanaka
K
K
Yoshifuji
S
S
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D003959:Diamines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000493:pharmacokinetics*
D000577:Amides; D003959:Diamines; D013449:Sulfonamides; D014747:Vinblastine