Novel inhibitors for multidrug resistance: 1,3,5-triazacycloheptanes.
1,3,5-Triazacycloheptanes were synthesized and examined for reversal of the multidrug resistance dependent on P-glycoprotein. Most of these compounds increased the intracellular uptake of vinblastine in multidrug-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) approximately 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 [1,5-bis(4-chlorobenzyl)-1,5,6,7-terahydro-4-(methylthio)-2H-1,3,5 - triazepin-2-one] potentiated the in vitro cell growth-inhibitory effect of vinblastine, adriamycin, and mitomycin C on P388/ADR cells and prolonged the life span of P388/ADR-bearing mice in combined therapy with vinblastine more than vinblastine alone.
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
H
H
Sawanishi
S
S
Wakusawa
R
R
Murakami
H
H
Muramatsu
H
H
Suzuki
A
A
Takashima
T
T
Aizawa
K
K
Miyamoto
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000494:pharmacology*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D016685:Mitomycin / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
C097607:1,5-bis(4-chlorobenzyl)-1,5,6,7-tetrahydro-4-(methylthio)-2H-1,3,5-triazepin-2-one; D000970:Antineoplastic Agents; D001381:Azepines; D003508:Cycloheptanes; D016685:Mitomycin; D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin