N-alkylated 1,4-dihydropyridines: new agents to overcome multidrug resistance.
New N-alkylated 1,4-dihydropyridine derivatives were synthesized and their ability to overcome multidrug resistance was examined in vincristine-resistant P388 cells (P388/VCR cells). Compounds that possessed an arylalkyl substituent on the dihydropyridine ring nitrogen were more potent than verapamil in potentiating the cytotoxicity of vincristine against P388/VCR cells. However, neither drug effectively enhanced the antitumor activity of vincristine in tumor-bearing mice. Introduction of basic nitrogen-containing substituents on the side chain of 1,4-dihydropyridines gave improved activity in vitro and in vivo. The piperazine derivative 12c and 12o were more than 10 times as potent as verapamil in vitro. Four compounds selected for in vivo testing showed superior antitumor activity in P388/VCR-bearing mice in combination with vincristine. The structure-activity relationships of the compounds are discussed.
Ohsumi
K
K
Central Research Laboratories, Ajinomoto Co., Inc., Kawasaki, Japan.
Ohishi
K
K
Morinaga
Y
Y
Nakagawa
R
R
Suga
Y
Y
Sekiyama
T
T
Akiyama
Y
Y
Tsuji
T
T
Tsuruo
T
T
D000478:Alkylation; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000633:toxicity
D004095:Dihydropyridines; D014750:Vincristine; C038806:1,4-dihydropyridine; D014700:Verapamil