Synthesis and structure--activity analysis of novel dihydropyridine derivatives to overcome multidrug resistance.
The structure activity relationships were studied on newly synthesized 1,4-dihydropyridine derivatives possessing a 1-pentyl group at the 4-position, and 3-pyridylpropylester was found to be one of the effective fragments for overcoming P-glycoprotein mediated multidrug-resistance (MDR) in cultured human cancer cells, in vitro. 3-Pyridylpropylester was also found to be one of the effective fragments for increasing the life span of P-glycoprotein overexpressing MDR P388 leukemia-bearing mice, in vivo. All compounds had weak calcium antagonistic activities, but there appeared no relationship between MDR reversing effect and calcium antagonistic activity.
Tasaka
S
S
Omiya Research Laboratory, Nikken Chemicals Co., Ltd., Omiya, Japan.
Ohmori
H
H
Gomi
N
N
Iino
M
M
Machida
T
T
Kiue
A
A
Naito
S
S
Kuwano
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors; D020650:Combinatorial Chemistry Techniques; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006801:Humans; D020128:Inhibitory Concentration 50; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004095:Dihydropyridines; D014750:Vincristine; D002118:Calcium