3,5-diacetyl-1,4-dihydropyridines: synthesis and MDR reversal in tumor cells.
Eleven 4-phenyl-3,5-diacetyl-1,4-dihydropyridines (AcDHPs) [G1-11] substituted at the phenyl ring were synthesized and compared for their cytotoxic activity and multidrug resistance (MDR)-reversing activity in in vitro assay systems. Among them, compound [G7] showed the highest cytotoxic activity against human promyelocytic leukemia HL-60 and human squamous cell carcinoma HSC-2 cells. However, no compounds tested produced radicals at pH 7.4-12.5. The activity of P-glycoprotein (Pgp) responsible for MDR in tumor cells was reduced by compounds [G2, 3, 6, 5, 8, 1, 11], verapamil [VP] and nifedipine [NP]. However, compounds [G4, 7, 10] were hardly active while G9 did not show a MDR reversing effect at 2.0-20.0 micrograms/mL. These data show a relationship between chemical structures and MDR-reversing effect on tumor cells.
Shah
A
A
Department of Chemistry, Saurashtra University, Rajkot, India.
Gaveriya
H
H
Motohashi
N
N
Kawase
M
M
Saito
S
S
Sakagami
H
H
Satoh
K
K
Tada
Y
Y
Solymosi
A
A
Walfard
K
K
Molnar
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005456:Fluorescent Dyes / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D020112:Rhodamine 123 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D005456:Fluorescent Dyes; D020112:Rhodamine 123