N-ALKYLATED 1,4-DIHYDROPYRIDINES - NEW AGENTS TO OVERCOME MULTIDRUG-RESISTANCE

New N-alkylated 1,4-dihydropyridine derivatives were synthesized and t heir ability to overcome multidrug resistance was examined in,vincrist ine-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-di hydropyridines gave improved activity in vitro and in vivo. The pipera zine derivative 12c and 12o were more than 10 times as potent as verap amil in vitro. Four compounds selected for in vivo testing showed supe rior antitumor activity in P388/VCR-bearing mice in combination with v incristine. The structure-activity relationships of the compounds are discussed.