Antimitotic agents: structure-activity studies with some pyridine derivatives

• Published in: Journal of medicinal chemistry 1992-10, Vol.35 (20), p.3686-3690
• Main Authors: Temple, Carroll, Rener, Gregory A, Waud, William R, Noker, Patricia E
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Cell Division - drug effects; Chemistry; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Leukemia L1210 - drug therapy; Mice; Organic chemistry; Preparations and properties; Pyridines - chemical synthesis; Pyridines - metabolism; Pyridines - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00098a014

Antitumor activity in mice was observed for the oxime of the previously reported ethyl [6-amino-4-[(1-methyl-2-phenyl-2-oxoethyl)amino]-5-nitropyridin -2-yl] carbamate (8) and several related compounds. These compounds are precursors of the active ethyl pyrido[3,4-b]pyrazin-7-ylcarbamates (e.g., 4), which are potent antimitotic agents. In the 5-nitropyridine series overall biological activity was reduced by replacement of the oxime moiety with a keto or alcohol group and by replacement of the 1-methyl group of the side chain with hydrogen. Reduction of the nitro group of the 5-nitropyridines containing an alcohol in the side chain to the corresponding 5-aminopyridines increased biological activity. Preliminary studies showed that the 5-nitropyridine oximes were considerably less potent than the pyridopyrazines as antimitotic agents and that the former are apparently not converted to the latter in vivo. The inhibition of the incorporation of pyrimidine nucleosides into DNA and RNA was identified as another possible mode of action of the 5-nitropyridine oximes.