Potential antitumor agents. 51. Synthesis and antitumor activity of substituted phenazine-1-carboxamides.
In a further investigation of electron-deficient DNA-intercalating ligands as antitumor drugs, a series of substituted N-[2-(dimethylamino)ethyl]phenazine-1-carboxamides have been synthesized and evaluated. Fluorine-directed ring closure of N-phenyl-3-nitroanthranilic acids provided a new, unequivocal synthesis of several of the required phenazine-1-carboxylic acids, and the corresponding carboxamides were prepared and evaluated against L1210 leukemia in vitro and against P388 leukemia and Lewis lung carcinoma in vivo. Substitution on the phenazine ring was broadly tolerated, and the cytotoxicity of the resulting compounds correlated positively with the electron-withdrawing power of the substituent group. The positional effects of substituents were even more evident, with 9-substituted compounds being the most active. One derivative, N-[2-(dimethylamino)ethyl]-9-methoxyphenazine-1-carboxamide, had activity against Lewis lung carcinoma in mice equal to that of the best DNA-intercalating agents yet described, being capable of effecting a high-proportion cure of the advanced disease.
D000577:Amides / Q000138:chemical synthesis / Q000627:therapeutic use; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010619:Phenazines / Q000138:chemical synthesis / Q000627:therapeutic use*; D011067:Poly dA-dT; D011089:Polydeoxyribonucleotides / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D010619:Phenazines; D011089:Polydeoxyribonucleotides; C016681:poly(dG).poly(dC); D011067:Poly dA-dT