Potential antitumor agents. 48. 3'-Dimethylamino derivatives of amsacrine: redox chemistry and in vivo solid tumor activity.
Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported. The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine (1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2. Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100% cures of the Lewis lung solid tumor. The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D003110:Colonic Neoplasms / Q000473:pathology; D004247:DNA / Q000378:metabolism; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D000677:Amsacrine; D004247:DNA