Potential antitumor agents. 26. Anionic congeners of the 9-anilinoacridines.
To investigate the possible importance of small levels of sulfonamide anion in the antileukemia (L1210) 4'-(9-acridinylamino)methanesulfonanilides, an anionic derivative was prepared, in which -COOH replaced -NHSO2CH3, and shown to have experimental antitumor activity. Analogue synthesis and evaluation show that acceptable placement of the carboxylate function on the 9-anilino ring is restricted to the 1'-position. While the 1'-COOH and 1'-(CH2)2COOH analogues proved active, the intermediate acetate variant (1'-CH2COOH) was inactive. There were marked differences in the effects of added acridine ring substituents, on biologic activity, depending on the function attached to the 9-anilino ring (1'-NHSO2CH3 or 1'-COOH). Consideration of the vector components of possible drug-binding forces, acting on a DNA-intercalated agent, suggests that there may be low-energy barriers to two-dimensional reorientation of a planar, intercalated chromophore in relation to the neighboring purine-pyrimidine base pairs. It is proposed that site forces from an added substituent could lead to modified DNA-binding orientations. Observed acridine-ring substituent effects on biologic activity would then depend on the 9-anilino ring function (1'-NHSO2CH3, 1'-COOH) employed.
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D013329:Structure-Activity Relationship
D000166:Acridines; D000970:Antineoplastic Agents