Potential antitumor agents. 26. Anionic congeners of the 9-anilinoacridines

Abstract

To investigate the possible importance of small levels of sulfonamide anion in the antileukemic [mouse] (L1210) 4''-(9-acridinylamino)methanesulfonalides, an anionic derivative was prepared, in which -COOH replaced-NHSO2CH3, and had experimental antitumor activity. Analogue synthesis and evaluation showed 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 2-dimensional reorientation of a planar, intercalated chromophore in relation to the neighboring purine-pyrimidine base pairs. 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.