Synthesis of 9-O-substituted derivatives of 9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylic acid (2-(dimethylamino)ethyl)amide and their 10-and 11-methyl analogues with improved antitumor activity

Analogues of the antitumor drug S 16020-2 modified at the 9, 10, or 11 posi tion were synthesized and evaluated in vitro and in vivo on the P388 leukem ia and B16 melanoma models. Starting from 9-methoxy-5,11-dimethyl-6H-pyrido [4,3-b] acid ethyl ester, the 11-CH3 analogue of 9-hydroxy-5,6-dimethyl-6H- pyrido[4,3-b]carbazole (2-(dimethylamino)ethyl)amide (1), compound 4, was s ynthesized using a four-step sequence, whereas its 10-CH3 analogue 5 was pr epared using a two-step pathway, starting from compound 1. Finally starting from the 9-OH compounds 1, 4, and 5, a series of variously 9-O-substituted derivatives were synthesized. In these series, the most active-compounds r esulted from esterification of the 9-OH group with various aliphatic diacid s, which led to 9-O-CO-()-COOH derivatives of 1, 4, and 5. For these compou nds, the number of long-term surviving mice obtained at the optimal dose we re 60-100% in the ip/iv P388 leukemia and 10-35% in the ip/ip B16 melanoma, corresponding to an improved therapeutic index with respect to 1 and 4. Th is high antitumor activity, with curative examples in both models, was not due to a higher cytotoxicity since these compounds were equally or slightly less potent in vitro than 1 and 4. The most active compounds were thus sel ected for further in vivo evaluation.