231297-45-3Relevant academic research and scientific papers
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
Guillonneau, Claude,Pierré, Alain,Charton, Yves,Guilbaud, Nicolas,Kraus-Berthier, Laurence,Léonce, Stéphane,Michel, André,Bisagni, Emile,Atassi, Ghanem
, p. 2191 - 2203 (1999)
Analogues of the antitumor drug S 16020-2 modified at the 9, 10, or 11 position were synthesized and evaluated in vitro and in vivo on the P388 leukemia and B16 melanoma models. Starting from 9-methoxy-5,11-dimethyl-6H- pyrido[4,3-b]carbazole-1-carboxylic acid ethyl ester, the 11-CH3 analogue of 9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylic (2- (dimethylamino)ethyl)amide (1), compound 4, was synthesized using a four- step sequence, whereas its 10-CH3 analogue 5 was prepared 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 resulted from esterification of the 9-OH group with various aliphatic diacids, which led to 9-O-CO-()-COOH derivatives of 1, 4, and 5. For these compounds, the number of long-term surviving mice obtained at the optimal dose were 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. This 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 selected for further in vivo evaluation.
