Synthesis and Evaluation of 9-Hydroxy-5-methyl- (and 5,6-dimethyl)-6H-pyrido[4,3-b]carbazole-1-N-[(dialkylamino)alkyl]carboxamides, a New Promising Series of Antitumor Olivacine Derivatives

• Published in: Journal of medicinal chemistry 1994-07, Vol.37 (15), p.2445-2452
• Main Authors: Jaszfold-Howorko, Richard, Landras, Corinne, Pierre, Alain, Atassi, Ghanem, Guilbaud, Nicolas, Kraus-Berthier, Laurence, Leonce, Stephane, Rolland, Yves, Prost, Jean-Francois, Bisagni, Emile
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - pathology; Animals; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - pharmacology; Carbazoles - chemical synthesis; Carbazoles - pharmacology; Cell Survival - drug effects; Chemistry; Colonic Neoplasms - pathology; Ellipticines - chemical synthesis; Ellipticines - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Leukemia L1210 - pathology; Mice; Neoplasm Transplantation; Organic chemistry; Preparations and properties; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00041a024

Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)-olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy-1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 degrees C or 9-methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 degrees C. Biological testing of the newly obtained 1-carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.