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
| Autor: | R. Jasztold‐Howorko, Prost Jf, Yves Rolland, Emile Bisagni, Stéphane Léonce, Alain Pierre, C. Landras, Laurence Kraus-Berthier, Ghanem Atassi, Nicolas Guilbaud |
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| Rok vydání: | 1994 |
| Předmět: |
medicine.drug_class
Cell Survival Carbazoles Carboxamide Olivacine Adenocarcinoma Medicinal chemistry chemistry.chemical_compound Mice Drug Discovery medicine Tumor Cells Cultured Animals Phenols Ellipticines Leukemia L1210 Alkyl Demethylation chemistry.chemical_classification Carbazole Biological activity Antineoplastic Agents Phytogenic chemistry Colonic Neoplasms Molecular Medicine Boron tribromide Neoplasm Transplantation |
| Zdroj: | Journal of medicinal chemistry. 37(15) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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