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.

Abstract

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.

• Authors: R Jasztold-Howorko, C Landras, A Pierré, G Atassi, N Guilbaud, L Kraus-Berthier, S Léonce, Y Rolland, J F Prost, E Bisagni
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 37 Issue 15 Pg. 2445-52 (Jul 22 1994) ISSN: 0022-2623 [Print] United States
• PMID: 8057291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Carbazoles
• Ellipticines
• olivacine

Topics

• Adenocarcinoma (pathology)
• Animals
• Antineoplastic Agents, Phytogenic (chemical synthesis, pharmacology)
• Carbazoles (chemical synthesis, pharmacology)
• Cell Survival (drug effects)
• Colonic Neoplasms (pathology)
• Ellipticines (chemical synthesis, pharmacology)
• Leukemia L1210 (pathology)
• Mice
• Neoplasm Transplantation
• Tumor Cells, Cultured