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

Article abstract of 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 °C or 9- methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 °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.