ABSTRACT
A pyridine group was linked to the tetrahydronaphthalene moiety of the derivatives described in the preceding paper, to afford new combined thromboxane receptor (TP-receptor) antagonists and synthase inhibitors. The most interesting compound 2f inhibits TXA2 synthase with an IC50 value of 0.64 microM and the aggregation of human platelets with an IC50 value of 0.063 microM and shows a long duration of action in different species after oral administration.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Receptors, Thromboxane/antagonists & inhibitors , Sulfonamides/chemical synthesis , Tetrahydronaphthalenes/chemical synthesis , Thromboxane-A Synthase/antagonists & inhibitors , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/antagonists & inhibitors , Animals , Enzyme Inhibitors/pharmacology , Guinea Pigs , Humans , In Vitro Techniques , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/pharmacology , Pressure , Rabbits , Structure-Activity Relationship , Sulfonamides/pharmacology , Tetrahydronaphthalenes/pharmacology , Thromboxane-A Synthase/blood , Trachea/drug effects , Trachea/physiologyABSTRACT
Starting from 2-(6-methoxy-1-methylcarbazol-2-yl)ethylamine and diethyl-2,6-pyridine dicarboxylate, the title compounds were obtained through five or six steps. The new compounds retained significant cytotoxicity towards various tumor cell lines, but in vivo studies on murine P388 leukemia, B16 melanoma and Lewis lung carcinoma showed a lowered antitumor activity with respect to that of the related olivacine lead compound 1.
Subject(s)
Antineoplastic Agents/chemical synthesis , Pyridines/chemical synthesis , Animals , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Lewis Lung/drug therapy , Cell Survival/drug effects , DNA, Neoplasm/drug effects , Doxorubicin/pharmacology , Drug Screening Assays, Antitumor , Humans , Leukemia P388/drug therapy , Melanoma, Experimental/drug therapy , Mice , Pyridines/pharmacology , Tumor Cells, CulturedABSTRACT
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.
