New pyridocarbazole derivatives. Synthesis and their in vitro anticancer activity.

In this paper, we describe our results of the synthesis and biological testing of analogues of the natural alkaloids olivacine and ellipticine. We have synthesized fourteen new 1-substituted pyrido[4,3-b]carbazole derivatives. All of them were tested in vitro for their anticancer activity on three human tumor cell lines: CCRF/CEM (T lymphoblast leukemia), A549 (lung adenocarcinoma), and MCF7 (breast cancer). Cytotoxicity to non-cancer cells was estimated in cultures of the mice fibroblast cell line 3T3 BALB. The anticancer activity of 9-methoxy-5,6-dimethyl-1-[(1,1-bis-hydroxymethyI-propylamino)-methyl]-6H-pyrido[4,3-b]carbazole (compound 9) was the strongest amongst compounds tested on the three cancer cell lines; it was about 5 times higher than ellipticine and about 10% higher than doxorubicin.

Synthesis of new 1-phenyl-6H-pyrido[4,3-b]carbazole derivatives with potential cytostatic activity.

A number of new 1-substituted-6H-pyrido[4,3-b]carbazole derivatives have been synthesized. Nine of the newly obtained compounds were subjected to preliminary in vitro cytostatic activity screening against murine leukemia (L1210), human lung cancer (A549) and human colon cancer (HT29) cell lines. One particular compound 6f exhibited over 20 times better activity against L1210 tumor cell line than the reference ellipticine.

Synthesis and structure-activity relationship analysis of new olivacine derivatives.

The number of 3'- and 4'-substituted 1-phenyl-6H-pyrido[4,3-b]carbazole derivatives have been synthesized and tested biologically. Eleven of the newly obtained compounds were subjected to the preliminary cytostatic screening for their activity against L1210 (murine leukemia), A498 (human kidney cancer), A549 (human lung cancer) and HT29 (human colon cancer) cell lines. Eight of tested derivatives exhibited significant biological activities, which only weakly depended on side chain length and position of the substituent.

New amides of 5-(4-chlorobenzoyl)aminoorotic acid: their synthesis and biological activity.

The synthesis and in-vitro biological evaluation of the amide series 4 of 5-(4-chlorobenzoyl)aminoorotic acid 2 are presented. The biological properties of a few 5-(4-chlorobenzoyl)amino-2,6-dihydroxy-N-substituted-4-pyrimidinecarboxamide derivatives 4 tested here were compared with those of the isosteric isothiazole derivative MR-2/94 (5-(4-chlorobenzoyl)amino-N-(4-chlorophenyl)-3-methyl-4-isothiazolecarboxamide), which possesses a strong immunosuppressive and anti-inflammatory activity [1, 2], It must be suggested that replacement of the isothiazole by a pyrimidine core ring system resulted in considerable lowering of the anti-inflammatory and immunotropic actions of the obtained amides. Physicochemical properties of 2-(4-chlorophenyl)-6,8-dihydroxy-4H-pyrimido[5,4-d]-1,3-oxazin-4-on 3 are also briefly described.

Synthesis and anticancer activity of new 1-substituted-6H-pyrido[4,3-b]carbazole derivatives.

This study examines the synthesis and cytostatic activity of new 5,6-dimethyl-1-substituted-6H-pyrido[4,3-b]carbazole derivatives. Their structures were confirmed by (1)H-NMR and elemental analysis. Seven of the new compounds were tested by the SRB method in vitro against human lung cancer (A549) and human kidney cancer (A498) cell lines. Biological tests indicated remarkable cytostatic effects of four compounds tested in comparison with ellipticine and cisplatin as reference drugs. One particular compound 3c was about four times more active on A498 than ellipticine with similar activity on the A549 cell line, and outperformed cisplatin activity on both tumor cell lines.

Synthesis of 5,6-dimethyl-9-methoxy-1-phenyl-6H-pyrido[4,3-b]carbazole derivatives and their cytotoxic activity.

Starting from 2-(6-methoxy-1-methyl-9H-carbazol-2-yl)ethylamine 7 and mixed anhydrides of 4-nitrobenzoic acid or 4-methoxybenzoic acid, the corresponding 5,6-dimethyl-9-methoxy-1-(4-substituted phenyl)-6H-pyrido[4,3-b]carbazoles 11a-b, 5,6-dimethyl-9-hydroxy-1-(4-substituted phenyl)-6H-pyrido[4,3-b]carbazoles 12a, 12c, and their quaternary salts 13a-d were obtained. The four new pyridocarbazole derivatives 12a-c and 13d satisfy the international activity criterion for synthetic compounds, namely an ID(50) value lower then 4 microg/mL in preliminary in vitro cytotoxic activity screening against the A549 cell line (non-small cell lung cancer).

An alternative way of the synthesis of 1-substituted 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole derivatives.

A keystone of this work was a modification of synthesis of the title compounds, which were used as substrates for the preparation of amides 5, 9-methoxyolivacine (4a) and ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate (4b) were obtained in good overall yields (4a--72%, and 4b--31%) on alternative ways of the synthesis. The pilot results of the cytostatic activity of iminium salts 12a (IC50 = 8 microM) and 12b (IC50 = 2 microM) were determined on L1210 mouse leukaemia cells.

Synthesis, structure, and cytostatic properties of new olivacine derivatives.

Starting from 2-(6-methoxy-1-methyl-9H-carbazol-2-yl)ethylamine and 6-methylpicolinic acid, 9-methoxy-5-methyl-1-(6-methylpyridin-2-yl)-6H-pyrido[4,3-b]carbazole 10 and its 6-alkylderivatives 12-17 were obtained. The newly obtained compounds showed significant cytostatic activity against cultured L1210 cells and high cytotoxicity towards various human tumor cell lines.

Synthesis and cytostatic properties of some 6H-Indolo[2, 3-b][1, 8]naphthyridine derivatives.

The new and efficient synthesis of the title heterocyclic ring system is described starting from suitable 2-chloro-1, 8-naphthyridines. The synthesized 6H-indolo[2, 3-b][1, 8]naphthyridine derivatives were tested in vitro on 55 tumor cell lines for their anticancer properties. The presence of the acetylamino moiety at position 3 in the main ring system proved to be crucial for the cytostatic activity of this class of compounds.

A new method for the synthesis of ranitidine.

An improved synthesis of the antiulcer drug Ranitidine from an oxazolidine derivative is reported.