Introduction . The report considers the prospect of rational approach to the new anticancer agents creation based on indolocarbazole derivatives.Objective . To conduct a comparative study of 12 domestic N-glycosides, indolo[2,3-a]pirrolo[2,3-a]carbazole derivatives in the course of “structure – activity” bond analysis.Materials and methods . The investigation of influence of 12 carbohydrate – containing indolocarbazoles, synthesized in N. N. Blokhin Russian Cancer Research Center of the Ministry of Health of Russia, performed on models of solid transplantable mouse tumors: lung Lewis epidermoid carcinoma and B16 melanoma. The antitumor effect was assessed by Lewis epidermoid carcinoma and B16 melanoma tumor growth inhibition (TGI %) criterion.Results . A variety of indolocarbazoles modifications allowed revealing the dependence of their antitumor properties on the structure of both, the aglycone and the glycoside residue. Imino-nitrogen interchange of atoms in upper heterocycle influences on indocarbazole derivatives antitumor activity change. During a comparative study of 12 N-glycosides indolocarbazole derivatives on lung Lewis epidermoid carcinoma and B16 melanoma models, 8 derivatives showed antitumor activity.Conclusion . The formulated concepts on the modification features in indolocarbazole derivatives structure can be used for more active compounds creation with greater action selectivity.
The paper discusses the possible mechanisms of antitumor action of indolocarbazole derivatives. Here we present a data that show interaction drugs based on indolocarbazole derivatives with several intracellular targets and consequently activation different pathways of cell death. Also we present results of our studies on the mechanisms of antitumor action of compounds LCS-1006 and LCS-1208 synthesized in the N.N. Blokhin Russian Cancer Research Center, Ministry of Health of Russia.
Introduction. The search for new antineoplastic agents in a series of indolo[2,3-a]-carbazole derivatives is an urgent and promising direction, since compounds with antitumor activity have been found in this class. In the chemical fusion laboratory, N.N. Blokhin National Medical Research Center оf the Ministry of Health of Russia has developed an original and effective method for the synthesis of glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazoles, which makes it possible to synthesize derivatives of N-glycosides of indolo[2,3-a]carbazoles with different substituents in the heterocyclic parts including at the maleimide nitrogen atom and with different carbohydrate residues.The purpose of the study – the primary assessment of the antitumor activity of new derivatives of indolocarbazoles with a carbohydrate residue xylose in models of tumor growth mice.Materials and methods. The compounds studied at transplanted tumors of mice: the Lewis epidermoid carcinoma (LLC), colon cancer ACATOL, cervical cancer RSHM-5, breast adenocarcinoma CA-755. Studies were performed on immunocompetent mice: males and females of BDF1 hybrids (C57Bl/6 × DBA/2), females CBA/Lac and Balb/c. Compound solutions were prepared ex tempore and administered to the mice intraperitoneally at a dose of 60 mg/kg daily for five days. The antitumor effect was evaluated as to of tumor growth inhibition and increase of life span of the treated animals as compared with the control ones.Results. Eight compounds studied, containing D-xylose as a carbohydrate component and various substituents at the maleimide nitrogen atom, showed different degrees of antitumor activity. Two derivatives have been identified: N-[5,7-dioxo-12-(β-D-xylopyranosyl)-indole[2,3-a]pyrrolo[3,4-c]carbazol-6-il]benzamide (compound 4) and N-[5,7-dioxo-12-(β-D-xylopyranosyl)-5,7,12,13-tetrahydro-6H-indole[2,3-a]pyrrolo[3,4-c]carbazole-6-il]pyridin-2-carboxamide (compound 8), which showed high antitumor activity on 4 solid tumors of mice with a duration of effect of 12 days or more. The most pronounced antitumor effect was obtained in compounds 4 and 8 in RSHM-5 and Ca-755, tumor growth inhibition was amounted, respectively: in RSHM-5 – 68–82 % and 80–72 %; for Ca-755 – 57–62 % and 86–68 % (p <0.05).Conclusion. For further research, we chose the compound (N-[5,7-dioxo-12-(β-D-xilopiranosil)-5,7,12,13-tetrahydro-6H-indole[2,3-a] pyrrolo[3,4-c]carbazol-6-il]pyridin-2-carboxamide).
Introduction: The creation of highly effective original anticancer drugs remains an urgent direction of scientific research in tumor therapy. One of the promising groups in this regard is indolocarbazoles and their derivatives, which are capable of initiating various pathways of tumor cell death. The aim of the study was to evaluate an antiproliferative activity of a new, Russian derivative of N-glycoside substituted indolocarbazole 6-amino-12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1208) on models of transplantable tumors of mice and on human tumors in Balb/c nude mice. Materials and methods: Indolocarbazole sensitivity to LCS-1208 was assessed on transplantable tumors of mice – lymphatic leukemia L-1210, cervical carcinoma (CC-5), and colon adenocarcinoma (CAC) by five-fold intraperitoneal administration (ip) of the LCS-1208 substance in single doses of 50, 75, 100 mg/kg. Investigation into the effectiveness of the LCS-1208 lyo dosage form was performed on subcutaneous xenografts of human colon cancer SW620 by an intravenous administration (iv). The antitumor effect was evaluated by the tumor growth inhibition (TGI) and an increase in life span (ILS) of the treated animals as compared with the control ones. Evaluation of specific antitumor activity on xenografts was performed according to the tumor/control (T/C%) criterion (maximum criterion T/C≤42%). Results and discussion: According to the results of the study, the most sensitive to the action of the LCS-1208 substance in the case of an ip administration of a total dose of 375 mg/kg were CAC with TGI=97–62%, p≤0.001 up to 16 days after the treatment, and ILS=36% (criteria for TGI≥70% and ILS≥25%). On xenografts of a human colon cancer SW620, the effectiveness of the LCS-1208 lyo drug dosage form within the range of total doses from 50 to 150 mg/kg in case of iv to Balb/c nude mice was set at T/C = 35–2% (criterion T/C<42%). Conclusion: The presented results suggest possible effectiveness of LCS-1208 in treatment of colon malignant tumors of humans.
Indolocarbazole glycosidic derivative LCS-1269 with significant antiproliferative activity has been synthesized in N.N. Blokhin National Medical Research Center of Oncology. To control the quality of the substance, the chromatographic method of the assay was created and validated. The technique was carried out in a gradient mode using mobile phases consist of acetonitrile, trifluoroacetic acid and purified water. The specificity of the method was shown by checking of test solutions and the special solvent chromatograms. The method linearity was confirmed, and the parameters of linear dependence have been estimated, and the relationship was described by the equation: y = 49.23× – 35.51 with correlation coefficient 0.9998. The method’s precision was determined as the repeatability with a relative error of the mean 1.49% and was 2.433 ± 0.036. Was shown, that the results obtained in the intermediate precision estimation were not burdened with a systematic error. The detection limit and quantitation limit were calculated based on the linear relationship data as 3.15 μg/mL and 9.57 μg/mL, respectively. Sensitive HPLC method for LCS-1269 assay in substance has been developed and validated.
Introduction. N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia synthesized an original derivative of indolocarbazole with the carbohydrate residue xylose, which has a pronounced cytotoxic and anti-angiogenic activity. The substance LCS-1269 is an amorphous powder that is almost insoluble in water, which causes difficulties in the development of an injectable dosage form (IDP). To solve this problem, a technological approach to obtain a solid dispersion (SD) of LCS-1269 has been proposed.Aim. To develop a model of IDP of the indolocarbazole derivative LCS-1269 based on SD.Materials and methods. We used a substance LCS-1269 synthesized in the Chemical Synthesis Laboratory of the N. N. Blokhin National Medical Research Center of Oncology. Emuxol 268, Kolliphor® P 188, Soluplus®, Lutrol® F68, Kollidon® 12 and Kollidon® 17, soybean phosphatidylcholine unsaturated S PC and saturated S PC-3 were investigated as carriers of the active substance. SD LCS-1269 was obtained by solvent removal: the active substance was dissolved in acetone, the carrier − in chloroform, the obtained solutions were mixed, transferred into a bottle and evaporated under vacuum (50 ± 5 mbar) in the desiccator at water bath temperature 65 ± 2 °С. To obtain aqueous solution of LCS-1269 dry mass was dissolved using different auxiliary substances or their mixtures: water for injection, ethanol 95 %, benzyl alcohol, Kollisolv® PEG 400, MONTANOX™ 80. To increase stability, the aqueous solution of LCS-1269 was lyophilized in an Edwards Minifast DO.2 freeze dryer.Results and discussion. Kollidon® 17 was chosen as the carrier material for the SD active substance. It was found that a clear solution of LCS-1269 with the concentration of the active substance 0.5 % was formed by dissolving the SD in ethanol 95 % and then gradually diluting the alcohol mixture with water for injection. In this case, the mass ratio of the components of the developed model IDF LCS : Kollidon® 17 : ethanol : water is 1 : 40 : 32 : 127. As a result of freeze-drying of the water-ethanol solution of LCS-1269 the IDF in the form of lyophilizate easily soluble in a 10 % solution of ethanol was obtained.Conclusion. An IDF model of the hydrophobic derivative of indolocarbazole LCS-1269 based on SD was developed and submitted for biological studies to evaluate its effectiveness.
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