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.
Background. The new anticancer chemical compound LHS-1269 from the class of indolocarbazoles is undergoing preclinical studies at the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia. LHS-1269 has a high antitumor activity on transplanted tumors of mice, showed high cytotoxic activity on many tumor cells lines in vitro, and has shown an inhibitory effect on vasculogenic mimicry in tumors in vitro. LHS-1269 does not affect the catalytic activity of human topoisomerases I and IIα. An antiangiogenic mechanism of the drug’s antitumor action is suggested.Aim. To evaluate the effect of LHS-1269 on the morphological features and angiogenesis of transplanted Lewis lung carcinoma (LLC) in BDF1 mice.Materials and methods. In BDF1 mice (n = 20) with transplanted LLC tumor on days 1 and 3 after 5-fold intraperitoneal administration of LHS-1269 in a single dose of 60 mg (total dose – 300 mg/kg), mice (n = 20) on days 5 and 8 after a single intravenous injection of LHS-1269 at a dose of 100 mg/kg, mice (n = 20) with transplanted LLC tumor without administration of LHS-1269 (control). The assessment of the antitumor effect was carried out according to the criterion of inhibition of tumor growth (%) and the study of the morphological features of the tumors. To assess the effect of LHS-1269 on tumor angiogenesis in LLC tumor sections, a visual calculation of the average number (density) of blood vessels and immunohistochemical detection of expression of the CD31+ endothelial marker were performed.Results. The LHS-1269 compound in animal groups with 5-fold and 1-fold use caused tumor growth inhibition – 59–70 and 67–79 %, with pronounced morphological changes and tumor cell death. There is an uneven distribution of blood vessels in tumors and surrounding tissues in all groups. LHS-1269 caused a statistically significant decrease in the average number of blood vessels in the tumor both after 5-fold and after 1-fold administration. The statistically significant decrease in the average number of blood vessels in the surrounding connective tissue tumor was observed only after 5-fold administration of the drug. The decrease in the average number of CD31+ endothelial cells after five times intraperitoneal administration was statistically insignificant compared to control (83.1 ± 8.7 and 59.6 ± 18.9, respectively). The increase in this indicator after a single intravenous injection of LHS-1269 was statistically significant.Conclusion. LHS-1269, when administered five times and once in mice, caused pronounced morphological changes in the form of damage and death of LLC tumor cells. The results of a study of angiogenesis in a tumor do not allow an unambiguous conclusion about the inhibitory effect of LHS-1269 on angiogenesis in LLC tumors in mice.
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