Abstract. . In the study, the pharmacological activity of the pyridine derivative LHT-17-19 was studied in relation to the culture of pancreatic cancer cells PANC-1 and the culture of bladder cancer cells HT-29 expressing the epidermal growth factor receptor. The cultures were obtained from the library of tumor strains of the Moscow Research Institute of Oncology. P.A. Herzen - a separate structural subdivision of the Federal State Budgetary Institution "NMITs Radiology" of the Ministry of Health of Russia. LHT-17-19 was synthesized in the Department of Chemistry, Technology of Synthetic Medicines and Analytical Control of JSC VNTs BAV (Russia). LHT-17-19 and the reference drug "Doxorubicin" 50 mg each were added to the cultivation medium in the concentration range from 10-8 to 10-v. Compounds LHT-17-19 were shown to be able to induce death and suppress the growth of pancreatic cancer squamous culture (PANC-1) and bladder (HT-29) tumor cells expressing EGFR over a wide range of concentrations. So for pancreatic cancer (PANC-1), the effective inhibitory concentration for the compound LHT-17-19 was 1.3 × 10-7 M, while for the reference substance doxorubicin it was 6.0 × 10-5 M. bubble (NT-29) - 2.4 × 10-7 M and 5.2 × 10-4 M, respectively.
Introduction: The study aim was to explore a toxicological property and antitumor action of the novel pyridine derivative LHT-17-19 in cell culture and on experimental models of lung cancer in mice. Materials and methods: The study was performed on male and female ICR(CD-1), male BALB/c, male BALB/c nu/nu mice. Pyridine derivative (LHT-17-19) was studied as water-soluble pharmaceutical substance. Acute toxicity was evaluated in groups of 5 animals, and the results were analyzed by Finney. Antitumor and antimetastatic activity was studied in syngeneic and xenograft models of lung cancer in mice. Results and discussion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with GOST 12.1.007–76. The substance demonstrated an antitumor and antimetastatic property in mice with syngeneic tumor Lewis lung carcinoma as well as on the heterotopic tumor model of non-small cell lung cancer in humanized animals. Conclusion: LHT-17-19 belongs to class 3 of the toxicity classification of chemicals in accordance with WHO recommendation. LHT-17-19 exerts antitumor and antimetastatic property on both syngeneic and patient-derived lung cancer xenograft murine models. Graphical abstract
The work identified potential molecular targets for the implementation of the antitumor effect of a new domestic compound, an analogue of pyridine LHT-13-19. Using the "Autodock 4.2" software environment, flexible receptor-directed molecular biological docking was carried out in virtual reality, which makes it possible to most accurately predict the formation of a complex between a molecular structure and a biological target in real conditions of a specific biological system. For molecular docking, three-dimensional structures of the epidermal growth factor receptor (EGFR, PDB ID: 1M17, 4KN2) from the open electronic library Protein Data Bank (USA) were used. The ligands were prepared using the MGL Tools 1.5.6 software environment, and their optimization was performed using the Avogadro software (USA). The molecule of the compound, an analogue of pyridine nucleoside, was synthesized in the Department of Chemistry, Technology of Synthetic Medicines and Analytical Control of All-Union Research Center for Biological Active Compounds Safety (Russia). As a result of the experiments, it was found that the LHT-13-19 molecule forms a conformational intermolecular interaction with the active centers 1M17, 4KN2 of the epidemic growth factor EGFR. The affinity is based on the formation of hydrogen and electron-acceptor bonds, characterized by high values of the scoring function and free energy value. Moreover, in terms of the strength of the affinity, the LHT-13-19 substance is not inferior to the reference molecule erlotinib.
Abstract. The study was the antitumor activity of a new compound - a pyridine derivative (LHT-13-19). On the culture of human colon cancer HCT116, the suppressive concentration of LHT-13-19 was determined during incubation of tumor cells in the concentration range from 10-9 to 10-7 M. The survival of tumor cells was also determined in the MTT test. Antitumor activity in vivo was studied on thirty athymic humanized 12-week-old female mice of the BALB / c nu / nu line with xenograft adenocarcinoma of the large intestine, divided into 3 groups, 10 mice each, which received intraperitoneal injections of 0.9% sodium chloride solution in a volume of 0.5 ml, cyclophosphamide at a dose of 10 mg / kg, LHT-13-19 at a daily dose of 3.7 mg / kg, respectively, for 10 days. Daily incubation of human colon tumor cells with LHT-13-19 is accompanied by the formation of the cytotoxic effect of the compound. In a xenograft model of colon adenocarcinoma, 10-day intraperitoneal administration of compound LHT-13-19 at a daily dose of 3.7 mg / kg was accompanied by the formation of an antitumor effect in the form of an increase in the doubling time of the tumor size, the survival rate of animals - carriers of xenograft, and a decrease in the frequency of metastasis. Keywords. Pyridine derivatives, LHT-13-19, cell culture, anticancer activity, inhibitory concentration
Abstract. In the work, a pre-experimental screening of pyridinecarboxylic acid derivatives was performed by the PASS program, The work identified potential molecular targets for the implementation of the antitumor effect of a new domestic compound, an analogue of pyridine LHT-13-19. Using the "Autodock 4.2" software environment, flexible receptor-directed molecular biological docking was carried out in virtual reality, which makes it possible to most accurately predict the formation of a complex between a molecular structure and a biological target in real conditions of a specific biological system. For molecular docking, three-dimensional structures of the epidermal growth factor receptor (EGFR, PDB ID: 1M17, 4KN2) from the open electronic library Protein Data Bank (USA) were used. Molecules of compounds - pyridine derivatives LHT-13-19, LHT-16-19 and LHT-17-19 were synthesized in the Department of Chemistry, All-Union Research Center for Biological Active Compounds Safety (Russia). As a result of the experiments, it was found that all the studied molecules have inhibitory activity against proto-oncogenic kinases, however, in terms of the totality of predictive characteristics, as well as the likelihood of forming an antitumor effect, LHT-17-19, which was studied in docking studies, turned out to be the most promising compound. It was shown that LHT-17-19 has a high affinity for the epidermal growth factor kinase receptor EGFR-K, exhibits an affinity for the CSF1 receptor system, superior to that of all comparators - imatinib, erlotinib and pemetrexed. Also, in the process of docking approach and subsequent docking with the active site of tyrosine kinase EGFR-K and the human folate receptor FOLR2, an additional hydrogen bond is formed inside the LHT-17-19 molecule between the hydrogen proton of the amino group and the oxygen atom of the carbonyl group with atomic distances of 2.21 Å and 2 .49 Å, respectively.
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