Medchem Russia 2019

Ural Branch of the Russian Academy of Sciences MedChem Russia 2019 4th Russian Conference on Medicinal Chemistry with international participants June 10-14, 2019 Ekaterinburg, Russia Abstract book © Ural Branch of the Russian Academy of Sciences. All rights reserved © Authors, 2019 The conference is held with the financial support of the Russian Foundation for Basic Research, project No. 19-03-20012 4th Russian Conference on Medicinal Chemistry with international participants. MedChem Russia 2019 Abstract book – Ekaterinburg : Ural Branch of the Russian Academy of Sciences, 2019. – 448 p. ISBN 978-5-7691-2521-8 Abstract book includes abstracts of plenary lectures, oral and poster presentations, and correspondent presentations of the Conference ORGANIZERS OF THE CONFERENCE Russian Academy of Sciences Ural Branch of the Russian Academy of Sciences Ministry of Science and Higher Education of the Russian Federation Ministry of Health of the Russian Federation Ural Federal University named after the First President of Russia B.N. Yeltsin Sverdlovsk Oblast Government Ministry of Industry and Science of Sverdlovsk Oblast Ekaterinburg City Administration Department of Chemistry and Material Sciences of RAS Scientific Council on Medical Chemistry of RAS Lomonosov Moscow State University, Faculty of Chemistry Postovsky Institute of Organic Synthesis of UBRAS Institute of Immunology and Physiology of UBRAS M.N. Mikheev Institute of Metal Physics of of UBRAS Institute of Physiologically Active Compounds of RAS N.N. Blokhin National Medical Research Center of Oncology of the Health Ministry of Russia Ural State Medical University Mendeleev Russian Chemical Society CONTENT Plenary Lectures ............................................ 7 Oral Presentations ...................................... 45 Poster Presentations ................................... 89 Correspondent Presentations ................... 153 Author Index ..............................................619 Partners and Sponsors ................................639 PLENARY LECTURES 8 MedChem Russia 2019 Synthesis of substances with high anti-cancer and anti-parasitic activity based on a new type of reactivity of aliphatic nitro compounds Aksenov A.V.1, Aksenov N.A.1, Aksenov D.A.1 and Rubin M.1,2 1Department of Chemistry, North Caucasus Federal University, 355009, Russian Federation, Stavropol, Pushkin St., 1a 2Department of Chemistry, Kansas University, 66045, United States, Lawrence, Kansas, Wescoe Hall Drive, 1251 Creating new classes of drugs is an urgent task, the solution of which involves a significant number of research teams. A special place is intended to search for new molecular scaffolds on base of which anticancer drugs can be found and more effective ways of synthesizing already known structures with anticancer activity. Recently, among the new synthetic methods of great importance can be distinguished: metalfree C-H -functionalization, transannulation, ring economy - processes. this report is devoted to the development of such methodologies in combination with the methodology of “smart reaction medium”, which is being successfully developed in our laboratory. It includes the development of synthetic methods based on the reaction of indoles with unsaturated nitro compounds and nitroalkanes. Based on this methodology, it was possible to obtain a large number of compounds with high anticancer activity, and a number of substances exhibit a rare property — reverse differentiation. Some compounds have antiparasitic activity against leishmaniasis. This work was supported by the Russian Science Foundation № 18-13-00238. Plenary lectures 9 Selective Inhibitors of BET-Proteins as Epigenetic Strategy in Oncology 1 2 2 1 Voitovich Iu.V. , Combes S. , Morelli X. , and Fedorov A.Yu. 1Department of organic chemistry, N.I. Lobachevsky Nizhny Novgorod State University, 603950 Russian Federation,Nizhny Novgorod, Gagarin avenue, 23 2CRCM, CNRS, Inserm, Institut Paoli-Calmettes, Aix-Marseille University, 13009 Marseille, France BET proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation. BET inhibitors provide a novel approach to epigenetic anticancer therapy. These inhibitors exhibit selectivity for tumor cells by preferentially binding to regions of DNA critical for the transcription of genes that determine a cell’s identity. Using the combination of different computational and experimental methods: virtual screening and FRET-methodologies, organic and diversity-oriented target-focused synthesis (DOTS), as well as crystallographical and biochemical approaches, several inhibitors of human BET-proteins with unforeseen selectivity profiles were identified. The hit-compounds contain xanthine, triazolopyrimidinyl and tetrahydrobenzazepine scaffolds and are able to bind preferentially to Brd4(BD1) and Brds(BD1) sites of BET-proteins and to provide the dose-response downregulation of c-Myc levels. References [1] J. Med. Chem., 2016, 59, 1634 [2] J. Med. Chem., 2018, 61, 5719 10 MedChem Russia 2019 Translational Approach to the Development of Drugs on the Example of Regulating the Activity of Signaling Proteins Garabadzhiu A.1 and Tribulovich V.1 1St. Petersburg State Institute of Technology (Technical University), 190013, Russia, St. Petersburg, Moskovskii pr., 26 The modern term “translational research” describes efforts aimed at on-the-fly use of fundamental results to develop potential methods for the treatment of diseases. One of the most promising objects in the targeted therapy of tumor diseases is the tumor suppressor p53 protein, which makes the vital activity of cancer cells impossible due to the activation of various signaling pathways. However, after the first successes in the rational development of small molecule p53 reactivators, problems were revealed. It was shown that when using MDM2-p53 protein-protein interaction inhibitors, the formation of resistant tumor cell subpopulations is observed. In such a situation, the main function of an effective drug is to trigger the most aggressive and selective mechanisms for the destruction of cancer cells [1]. Our aim is to establish the relationship between the structure of MDM2 inhibitors and the direction of transcriptional activity of the p53 protein saved from proteolysis. Multiple responses to the effects of small molecule compounds are not less pronounced in the case of AMPK, a key kinase that maintains energy homeostasis at the cellular and whole-body levels. Ubiquitous expression, as well as the presence of direct and indirect activation mechanisms determines the possibility of energy control of a large number of various processes occurring in the body. Three sites of direct binding for small molecule compounds, as well as the two-step nature of the AMPK activation allows varying the activation degree of within two orders of magnitude and, accordingly, achieving different effects [2]. In this case, our aim is to establish the relationship between the structure of the activator and integral effects of the AMPK activation. This work was supported by the Russian Science Foundation (project no. 16-13-10358). References [1] O. Fedorova, V. Tribulovich, et al. Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis. Cell Cycle. 2018, 17(15), 1917-1930. [2] D. Novikova, A. V. Garabadzhiu, et al. Activating effect of 3-benzylidene oxindoles on AMPK: from computer simulation to high-content screening. ChemMedChem. 2019, (in press). Plenary lectures 11 Dipeptide mimetics of neurotrophins: design and pharmacological properties Gudashevа T.A.1 and Seredinin S.B.2 1Department of Medicinal Chemistry, 2Department of Pharmacogenetics, FSBI “Zakusov institute of pharmacology”, 125315, RF, Moscow, Baltiyiskaya street, 8 Neurotrophins are a small family of closely related proteins that controls many aspects of the survival, development and functioning of neurons. There are 4 neurotrophins - NGF, BDNF, NT3 and NT4 – expressed in mammals. They are variously involved in the growth, differentiation of neurons, in neurogenesis, synaptogenesis and brain plasticity. Neurotrophins carry out their main effects through Trk tyrosine kinase receptors, which are activated due to dimerization caused by the ligand and subsequent autophosphorylation of tyrosine residues of the cytoplasmic domain. As a result, the binding sites of adapting and signaling proteins are formed on Trk. The complexes of these proteins with Trk activate the signaling cascades PI3K/AKT, MAPK/ERK and PLC-γ. These cascades are involved in neuroprotection, differentiation, synaptic plasticity and neurogenesis. The most studied neurotrophins are NGF and BDNF, which interact with TrkA and TrkB, respectively. BDNF plays the key role in depression and NGF in the pathogenesis of neurodegenerative disorders such as cerebral ischemia, Alzheimer’s disease and Parkinson et al. Full-length neurotrophins are pharmacologically unusable due to their pharmacokinetic limitations and the presence of serious side effects such as hyperalgesia, catastrophic loss of weight, carcinogenesis. In this case, for example, hyperalgesia caused by NGF is due to the activation of MAPK. However, it is known that the ability of neurotrophins to prevent the development of apoptosis is caused by the activation of the AKT signaling pathway. Neurotrophins are represented as symmetric homodimers, the monomeric units of it contain 7 beta turns connected by 4 hairpin loops, three of which are exposed to the outside (loops

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