Laboratory of molecular modeling and synthesis of biologically active compounds

The development of fundamental principles for the creation and implementation of new effective anticancer drugs makes it possible to reduce the burden of socially significant cancer diseases. Currently, the development of new effective drugs is often hampered by low bioavailability and selectivity of the antitumor effect of the resulting biologically active compounds, which subsequently have undesirable side effects. A separate problem is the development of materials as a system for targeted delivery and restoration of defects that arise after tumor removal with partial tissue resection. Such materials should have antitumor activity, while promoting tissue regeneration and not causing excessive immune reactions, such as inflammation and rejection. From the point of view of developing means of targeted delivery, the use of materials that undergo too long degradation reduces the effectiveness of drug therapy, since the rate and volume of drug delivery into the tissue or systemic bloodstream decreases. The project is aimed at solving the problem of increasing the life expectancy of cancer patients by creating new effective anticancer drugs with improved bioavailability and selectivity and materials based on them for targeted therapy. The proposed project is a comprehensive interdisciplinary study, including molecular design, synthesis of original hybrid structures based on chemical modifications containing pharmacophoric groups, assessment of the spectrum of biological activity of new compounds, and the electrospinning method for obtaining materials based on biodegradable polymers containing biologically active substances. Derivatives of ninhydrin (2,2-dihydroxyindan-1,3-dione) and indenoquinoxaline, which have anticancer activity, will be used as basic pharmacophores for creating hybrid structures. The project will use the concept of replacing the C-H bond with a C-F bond through organic synthesis, since the replacement of hydrogen atoms of benzene (and other aromatic) fragments with fluorine atoms often modifies physicochemical, biological, including pharmaceutical properties. The program of chemical modifications will also be based on the results of molecular modeling of the interaction of hybrid structures with the active sites of a wide range of cancer biotargets, the creation of libraries of compounds planned for synthesis and their virtual screening. The ADMET profile of the resulting compounds will be assessed to characterize their bioavailability and safety. To assess safety, the cytotoxicity of promising compounds will also be determined based on the results of screening in cell culture. Optimization of compounds from the point of view of the spectrum of their biological activity and safety will be carried out using computer modeling methods, including multi-target structure-activity relationship analysis (SAR and QSAR models). The scientific novelty of the research lies in the preparation of an original class of organic compounds based on fluorine-containing indenoquinoxalines and ninhydrins and the study of various parameters of their bioavailability, solubility and safety using targeted organic synthesis, molecular modeling and quantum chemical calculations. The most promising agents will be included for the first time in the composition of biodegradable materials, and the dynamics of the release of these compounds from their volume will be studied. The physicochemical properties of the obtained materials will be studied and a conclusion will be drawn about the possibility of their further use in anti-relapse therapy after removal of tumors and delivery of fluorocarbon aza heterocycles. The results of this project will become a fundamental basis for the development of new approaches to the treatment of cancer and a step towards personalized medicine. ((Grant RSF No. 24-73-00202)