Poliudov A. Functionalized cyclic sulfonates

The dissertation consists of an introduction, four chapters, conclusions, a list of sources used and appendices. The total volume of the dissertation is 287 pages, 151 figures, 37 diagrams, 4 tables, 7 appendices, 132 sources. Keywords: sultones, sulfonates, oncogenicity, receptor, molecular docking, DFT, synthesis, biological activity, reactivity, tautomerism, X-ray. The object of the study is 5,5-disubstituted and spirocyclic β-keto-γ-sultones (1,2λ6-oxathiolane-2,2,4-triones), their tautomeric transformations, chemical and physicochemical properties, reactivity, and biological activity. The aim of the work is the development of effective preparative synthetic methods and directed functionalization of new 5,5-dialkyl- and 5,5-spirosubstituted 1,2λ6-oxathiolane-2,2,4-triones as structural bioisosteres of tetronic acid, as well as a comprehensive study of their tautomeric properties, reactivity, and biological activity using in silico and in vitro methods. To achieve the set objective, a comprehensive methodological approach was applied, which includes classical and scaled-up preparative organic synthesis, NMR spectroscopy (1H, 13C, 19F), IR spectrometry, chromatography-mass spectrometry, and X-ray diffraction analysis (XRD). In addition, quantum chemical modeling was performed using density functional theory (DFT) in the Orca software package, alongside computer modeling, molecular docking (in silico), and biological screening (in vitro). The scientific novelty of the obtained results lies in the fact that the methods for obtaining dimethyl-substituted 1,2λ6-oxathiolane-2,2,4-trione based on the intramolecular sulfa-Dieckmann condensation of sulfonylated α-hydroxy acid esters have been improved. A series of new spirocyclic sultones with carbocyclic fragments (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) at the C(5) atom have been synthesized for the first time. The interaction of the ketomethylene fragment of the core with C-, N-electrophiles via alkylation, acylation, nitrosation, and azo-coupling reactions, as well as with N-, C-nucleophiles, was systematically investigated, allowing the preparation of the corresponding enamines, hydrazones, and Wittig reaction products. Using DFT calculations and NMR spectroscopy, the regularities of the substituent influence at the 3-position on the tautomeric equilibrium were established for the first time. A significant achievement is the first scale-up of the synthesis of base sultones up to 0,5 kg in a glass reactor with the development of their principal process flow diagram. The practical significance of the work consists in the creation of a universal and scalable procedure for the preparation of rigid spirocyclic sultones that are resistant to metabolic attack due to the presence of a quaternary carbon atom. Innovative pathways for the directed modification of the sultone core have been developed to create libraries of focused compounds. Based on comprehensive in silico and in vitro studies, new promising multitarget hits with antitumor and neuromodulatory activities, acting as inhibitors of CLK4 kinase and monoamine oxidase MAO B, have been identified. A standardized laboratory procedure and an algorithm for the search for potential drug candidates based on ketosultones have been proposed for the needs of medicinal chemistry and pharmacy.