Shulga Y. Phosphonic, phosphinic, and phosphoric acids as inhibitors of glutathione S-transferases

The dissertation is devoted to the investigation of the properties of new effective inhibitors of glutathione-S-transferases among calix[4]arene methylenebisphosphonic, calix[4]arene phosphinic and calix[4]arene phosphoric acids, as well as among photoactive α-ketophosphonic acids with aliphatic, aromatic, and macrocyclic scaffolds. For the first time, the laws of influence of amphiphilic calix[4]arene methylenebisphosphonic, calix[4]arene α-hydroxymethylenebisphosphonic and calix[4]arene α-ketophosphonic acids on the activity of glutathione-S-transferases were established. The dependence of the activity of the new inhibitors on their structure, in particular on the nature of the substituents and the macrocyclic scaffold, was analyzed. The selective effect of inhibitors on the activity of human GSTA1-1 compared to inhibition of GSTP1-1 was demonstrated. On the basis of kinetic studies and molecular docking, the mechanisms of the inhibitory effect of phosphonic acids and their derivatives on the activity of glutathione-S-transferases was proposed. For the first time, the photodependent effect of α-ketophosphonic acids with aliphatic, aromatic, and macrocyclic scaffolds as inhibitors of glutathione-S-transferases was established, the peculiarities were clarified, and the kinetics of enzyme inactivation from various sources was studied. Based on this approach, new micromolar GSTase inhibitors from human placenta were found. The effectiveness of calix[4]arene α-ketophosphonic acids as photodependent inhibitors of glutathione-S-transferases was described for the first time. The process of inactivation of these enzymes at different inhibitor concentrations was represented by pseudo-first-order rate constants and second-order rate constants. It was demonstrated that the course of photoinactivation of GSTase can be influenced by the nature of the substituents on the lower ring, as well as the number of α-ketophosphonate groups on the upper ring of the macrocycle. The mechanisms of inactivation of GSTA1-1 and GSTP1-1 upon irradiation were proposed, which included the binding of calix[4]arene-α-ketophosphonates at the active center of the enzyme and the radical modification of its amino acid residues essential for catalysis. The results of the dissertation substantiate the relationship between the structure and inhibitory capacity of new phosphorus-containing inhibitors of glutathione-S-transferases and form approaches to the creation of new effective and selective inhibitors of glutathione-S-transferases among derivatives of methylenebisphosphonic, phosphinic and phosphoric acids with a calix[4]arene scaffold, as well as among photoactive α-ketophosphonic acids. The obtained data can be useful in the development of new potentially bioactive compounds and drugs.