Reactions of radicals with PERK kinase inhibitor and its analogue under oxidative and reductive stress conditions. Pulse radiolysis study

Abstract The scavenging of primary free radicals generated during radiolysis of water ( e aq − , •OH, •H) and CO2•‒ (reducing radical) or N3• (oxidizing radical) by PERK inhibitor, AMD (3-acetyl-6-methylheptane-2,4-dione) and APD (3-acetyl-2,4-pentanedione) has been studied with details. AMD is a low molecular weight inhibitor of the PERK-dependent antiproliferative signaling pathway and constitutes the foundation of an innovative therapeutic strategy in the treatment of cancer diseases. The applied compounds exist in the three different forms depending on pH of aqueous solution: ketone, enol and enolate form. The effect of pH on the absorption spectra of AMD and APD has been studied and the value of pKa for the keto – enol equilibrium (conversion of the ketone to enol) and pKa for the enol – enolate form were calculated. Redox processes studied by pulse radiolysis method were more effective at neutral or alkaline pH than in an acidic solution. The influence of human serum albumin (HSA) on the oxidation and reduction process of examined compounds was studied. The kinetics of radicals reaction with tested compounds has been compared for neat buffer solution and systems containing HSA. The results indicate competitive electron scavenging by studied scavengers and protein.