[Antiglycation Activity of Isoindole Derivatives and Its Prediction Using Frontier Molecular Orbital Energies].

Abstract

The extracellular matrix (ECM) provides structural support and regulates cell activity. ECM dysfunction due to metabolic pathologies or aging can lead to disease. Developing ECM protectors is crucial for the etiological prevention and treatment of pathologies associated with ECM alterations. Key mechanisms of pathological changes in the ECM include nonenzymatic reactions, such as glycation and glycoxidation. The potential of agents as ECM protectors can be assessed by their capability of inhibiting these processes. Compounds based on heterocyclic scaffolds with partially hydrogenated isoindole fragments were tested for capability of slowing down the formation of advanced glycation end-products (AGEs). A combination of in silico and in vitro approaches was employed. In the in silico study, the energies of the frontier molecular orbitals of the compounds were determined using the ab initio method with the 6-311G(d,p) basis set. Antiglycation activity was then investigated in the glycation reaction of bovine serum albumin (BSA) with glucose, using BSA as a model protein. Pyridoxamine served as a reference compound. Antiglycation activities of the compounds were evaluated spectrofluorometrically by measuring the fluorescent products at excitation/emission wavelengths of 440/520 nm, which are not typically used for assessing antiglycation properties. Glycation and oxidation products in the human skin can be detected at these wavelengths. Their amount correlates with chronological age, in contrast to certain other glycation products. It was found experimentally that the energies of the frontier molecular orbitals of the compounds can serve as predictors of their capability of slowing down the formation of fluorescent products detected at 440/520 nm. Inhibiting the formation of the products may be significant for treatment and prevention of diseases, including metabolic, fibrotic, or age-associated conditions. At 100 μM, series of hydrogenated 3a,6-epoxyisoindole-7-carboxylic acids (compounds of type XIII) and cyclopenta[b]furo[2,3-c]pyrrole-3-carboxylic acids (structures of type XIX) were found to display the most pronounced antiglycation properties.