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

The extracellular matrix (ECM) provides structural support and regulates cellular activity. Its disruption during metabolic pathologies or aging can lead to disease development. 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 non-enzymatic reactions such as glycation and glycoxidation. The potential of agents as ECM protectors can be assessed by their ability to inhibit these processes. In this study, compounds based on heterocyclic scaffolds, including partially hydrogenated isoindole fragments, were investigated for their ability to slow down the formation of advanced glycation end-products (AGEs). The study employed a combination of in silico and in vitro approaches. 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. Their antiglycation activity was then investigated in the glycation reaction of bovine serum albumin (BSA) with glucose, using albumin as a model protein. Pyridoxamine served as a reference compound. The antiglycation activity of the compounds was evaluated spectrofluorometrically by measuring the fluorescent products at excitation/emission wavelengths of 440/520 nm, which are not typically used for assessing antiglycation properties. At these wavelengths, glycation and oxidation products in human skin can be detected, which correlate with chronological age, unlike some other glycation products. Experimentally, it was found that the energies of the frontier molecular orbitals of the compounds can serve as predictors of their ability to slow down the formation of fluorescent products detected at 440/520 nm. Inhibiting the formation of such products may be significant for the treatment and prevention of diseases, including metabolic, fibrotic, or age-associated conditions. It was also established that at a concentration of 100 µM, the antiglycation properties are most pronounced in the 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).