Theoretical Studies of Structures and Thermodynamic Parameters of Melatonin and its Metabolites: N1-Acetyl-N2-formyl-5-metoxy kynuramine and N1-Acetyl-5 metoxykynuramine

Abstract

Melatonin, a neurohormone is well known regulator of a number of physiological processes. In addition, numerous studies both in vitro and in vivo showed a strong antioxidant and free radical scavenging activity usually considered as a result of direct melatonin reactivity. However, two major metabolites of melatonin, N1-acetyl-N2-formyl-5-metoxy kynuramine (AMFK) and N1-acetyl-5-metoxykyunaramine (AMK) also showed strong free radical scavenging activity, but towards different biological free radicals. Melatonin oxidation mechanism in a complex biological environment has been studied at different conditions but still is partially understood. Reactivity of the molecule is always governed but its electronic properties and kinetic and thermodynamic stability. Thus, we performed theoretical calculations using Density Functional Theory (DFT) at with B3LYP/6-31G* basis set to calculate geometries, atomic charges and thermodynamic parameters for all three molecules. Semi-empirical calculations at PM1 level are also performed and compared with DFT data. Calculated atomic charges showed that nitrogen atoms as the most possible sites for interactions with electrophilic species such as free radicals. Oxygen atom in metoxy group also shows pronounced negative atomic charge. The most stable molecule is AMFK, followed by AMK and melatonin respectively. This trend can partially explain high melatonin reactivity and its fast decomposition in biological systems. Obtained values calculated at semi-empirical and ab inition levels are significantly different implying that conclusions based on calculations done at lower levels of theory can not be used as reliable when explaining experimental data.