The importance of molecules with antiradical potency that are produced in the human body has significantly increased. Among others, neurotransmitters and their metabolites act as the first line of defense against oxidative stress in the peripheral endocrine and the central nervous systems. Dopamine (DO), epinephrine (EP), norepinephrine (NE), l-DOPA, catechol, and three metabolites of dopamine (3-methoxytyramine (3-MT), homovanillic acid (HO), and 3,4-dihydrophenylacetic acid (DOPAC)) were investigated for their antiradical potency via computational methods and DPPH assay. Density functional theory calculations were used to determine the most probable reaction mechanism based on the thermodynamic parameters. These results suggested that hydrogen atom transfer (HAT)/proton-coupled electron transfer (PCET) and sequential proton loss electron transfer (SPLET) mechanisms are preferable in polar solvents. Several techniques were employed to differentiate between HAT and PCET mechanisms via examination of the transition state structures. Kinetic studies of HAT/PCET and electron transfer (ET) reactions, the second step of SPLET, have proven that ET is much faster for an order of 10-10. Based on this, it was concluded that SPLET was the dominant mechanism for the antiradical activity towards DPPH radicals in polar solvents. The findings suggest that all the investigated molecules can be classified as excellent antiradical scavengers, except for 3-MT and homovanillic acid.
It has been generally accepted that, due to high ionization potential values, single electron transfer followed by proton transfer (SET-PT) is not a plausible mechanism of antioxidant action in flavonoids. In this paper the SET-PT mechanism of quercetin (Q) was examined by revealing possible reaction paths of the once formed quercetin radical cation (Q(+)˙) at the M0-52X/6311+G(d,p) level of theory. The deprotonation of Q(+)˙ was simulated by examining its chemical behavior in the presence of three bases: methylamine (representative of neutral bases), the MeS anion (CH3S(-)) and the hydroxide anion (representative of anionic bases). It was found that Q(+)˙ will spontaneously be transformed into Q in the presence of bases whose HOMO energies are higher than the SOMO energy of Q(+)˙ in a given medium, implying that Q cannot undergo the SET-PT mechanism in such an environment. In the reaction with the MeS anion in both gaseous and aqueous phases and the hydroxide anion in the gaseous phase Q(+)˙ accepts an electron from the base, and so-formed Q undergoes the hydrogen atom transfer mechanism. On the other hand, SET-PT is a plausible mechanism of Q in the presence of bases whose HOMO energies are lower than the SOMO energy of Q(+)˙ in a given medium. In such cases Q(+)˙ spontaneously donates a proton to the base, with energetic stabilization of the system. Our investigation showed that Q conforms to the SET-PT mechanism in the presence of methylamine, in both gaseous and aqueous phases, and in the presence of the hydroxide anion, in the aqueous solution.
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