Free radicals have been implicated in various pathological conditions such as, stroke, aging and ischemic heart disease (IHD), as well as neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s disease. The role of antioxidants in protection from the harmful effects of free radicals has long been recognized. Trapping extremely reactive free radicals and eliminating them from circulation has been shown to be effective in animal models. Nitrone-based free radical traps have been extensively explored in biological systems. Examples include nitrones such as PBN, NXY-059, MDL-101,002, DMPO and EMPO. However, these nitrones have extremely high oxidation potentials as compared to natural antioxidants such as Vitamin E (á-tocopherol), and glutathione. Becker et al. (1995) synthesized novel azulenyl nitrones, which were shown to have oxidation potentials much lower than that of any of the previously reported nitrone based spin traps. Another azulenyl nitrone derivative, stilbazulenyl nitrone (STAZN), was shown to have an even lower oxidation potential within the range of natural antioxidants. STAZN, a second generation free radical trap, was found to be markedly superior than the two most studied nitrones, PBN and NXY-059, in animal models of cerebral ischemia and in an in vitro assay of lipid peroxidation. In this study, a third generation azulenyl nitrone was synthesized with an electron donating group on the previously synthesized STAZN derivative with the aim to lower the oxidation potential even more. Pseudoazulenes, because of the presence of an annular heteroatom, have been reported to possess even lower oxidation potential than that of the azulenyl counterpart. Therefore, pseudoazulenyl nitrones were synthesized for the first time by extracting and elaborating valtrate from the roots of Centranthus ruber (Red valerian or Jupiter’s beard). Several pseudoazulenyl nitrones were synthesized by using a facile experimental protocol. The physical and biological properties of these pseudoazulenyl nitrones can be easily modified by simply changing the substituent on the heteroatom. Cyclic voltammetry experiments have shown that these pseudoazulenyl nitrones do indeed have low oxidation potentials. The oxidation potential of these nitrones was lowered even more by preparing derivatives bearing an electron donating group at the 3-position of the five membered ring of the pseudoazulenyl nitrone.

Melatonin is a neurohormone produced by the pineal gland in the brain. It functions as an antioxidant to scavenge free radicals. Free radicals are reactive species; they often oxidize the cells leading to oxidative stress which may lead to severe health complications. Reaction of melatonin with free radicals is known to be stepwise, as such the stability of the intermediates can be examined. Thus, the possibility of using melatonin as an in vivo spin trap can be determined. Spin traps allow characterization of unstable radical species using electron spin resonance spectroscopy. In this research, ab initio quantum chemistry techniques were used to calculate the energies of selected intermediates formed during the partial oxidation of melatonin by hydroxyl radical. Specifically, optimized geometries for melatonin, and selected intermediates with ·OH were obtained at the DFT/B3LYP/cc-pVXZ and HF/cc-pVXZ (X = D, T, Q) levels of theory. Extrapolations to the complete basis set limit were also performed.

The presence of excess free radicals in the body can result in severe health consequences because of oxidative damage to cells. Spin traps may be used as a probe to examine radical reactions in cells, but there is a need for less toxic and more lipid soluble examples. Melatonin is one of the numerous antioxidants used to scavenge free radicals in the body and reportedly one of the most efficient radical scavengers known. It is relatively nontoxic and easily crosses the lipid bilayer in cell membranes. Melatonin is thought to undergo a multistep oxidation process and this work investigates the potential for it to be used as a spin trap. The presence of electron withdrawing or donating groups added to melatonin may stabilize an intermediate and allow it to function as a spin trap. The essence of this study is to conduct a computational inquiry into the relative stability of melatonin, selected derivatives, and the partial oxidation products formed from the scavenging of hydroxyl radical. To determine this, geometries were optimized for each molecule at the DFT/B3LYP/6-31G(d) and HF/6-31G(d) levels of theory.

The cyclic nitrone 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), and the lesser known linear phenyl-N-tert-butylnitrone (PBN) and its phosphorylated analogues have been used as spin traps for the investigation of free radicals in biological systems. Theoretical work on these molecules suggests that there are important differences in their properties between biological systems and isolated molecules in the gas phase, most likely resulting from intra and intermolecular hydrogen bonding. Most dielectric solvation models such as the polarized continuum model and COSMO are incapable of direct determination of solvent-spin trap chemical interactions. To examine this, hybrid models incorporating COSMO for long range effects and discrete solvent molecules for short range effects, at the DFT/B3LYP/6-31G* level of theory, have been used to study the stabilization and alteration of the spin trap molecules properties in protic and aprotic polar solvents. The hybrid models have been successfully implemented to support the prominent role played by hydrogen bonding interactions in the stabilization of spin traps.

Melatonin (N-acetyl-5-methoxytryptamin, MLT) is a naturally occurring antioxidant which has shown some potential for use as a spin trap. Spin traps react with short lived hydroxyl radicals (HO·) to produce more stable products called spin adducts which may be characterized by electron paramagnetic resonance spectroscopy. However, the relative stability of hydroxyl spin adducts of melatonin derivatives (MLTD) compared to 2-hydroxymelatonin (HO-MLT) has not been examined computationally. Computational studies have been done on four selected MLTD; methylmelatonin (Me-MLT), chloromelatonin (Cl-MLT), cyanomelatonin (CN-MLT), and nitromelatonin (NO2-MLT). Geometry of the structures were optimized at the HF/6-31G(d), cc-pVXZ, (X=D and T) and DFT/B3LYP/6-31G(d), cc-pVDZ and cc-pVTZ levels of theory and extrapolated to the complete basis set limit using cc-pVXZ (X=D, T) basis sets. The lowest relative energy was found to be a mix of results for 2-OH-MLT-Me at HF and 2-OH-MLT-NO2 at DFT.

The DMPO type spin trap 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) and the exceptionally similar spin trap 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-l-oxide (EMPO) are widely studied in computational and theoretical works. This particular study examines the addition reactions that both these molecules undergo with the carcinogenic hydroxyl radical. This work used a relatively new approximation method, called the correlation consistent composite approach or ccCA, for carrying out quantum mechanical calculations to give the free energies of the products and reactants of the reactions. The free energies are to be used to extrapolate the rate constants of the reactions from the Arrhenius equation. Though both the spin traps studied have been widely examined and assessed in both theoretical and experimental work, accurately calculated rate constants have not been previously obtained using computational methods. The results obtained here will help to assess the efficiency and the accuracy of the ccCA method, as well as lead to the design of better, more novel spin traps.