Quantum-chemical investigation of the structure and the antioxidant properties of α-lipoic acid and its metabolites

Abstract

Quantum-chemical computations were used to investigate the structure-antioxidant parameter relationships of α-lipoic acid and its natural metabolites bisnorlipoic acid and tetranorlipoic acid in their oxidized and reduced forms. The enantiomers of lipoic and dihydrolipoic acid were optimized using the B3LYP/6-311+G(3df,2p), B3LYP/aug-cc-pVDZ and MP2(full)/6-31+G(d,p) levels of theory as isolated molecules and in the presence of water. The geometries of the metabolites and the values of their antioxidant parameters (proton affinity, bond dissociation enthalpy, adiabatic ionization potential, spin density, and the highest occupied molecular orbital energy) were calculated at the B3LYP/6-311+G(3df,2p) level of theory. The results obtained reveal similarities between these structures: a pentatomic, nonaromatic ring is present in the oxidized forms, while an unbranched aliphatic chain (as found in saturated fatty acids) is present in both the oxidized and the reduced forms. Analysis of the spin density and the highest occupied molecular orbital energy revealed that the SH groups exhibited the greatest electron-donating activities. The values obtained for the proton affinity, bond dissociation enthalpy and adiabatic ionization potential indicate that the preferred antioxidant mechanisms for α-lipoic acid and its metabolites are sequential proton loss electron transfer in polar media and hydrogen atom transfer in vacuum.

Fig. 1

Molecular structures of lipoic acid (1), the enantiomers of lipoic acid: R-(+)-LA (2a) and S-(−)-LA (2b), dihydrolipoic acid (3), the LA/DHLA redox pair (4), and lipoyllysine (5)

Fig. 2

Molecular structures of RLA/RDHLA metabolites: bisnorlipoic acid (RBLA, 1), 4,6-bisthiohexanoic acid (RDHBLA, 2), tetranorlipoic acid (STLA, 3), and 2,4-bisthiobutanoic acid (SDHTLA, 4)

Fig. 3

Antioxidant mechanisms of organosulfur compounds: HAT (1), SPLET (2), SET-PT (3). RSH organosulfur antioxidant, X ^• free radical. From [39]

Fig. 4

The geometries of RLA (1), RDHLA (2), SLA (3), and SDHLA (4) [obtained using rMP2(full)/6-31 + (d,p) and optimized in water]

Fig. 5

The geometries of RLA/RDHLA metabolites [obtained using rB3LYP/6-311 + G(3df,2p) and optimized in water]: RBLA (1), RDHBLA (2), STLA (3), and SDHTLA (4)

Fig. 6

The HOMO orbital distributions in RLA (1), SLA (2), RDHLA (3), SDHLA (4), RBLA (5), RDHBLA (6), STLA (7), and SDHTLA (8). The calculations were accomplished in vacuum with the isovalue 0.07