Antioxidant generation and regeneration in lipid bilayers: the amazing case of lipophilic thiosulfinates and hydrophilic thiols

Abstract

We demonstrate that the garlic-derived chemopreventive agent allicin and the related anamu-derived petivericin are poor radical-trapping antioxidants in lipid bilayers, but that the in situ reaction of a lipophilic analog and a hydrophilic thiol yields an extremely potent radical-trapping antioxidant that can be recycled in the presence of excess thiol.

Methods for determining the efficacy of radical-trapping antioxidants

“…An example of the latter is the application of the probe to study the RTA activity of allicin and petviercin, the purported antioxidants in garlic and anamu, respectively. 102 Here, there is no effect of allicin or petivericin on probe oxidation, even at very high loadings, corresponding to k inh values at least 100-fold smaller than for α-TOH. Lipid peroxidation arising due to oxidative stress has been linked to the onset of many degenerative diseases, such as atherosclerosis, 103 neurodegenerative disease, 104 and cancer.…”

Inspired by garlic: insights on the chemistry of sulfenic acids and the radical-trapping antioxidant activity of organosulfur compounds

“…26 Interestingly, the high reactivity of the compound translated from solution to the biphasic environment of the liposomes; in fact, 5 was found to be 10-fold more reactive than α-TOH. 26 In addition, it displayed the same powerful co-antioxidant cooperativity with NAC as did hexylated petivericin, 26 lending unequivocal support to the suggestion that a thiol can regenerate a sulfenic acid from its sulfinyl radical in biphasic systems.…”

“…To test this hypothesis, we synthesized a hexylated analogue of petivericin (4), with the anticipation that the more lipophilic substituent would better anchor the sulfenic acid derived from Cope elimination in the lipid bilayer. 26 Whilst the hexylated petivericin yielded measurable RTA activity (cf. retarding of the initial rate of fluorescence increase in Figure 2C relative to Figures 2A and 2B), it was still quite poor compared to established RTAs, such as α-TOH.…”

“…retarding of the initial rate of fluorescence increase in Figure 2C relative to Figures 2A and 2B), it was still quite poor compared to established RTAs, such as α-TOH. 25,26 However, since sulfenic acid formation from thiosulfinates can also be achieved via reaction with a good nucleophile, such as a thiol, we also investigated whether sulfenic acid formation could be promoted by addition of N-acetylcysteine (NAC) to the buffer in which the liposomes were suspended. While doing so had no effect on the (lack of) activity of allicin and petivericin, a remarkable effect was observed on the hexylated petivericin-inhibited oxidations (cf.…”

“…Figure 2D). 26 In fact, the combination of hexylated petivericin and an equivalent of NAC made for a more effective RTA than α-TOH! Moreover, the addition of more than one equivalent of NAC prolonged the inhibited period further.…”