Free-Radical Repair by a Novel Perthiol: Reversible Hydrogen Transfer and Perthiyl Radical Formation

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Abstract
2-(3-Aminopropyl-amino) ethaneperthiol (RSSH, the perthiol analogue of the thiol radioprotector, WR-1065) reacts with the α-hydroxy alkyl radical (CH3)2C.OH by donating a hydrogen atom as indicated by the characterization of perthiyl radicals (RSS.; λmax = 374 nm, ≈374 = 1680 ≈ 20 dm3 mol−1 cm−1) by pulse radiolysis. The perthiyl radical abstracts a hydrogen from the alcohol to establish a reversible hydrogen-transfer equilibrium. This equilibrium lies predominantly on the side of radical repair since the rate constants for the forward and reverse reactions at pH 4 are: k(RSSH + (CH3)2C−OH) = (2.4 ± 0.1) ± 109dm3 mol−1 s_1 and k(RSS− + (CH3)2CHOH) = (3.8 ± 0.3) × 103 dm3 mol−1 s−1 respectively. The pKa, (RSSH ← RSS− + H+) = 6.2 ± 0.1 was determined from the pH dependence of the rate of perthiol repair. Identical experiments have been performed with WR-1065 allowing a direct comparison of free-radical repair reactivity to be made with the parthiol analogue. At pH ≈ 7.4 the reactivities of the thiol and perthiol were similar, both repairing the alcohol radical with a rate constant of ∼ (2.4 ± 0.1) ← 108 dm3 mol−1 s−1. However, at pH 5 whilst the hydrogen-donation rate of the thiol was 15–20% higher than at pH 7.4, the perthiol reactivity was over an order of magnitude higher. The thermodynamic driving force for the observed enhanced free-radical repair reactivity of RSSH compared to RSH is attributed to the resonance stabilization energy of 8.8 kJ mol−1 within the RSS− radical. These results indicate a possible application of RSSH/RSS− as DNA-targeted antioxidants or chemoprotectors.

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