RESUMEN
The excellent medicinal efficacy of glutathione trisulfide, an endogenous compound consisting of sulfane sulfur and two molecules of reduced glutathione, has been reported in recent years. However, no efficient procedure for the synthesis of trisulfide is yet available. Herein, we investigated the optimal conditions for the oxidation reaction of oxidized glutathione to thiosulfinate and its subsequent trisulfidation reaction using commercially available materials. The optimized one-pot reactions enabled the isolation of glutathione trisulfide dihydrate by crystallization on a 20 g scale in high yield (up to 74% for the two steps, >95% purity). Liquid chromatography-mass spectrometry/MS (LC-MS/MS) measurements using Na234S as a sulfur source revealed that 34S was inserted only into the center of the trisulfide with high selectivity (>99% enrichment) during the reaction. The reaction mechanism indicated that disulfide bonds were cleaved by the reaction of thiosulfinate and a sulfur source, followed by trisulfide bond-formation via the dehydration condensation of sulfenic acid and persulfide.
Asunto(s)
Glutatión , Glutatión/química , Oxidación-Reducción , Sulfuros/química , Estructura Molecular , Espectrometría de Masas en TándemRESUMEN
Lipoic acid trisulfide, a sulfane sulfur-containing trisulfide of α-lipoic acid, holds promise in pharmaceuticals, yet knowledge gaps persist regarding its synthesis, properties, and stability. Here, we synthesized the lipoic acid trisulfide with a purity exceeding 99% from α-lipoic acid on a gram scale and obtained novel ß-cyclodextrin clathrates (84%-95% yield). Differential scanning calorimetry confirmed the inclusion of lipoic acid trisulfide in ß-cyclodextrins. The resulting ß-cyclodextrin clathrates exhibited significant improvements in water solubility and thermal stability. This pioneering study demonstrated a novel approach to the practical preparation of trisulfide and its ß-cyclodextrin clathrates as active ingredients, paving the way for clinical development.