Synthesis of Unprotected Cyclic Peptide Methylene Dithioacetals by Rhodium-Catalyzed Oxidation of Methanol to Formaldehyde.

In the presence of a rhodium catalyst, unprotected peptide dithiols possessing two cysteine residues are efficiently converted to their corresponding cyclic methylene dithioacetals in a mixed solvent of methanol and water (4:1) under an oxygen atmosphere (1 atm). The slow formation of formaldehyde inhibits side reactions by maintaining its concentration at a low level, which is a key feature of this reaction. This method can be applied to peptide dithiols containing amino acids such as Gly, Ala, Ser, Lys, Met, Phe, Tyr, and His and provides cyclic methylene dithioacetals without being affected by other functional groups. Primary alcohols, such as ethanol and isopropanol, can also be employed. Oxytocin can be cyclized to provide a cyclic methylene dithioacetal.

Rhodium-Catalyzed Synthesis of Peptide Polysulfides by Insertion of Sulfur into Unprotected Peptide Disulfides.

A rhodium-catalyzed insertion of sulfur into unprotected peptide disulfides in aqueous solvents has been developed, which yields mixtures of trisulfides and tetrasulfides. This method can be applied to peptides containing amino acids such as Gly, Phe, Tyr, Ser, Met, Asp, Gln, and Lys and provides polysulfides with various amino acid residues without being affected by functional groups. A reaction can be conducted on a gram scale. Vasopressin can also be converted into its corresponding polysulfides.

Antioxidant action of persulfides and polysulfides against free radical-mediated lipid peroxidation.

Hydrogen sulfide, hydropersulfides, and hydropolysulfides have been revealed to play important physiological roles such as cell signaling and protection against oxidative stress, but the underlying mechanisms and dynamics of action remain elusive. It is generally accepted that these species act by two-electron redox mechanisms, while the involvement of one-electron redox chemistry has received less attention. In this study, the radical-scavenging activity of hydrogen persulfide, hydrogen polysulfides (HSnH n = 2-4), and diallyl- or dialkyl-sulfides (RSnR, n = 1-4) was measured. Furthermore, their antioxidant effects against free radical-mediated human plasma lipid peroxidation were assessed by measuring lipid hydroperoxides. It was found that disodium disulfide, trisulfide, and tetrasulfide acted as potent peroxyl radical scavengers, the rate constant for scavenging peroxyl radical being 3.5 × 105, 4.0 × 105, and 6.0 × 105 M-1 s-1 in PBS pH 7.4 at 37 °C respectively and that they inhibited plasma lipid peroxidation efficiently, the efficacy is increased with the catenation number. Disodium tetrasulfide was 1.5 times as reactive as Trolox toward peroxyl radical and inhibited plasma lipid peroxidation more efficiently than ascorbate and Trolox. On the other hand, diallyl- and dialkyl-sulfides did not exert significant radical-scavenging activity, nor did they inhibit lipid peroxidation efficiently, except for diallyl tetrasulfide, which suppressed plasma lipid peroxidation, despite less significantly than disodium tetrasulfide. Collectively, this study shows that hydrogen persulfide and hydrogen polysulfides act as potent radical-scavenging antioxidants and that, in addition to two-electron redox mechanisms, one electron redox reaction may also play important role in the in vivo defense against deleterious oxidative stress.