Glutathione salts of O,O-diorganyl dithiophosphoric acids: Synthesis and study as redox modulating and antiproliferative compounds

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2018-01, Vol.99, p.179-188
• Main Authors: Akhmadishina, Rezeda A., Kuznetsova, Elena V., Sadrieva, Gulnaz R., Sabirzyanova, Leysan R., Nizamov, Ilyas S., Akhmedova, Gulnaz R., Nizamov, Ilnar D., Abdullin, Timur I.
• Format: Article
• Language: English
• Subjects: Ammonium dithiophosphates; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Antiradical activity; Cell Proliferation - drug effects; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; Glutathione; Glutathione - chemical synthesis; Glutathione - chemistry; Glutathione - pharmacology; Humans; MCF-7 Cells; Monoterpenes; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Peptides; Phosphates - chemical synthesis; Phosphates - chemistry; Phosphates - pharmacology
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2017.10.002

[Display omitted] •New bioactive glutathione O,O-diorganyl dithiophosphates were synthesized.•Improved Fenton reaction based assay was proposed to evaluate antioxidant peptides.•The dithiophosphates have enhanced redox modulating and antiproliferative activity.•The chemical approach can be used to develop bioactive derivatives of peptides. Reactions of glutathione (GSH) with O,O-diorganyl dithiophosphoric acids (DTPA) were studied to develop bioactive derivatives of GSH. Effective coupling reaction of GSH with DTPA was proposed to produce the ammonium dithiophosphates (GSH–DTPA) between the NH2 group in γ-glutamyl residue of GSH and the SH group in DTPA. A series of the GSH–DTPA salts based on O-alkyl or O-monoterpenyl substituted DTPA were synthesized. Enhanced radical scavenging activity of the GSH–DTPA over GSH was established with the use of DPPH assay and improved fluorescent assay which utilizes Co/H2O2 Fenton-like reaction. Similarly to GSH, the dithiophosphates induced both pro- and antioxidant effects in vitro attributed to different cellular availability of the compounds. Whereas extracellularly applied GSH greatly stimulated proliferation of cancer cells (PC-3, vinblastine-resistant MCF-7 cells), the GSH–DTPA exhibited antiproliferative activity, which was pronounced for the O-menthyl and O-isopinocampheolyl substituted compounds 3d and 3e (IC50≥1μM). Our results show that the GSH–DTPA are promising redox modulating and antiproliferative compounds. The approach proposed can be extended to modification and improvement of bioactivity of various natural and synthetic peptides.