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

Abstract

© 2017 Elsevier Inc. 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 ≥ 1 μM). 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.