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

Abstract

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.

Keywords: Ammonium dithiophosphates; Antiproliferative activity; Antiradical activity; Glutathione; Monoterpenes; Peptides.