Glutathione binding to dirhodium tetraacetate: a spectroscopic, mass spectral and computational study of an anti-tumour compound

Abstract

a See AcknowledgementsGlutathione (γ-L-glutamyl-L-cysteinyl-glycine) is a ubiquitous tripeptide found in all plants and animals. While a major participant in many biological reactions, glutathione has key roles as a metallochaperone, in the reduction of oxidative stress, in the transport of metabolites, and as a cellular thiol source. Here, we report its reaction with , dirhodium(II) tetraacetate (Rh2(OAc)4), a compound with anti-tumour properties, using electrospray ionization mass spectrometry and spectroscopic methods to observe in depth the stoichiometries of the final conjugate. Using computational analysis, we provide the first report of the orbital assignments for the resulting glutatathione-bound product. We also explore the competition by GSH for methionine-bound sites on Rh2(OAc)4 as a method for possible protection of its cellular-based therapeutic activity.

Aerobic reactions of antitumor active dirhodium(II) tetraacetate Rh2(CH3COO)4 with glutathione

“…However, it seems likely that in [Rh II 2 (AcO) 4 (H 2 A)] − the glutathione glycyl –COOH group of the H 2 A − ligand is deprotonated at the acidic pH of mixing Rh 2 (AcO) 4 and GSH, considering its low pK a value (3.22), rather than the coordinated cysteine thiol group (as assumed by Wong et al)[17]; see Scheme 2.…”

“…This band was attributed to LMCT from S -glutathionate (GS − ) dominated molecular orbitals to σ*(Rh 2 4+ ) in [Rh 2 (AcO) 4 (GS)(H 2 O)] − species, with axially coordinated thiolate to Rh 2 (AcO) 4 , retaining its paddlewheel structure. [17]…”

“…[5] Another recent spectroscopic, ESI-MS and computational study suggested that Rh 2 (AcO) 4 (GSH) 1-2 species form under anaerobic conditions in aqueous solution. [17]…”

Metallothionein: An Aggressive Scavenger—The Metabolism of Rhodium(II) Tetraacetate (Rh2(CH3CO2)4)

“…Another major cellular thiol, GSH, was found to rapidly form adducts with Rh 2 (OAc) 4 both aerobically and anaearobically. 76,77 If cytotoxicity by Rh 2 (OAc) 4 involves DNA adduct formation or inhibition of specific enzymes, then MT would be acting as a pretarget interference source. Alternatively, if the cytotoxicity involves the depletion of cellular thiols, then MT would be the desired target.…”

Positive and negative nano-electrospray mass spectrometry of ruthenated serum albumin supported by docking studies: an integrated approach towards defining metallodrug binding sites on proteins

“…So far, MS-based analysis of metallodrug binding to proteins has been performed almost exclusively in the positive ion mode, while the negative ion mode has been rarely applied. 14,15 This study describes identification of HSA binding sites for selected Ru compounds in both, positive and negative ion modes and discusses the advantages of each approach, as well as their complementarity and suitability for wider applications. Further, docking studies have been used to complement and rationalize the obtained experimental data.…”