Insights into the Reactivity of Gold–Dithiocarbamato Anticancer Agents toward Model Biomolecules by Using Multinuclear NMR Spectroscopy

Abstract

Some gold(III)-dithiocarbamato derivatives of either single amino acids or oligopeptides have shown promise as potential anticancer agents, but their capability to interact with biologically relevant macromolecules is still poorly understood. We investigated the affinity of the representative complex [Au(III)Br2(dtc-Sar-OCH3)] (dtc: dithiocarbamate; Sar: sarcosine (N-methylglycine)) with selected model molecules for histidine-, methionine-, and cysteine-rich proteins (that is, 1-methylimidazole, dimethylsulfide, and N-acetyl-L-cysteine, respectively). In particular, detailed mono- and multinuclear NMR studies, in combination with multiple (13)C/(15)N enrichments, allowed interactions to be followed over time and indicated somewhat unexpected reaction pathways. Whereas dimethylsulfide proved to be unreactive, a sudden multistep redox reaction occurred in the presence of the other potential sulfur donor, N-acetyl-L-cysteine (confirmed if glutathione was used instead). On the other hand, 1-methylimidazole underwent an unprecedented acid-base reaction with the gold(III) complex, rather than the expected coordination to the metal center by replacing, for instance, a bromide. Our results are discussed herein and compared with the data available in the literature on related complexes; our findings confirm that the peculiar reactivity of gold(III)-dithiocarbamato complexes can lead to novel reaction pathways and, therefore, to new cytotoxic mechanisms in cancer cells.

Anticancer Gold(III) Peptidomimetics: From Synthesis to in vitro and ex vivo Biological Evaluations

“…[13,14] This phenomenonw as recently explained by the presence of two differenti soformso ft he compounds (in dynamic equilibrium in solution). [56] Crystal structures Complex IT05, racemate IT03/IT04, and the urethane-protected precursor of ap eptide ligand,n amely Z-l-Pro-Aib-OtBu, were characterized by single crystal X-ray diffraction analysis. The molecular structure of IT05i sr eported in Figure2.T he metal exhibits asquare planar geometry achieved by the (S,S)chelate dithiocarbamato( dtc) ligand and by two bromide ions.…”

Structural Characterization of a Gold/Serum Albumin Complex

“…7,8 This compound consists of a square planar gold(III) centre with a bidentate dithiocarbamato ligand and two bromide ligands. 9 Notably, AuL12 has been shown to behave as a prodrug by releasing its bromide ligands. Significant oxidizing properties of the compound were also documented.…”

Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells

“…In fact, the [AuCl 2 (pipeDTC)] complex was poorly soluble in DMSO, while chloroform was not chosen because its volatility did not allow analyses at 37 °C. The molar ratio between the complex and the model molecule was 1:1 for DMS, and 1:2 for PrSH and 1-MeIm [ 26 ]. This study highlighted that all the three compounds are inert toward dimethyl sulfide and 1-methylimidazole, but underwent reduction in the presence of the thiol moiety ( Figures S3–S11 ).…”