Auranofin, a gold(I)-basedcomplex, is under clinicaltrials forapplication as an anticancer agent for the treatment of nonsmall-celllung cancer and ovarian cancer. In the past years, different derivativeshave been developed, modifying gold linear ligands in the search fornew gold complexes endowed with a better pharmacological profile.Recently, a panel of four gold(I) complexes, inspired by the clinicallyestablished compound auranofin, was reported by our research group.As described, all compounds possess an [Au{P(OMe)(3)}](+) cationic moiety, in which the triethylphosphine of the parentcompound auranofin was replaced with an oxygen-rich trimethylphosphiteligand. The gold(I) linear coordination geometry was complementedby Cl-, Br-, I-, and the auranofin-like thioglucose tetraacetate ligand. As previouslyreported, despite their close similarity to auranofin, the panel compoundsexhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overallpharmacokinetic profiles. To get better insight into the P-Austrength and stability, an extensive study was carried out for relevantbiological models, including three different vasopressin peptide analoguesand cysteine, using P-31 NMR and LC-ESI-MS. A DFT computationalstudy was also carried out for a better understanding of the theoreticalfundamentals of the disclosed differences with regard to triethylphosphineparent compounds. Acombined experimental and theoretical approach has beenused in order to assess how the structural modifications on the phosphineligand of auranofin impact the chemical features of the resultingderivatives. These structural modifications were able to stronglyaffect the -Au-P- bond strength until obtainingan inverted order of ligand exchangeability with respect to the AFbehavior, impacting the overall biological mode of action.