Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

Abstract

Au(PEt 3)I (AF-I hereafter), the iodide analog of the FDA-approved drug auranofin (AF hereafter), is a promising anticancer agent that produces its pharmacological effects through interaction with non-genomic targets such as the thioredoxin reductase system. AF-I is endowed with a very favorable biochemical profile showing potent in vitro cytotoxic activity against several cancer types including ovarian and colorectal cancer. Remarkably, in a recent publication, some of us reported that AF-I induces an almost complete and rapid remission in an orthotopic in vivo mouse model of ovarian cancer. The cytotoxic potency does not bring about highly severe side effects, making AF-I very well-tolerated even for higher doses, even more so than the pharmacologically active ones. All these promising features led us to expand our studies on the mechanistic aspects underlying the antitumor activity of AF-I. We report here on an integrated experimental and theoretical study on the reactivity of AF-I, in comparison with auranofin, toward relevant aminoacidic residues or their molecular models. Results point out that the replacement of the thiosugar moiety with iodide significantly affects the overall reactivity toward the amino acid residues histidine, cysteine, methionine, and selenocysteine. Altogether, the obtained results contribute to shed light into the enhanced antitumoral activity of AF-I compared with AF.

Molecular dynamics simulation of the Pb(II) coordination in biological media via cationic dummy atom models

“…Although these outcomes might represent a limitation to the employment of non-bonded topological schemes for the description of Pb(II) coordination by sulfur ligands, it should be also taken into account that the binding of thiol at metal centers may often be followed by deprotonation, leading to the corresponding thiolate complex. Several theoretical and experimental evidences have confirmed that a marked decrease of the thiol pKa occurs upon coordination at even soft metal centers such as Au(I) [66][67][68][69], Au(III) [70] and also Pb(II) [23]. Thus, the use of empirical force field implemented with non-bonded potentials describing the Pb(II) coordination at sulfur ligands may still be considered valuable by assuming the thiolate, and not thiol, as the metal-binding form.…”

Reactivity of arsenoplatin complex versus water and thiocyanate: a DFT benchmark study

“…In the present study, we assessed seven among the routinely employed and recently developed density functionals for their capability to predict the structure and reactivity of Cl-Pt(NH = C(CH 3 )-O) 2 As(OH) 2 , arsenoplatin (AP), in order to point out the adequate level of theory to use in future investigations on its mechanism of action. In particular, we considered the widely used hybrid GGA functional B3LYP [44,45] and its variant including Grimme's empirical dispersion correction B3LYP-D3 [46], the meta-GGA functional originally designed to study transition metal complexes M06-L [47], the Minnesota hybrid meta-GGA functional M06-2X [48], the one-parameter hybrid GGA functional PBE0 [49] and two more recent range-separated hybrid functionals which have been shown to provide good results for transition metal systems CAM-B3LYP [50] and ωB97X [51], which are known to give a good description of geometries and reaction profiles for transition or heavy metal-containing compounds [52][53][54][55][56], including structure and reactivity of transition metal complexes [57,58], and particularly antitumor Pt-based compounds [32,[59][60][61]. We also considered the influence of the use of three basis sets differing in their size and for the number of polarization and diffuse functions.…”

Anticancer effects against colorectal cancer models of chloro(triethylphosphine)gold(I) encapsulated in PLGA–PEG nanoparticles

“…It is now widely recognized that the pharmacologically active portion of the AF molecule is the cationic fragment [Au(PEt 3 )] + (Pratesi et al 2018 ; Zoppi et al 2020 ) while the thiosugar moiety mainly acts as a carrier ligand improving the bioavailability and the gold complex pharmacokinetic profile when orally administered (Marzo et al 2017 ). Based on these arguments, recently, we started a systematic and comparative evaluation of a series of AF-related compounds (Marzo et al 2017 , 2018 ; Tolbatov et al 2020 ). Our attention was firstly focused on AF-related complexes where the thiosugar moiety is replaced by halide ligands.…”