Gold(I)-Phosphine-N-Heterocycles: Biological Activity and Specific (Ligand) Interactions on the C-Terminal HIVNCp7 Zinc Finger

Abstract

The syntheses and the characterization by chemical analysis, (1)H and (31)P NMR spectroscopy, and mass spectrometry of a series of linear triphenylphosphine gold(I) complexes with substituted N-heterocycle ligands (L), [(PPh3)Au(I)(L)](+), is reported. The reaction of [(PPh3)Au(L)](+) (L = Cl(-) or substituted N- heterocyclic pyridine) with the C-terminal (Cys3His) finger of HIVNCp7 shows evidence by mass spectrometry (ESI-MS) and (31)P NMR spectroscopy of a long-lived {(PPh3)Au}-S-peptide species resulting from displacement of the chloride or pyridine ligand by zinc-bound cysteine with concomitant displacement of Zn(2+). In contrast, reactions with the Cys2His2 finger-3 of the Sp1 transcription factor shows significantly reduced intensities of {(PPh3)Au} adducts. The results suggest the possibility of systematic (electronic, steric) variations of "carrier" group PR3 and "leaving" group L as well as the nature of the zinc finger in modulation of biological activity. The cytotoxicity, cell cycle signaling effects, and cellular accumulation of the series are also reported. All compounds display cytotoxicity in the micromolar range upon 96 h continuous exposure to human tumor cells. The results may have relevance for the reported inhibition of viral load in simian virus by the gold(I) drug auranofin.

Effects of coordination mode of 2-mercaptothiazoline on reactivity of Au(I) compounds with thiols and sulfur-containing proteins

“…The [Zn-AuF] + is also observed for compound 2, as well as the unreacted ZF, and a very low intense peak of the apo-peptide. These results are consistent with previous studies on [(PPh 3 )AuL] where L = Cl -and N-heterocycles [22]. The main characteristic of the reaction of ZF with compound 3 is the presence of high abundance peaks of the disproportionation product, as well as the free unreacted zinc finger.The main products of the reaction are [Au n F] + and [(Ph 3 P)AuF] + .…”

“…[14,[18][19][20][21][22] The soft nature of Au(I) and Au(III) ions suggests selenols and thiolcontaining proteins as targets, for example thioredoxin, trypanothione, reverse transcriptase, cysteine proteases (cathepsins) and zinc fingers. [14,17] The relatively facile ligand substitution of Au(I) and especially Au(III) compounds means that speciation and identification of active species is complex.…”

“…Continuing the systematic studies of the interaction of HIV-1-NCp7 with gold(I) compounds, [22], the interaction of compounds 1-3 with the C-terminal-NCp7 zinc finger (ZF) were investigated to understand the role of cyanide versus phosphines in the zinc ejection and ligand loss of the complexes. Conformational changes were evaluated by CD and the binding at the molecular level was evaluated by mass spectrometry.…”

Gold(I)-Triphenylphosphine Complexes with Hypoxanthine-Derived Ligands: In Vitro Evaluations of Anticancer and Anti-Inflammatory Activities

“…Among linear gold(I) phosphine complexes, those involving ligands as e.g. dithiocarbamates [1], sulfanylpropenoates [11], naphthalimide derivatives [12], imidazole, pyrazole [13], [14] as well as purine derivatives [15], [16] have been investigated. It has been established that the gold(I)-phosphine moiety is responsible for the actual interactions [3], [17] with the target sites of the biological molecules, i.e.…”

Synthesis, Reactivity, and Biological Activity of Gold(I) Complexes Modified with Thiourea-Functionalized Tyrosine Kinase Inhibitors

“…1 While these interactions are often nonspecific due to relatively fast ligand exchange rates, fortuitous targeting of specific cysteine residues by gold(I) complexes containing sufficiently long-lived carrier ligands has also been reported. 2 Several new lines of research suggest that gold(I) has a significant potential as a component of therapies designed to inhibit therapeutically relevant targets, such as zinc-finger domains 3 and protein kinases. 4 …”