Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Abstract

In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1] + , two pyridyl rings coordinate to the metal via a Au–C bond (C ∧ N ∧ N ∧ C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2] + all four pyridyl rings of the ligand coordinate to the metal via a Au–N bond (N ∧ N ∧ N ∧ N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [ 3 H]dofetilide equally well from cell membranes expressing the K v 11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H 2 biqbpy2 and TrxR-inhibiting Au + ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au + ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.

Recent development of gold(i) and gold(iii) complexes as therapeutic agents for cancer diseases

“…245 has more selective anticancer characteristics than 244 and cisplatin because it was 10 times cytotoxic to human cancer cells (A549, A431, A375, and MCF-7) than to noncancerous cells (MRC5). Mechanistic study highlights the different modes of action—for 244 , high gold cell intake, nuclear DNA damage, and interaction with hERG may contribute to cell death; for 245 , extracellular reduction released TrxR-inhibiting gold ions that were taken up in the cytosol, and a toxic tetrapyridyl ligand accounted for the toxicity 189 (Fig. 24).…”

[(C C)Au(N N)]+ Complexes as a New Family of Anticancer Candidates: Synthesis, Characterization and Exploration of the Antiproliferative Properties

“…This feature is even more pronounced in the case of [(C N N C)Au] + scaffolds for which all the four coordination sites are blocked. [16] Thus, based on these statements, one way to improve the biological properties of [(C N C)Au(L)] + complexes would be to reorganize the coordination sphere around the Au(III) cation to preserve its redox stability while enhancing its reactivity.…”

“…In this manner, a large panel of ligands have been investigated for this purpose, to stabilize Au(III), and their antiproliferative properties have been tested against various cancer cell lines. The main classes of ligands explored to date are chelating N-donor ligands, [6,7] porphyrins, [8] dithiocarbamates [9,10] as well as (C N), [11,12] (C N N), [13] (C N C) [14,15] and very recently (C N N C) [16] cyclometalated ligands as depicted in Figure 1.…”

Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey

“…Recently, the anticancer properties of two bis-cyclometalated gold(III) complexes by N6,N6 -di(quinolin-2-yl)-[2,2 -bipyridine]-6,6 -diamine (Figure 17, structure 38) and N6,N6 -di(isoquinolin-3-yl)-[2,2 -bipyridine]-6,6 -diamine (structure 39) were studied in a joint experimental and computational study [99]. Complex 39 was found to be stable in the presence of biological thiols, whereas 38 produced the metastable Au(I) species after reduction in a millimolar concentration of glutathione, thus releasing the TrxR-inhibiting Au + ions.…”

“…Another relevant aspect in the computational investigation of Au(I) and Au(III) metallodrugs is represented by the viability of either Au(III)→Au(I) or Au(I)→Au(0) reduction processes. Indeed, due to the possible reductive elimination affecting either Au(I) or Au(III) scaffolds, many metallodrugs are coordinated by ligands that provide for redox stabilization [95,[99][100][101][102][103]. DFT and, more generally, ab initio approaches can be potentially employed to probe the redox stability of gold metallodrugs, even before and after the target metalation has occurred.…”