Gold(III) Dithiocarbamate Derivatives for the Treatment of Cancer:  Solution Chemistry, DNA Binding, and Hemolytic Properties

Abstract

Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target.

Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase

“…In this simple molecule the neutral triethylphosphine ligand was described as conferring membrane permeability while the mono-anionic tetraacetylthioglucose was reported as being displaced quite rapidly in vivo. Extensive multinuclear ( 1 H, 13 C and 31 P) NMR studies, which focused on the interaction of auranofin with serum albumin, have established that the drug appears to react at the albumin cys-34 site via a ligand-exchange reaction that displaces the sulphydryl group [5]. Both deacetylated auranofin and the parent [AuCl(PEt 3 )] complex form the same [(Et 3 P)Au(S-alb)] adduct by displacement of the anion.…”

“…Certain phosphine gold(I) 5 xanthate and dithiocarbamate compounds have proved to possess antiarthritic and in vitro antitumor activities [12]. Moreover, some gold(III)-DTC complexes have recently demonstrated an outstanding potential as anticancer agents able to overcome cisplatin resistance [13].…”

New applications of old metal-binding drugs in the treatment of human cancer

“…Because the cellular environment is generally reducing, Au (III) is expected to be reduced to Au (I) and metallic Au, making Au (III) complexes less effective (109). Interest in these complexes increased after Pt (II) complexes showed positive results, because Au (III) and Pt (II) are isoelectronic and tetracoordinate gold (III) complexes share the same square planar geometry as cisplatin (110). Many complexes were synthesized and tested against a variety of human cancers, including cisplatin-resistant cell lines (108).…”

The synthesis, chemical and biological properties of dichlorido(azpy)gold(III) chloride (azpy= 2-(phenylazo)pyridine) and the gold-induced conversion of the azpy ligand to the chloride of the novel tricyclic pyrido[2,1-c][1,2,4]benzotriazin-11-ium cation

“…Many gold(III) compounds are able to overcome to a large extent resistance to cisplatin, suggesting a different mechanism of action with respect to cisplatin [18][19][20][21]. Mechanistic studies indeed did suggest that, in contrast to cisplatin, DNA is not the primary target of gold complexes.…”