Design, physico-chemical characterization and in vitro biological activity of organogold(iii) glycoconjugates

Abstract

To develop new metal-based glycoconjugates as potential anticancer agents, four organometallic gold(III)–dithiocarbamato glycoconjugates of the type [Au^III(2-Bnpy)(SSC-Inp-GlcN)](PF₆) (2-Bnpy: 2-benzylpyridine; Inp: isonipecotic moiety; GlcN: amino-glucose scaffold; Au3–Au6) and the corresponding model non-glycosylated counterparts [Au^III(2-Bnpy)(SSC-Inp-R)](PF₆) (R: OEt (Au1), NH₂ (Au2)) have been generated and characterized by means of several analytical techniques (elemental analysis, FT-IR, ¹H-/¹³C-NMR, ESI-MS, UV-Vis, X-ray crystallography). Their stability under physiologically-relevant conditions (PBS solution) and n-octanol/PBS distribution coefficient (D_7.4) have also been evaluated. Gold(III) glycoconjugates showed an antiproliferative effect against ovarian carcinoma A2780 cells, with GI₅₀ values in the low micromolar range. Remarkably, their cell growth inhibitory effect increases upon the addition of a glucose transporter 1 (GLUT1) inhibitor, thus ruling out the involvement of GLUT1 in their transport inside the cell. Additional mechanistic studies have been carried out in A2780 cells, supporting the hypothesis of a facilitated diffusion mechanism (possibly mediated by glucose transporters other than GLUT1), and revealing their capability to act as topoisomerase I and II inhibitors and to disrupt mitochondrial membrane integrity, leading to the generation of ROS, thus resulting in the promotion of oxidative stress and, eventually, cell death.