Gold‐Dithiocarbamato Glycoconjugates as Potential Anticancer Agents: Design, Physico‐Chemical Characterization, and In Vitro Biological Activity

Metal-dithiocarbamato glycoconjugates based on gold(III), gold(I)-phosphino, and gold(I)-carbene scaffolds are here investigated as potential anticancer agents. Contrary to expectations, they induce cell death by acting at the extracellular level rather than targeting overexpressed glucose transporters.

To develop new metal-based glycoconjugates as potential anticancer agents, three gold(III)-dithiocarbamato glycoconjugates of the type [Au^IIIBr₂(SSC-Inp-GlcN)] (Au3-5), their gold(I)-phosphine counterparts [Au^I(SSC-Inp-GlcN)(PPh₃)] (AuP3-5), and gold(I)-carbene analogs [Au^I(SSC-Inp-GlcN)(Et₂BzImy)] (AuC3-5) (Inp: isonipecotic moiety; GlcN: amino-glucose scaffold; Et₂BzImy: 1,3-diethylbenzimidazol-2-ylidene moiety), as well as the corresponding non-glycosylated counterparts (Au1-2, AuP1-2, and AuC1-2) bearing a terminal ester or amide function, are generated and characterized by means of several analytical techniques (FT-IR, ¹H-/¹³C-NMR, UV–Vis, X-ray crystallography). Their stability under physiologically relevant conditions (phosphate-buffered saline solution) has also been evaluated. Contrary to the gold(III)-glycoconjugates, the glucose-functionalized gold(I) derivatives show a significant antiproliferative effect against colorectal adenocarcinoma (HT-29), metastatic breast adenocarcinoma (MDA-MB-231), and breast adenocarcinoma (MCF-7) cells, with IC₅₀ values in the low micromolar range, the gold(I)-phosphine derivatives turning up to be the best performers. Cell uptake studies show no evident correlation between cell growth inhibition and cellular uptake, and the use of glucose-free cell culture media and a GLUT1 inhibitor rules out the involvement of glucose transporters in cell internalization, thus suggesting alternative cell death pathways such as acting at extracellular level (especially for the gold(I) derivatives).

Zum Volltext