Metal-based dithiocarbamato glycoconjugates: a suitable strategy to target tumour glycolysis?

Abstract

Rapidly dividing tumour cells require higher amounts of nutrients and energy for their fast proliferation, and glucose is no exception (the so-called “Warburg effect”). Consequently, such increased demand of glucose by cancer cells makes it very attractive to selectively target tumour sites. In particular, tailored glucose-like substrates can be conjugated to chemotherapeutics (including metal-containing anticancer agents) to attain the site-specific delivery of drugs into the affected tissues. Accordingly, we have been focusing on the design of metal-dithiocarbamato glycoconjugates which can combine the antitumor properties and the favourable toxicological profile of the metal-dithiocarbamato scaffold, along with an improved selectivity and cellular uptake provided by the glucose-containing ligands coordinated to the metal center, through the exploitation of the glucose-mediated cellular internalization facilitated by glucose transporters (GLUTs). In this thesis, the generation of novel gold(I/III)-, manganese(I)-, and platinum(II)dithiocarbamato glycoconjugates via an innovative synthetic approach is reported. Starting from the rationale behind our research work, the main results achieved to date concerning the development of the aforementioned metal-based bioconjugates, solution studies and preliminary in vitro biological studies are here illustrated and discussed. In particular, gold(I)-carbene and gold(III)-organometallic dithiocarbamato derivatives showed promising cytotoxicity towards cancer cells making them interesting candidates for further studies. Interestingly, gold(I)-carbene derivatives do not seem to be internalized inside the cells, suggesting an extracellular mode of action. Finally, a concluding section will briefly describe some side-projects generated during this PhD research projects, in collaboration with other academic research group, regarding the design and obtainment of novel ruthenium(II)-arene dithiocarbamato glycoconjugates, heterometallic platinum(IV)-gold(III) adducts, and innovative methods for intracellular delivery of cytotoxic agents via encapsulation with nucleic acid nanoparticles (NANs) or mesoporous silica nanoparticles (MSNs).