ANNUNZIATA, ALFONSO (2022) Design, Synthesis and Study of Novel Glycoconjugate Organometallic Complexes as Potential Anticancer Agents. [Tesi di dottorato]

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An important application of coordination chemistry consists in the design of metal complexes with anti-tumor activity. The advantage of this methodology lies in the control of the properties of the compounds, through the wide choice of the metal, its oxidation state, the number of coordination and the relative geometry. Within this frame, the present PhD thesis proposed the design of new organometallic complexes containing carbohydrate-derived ligands. The presence of a sugar fragment can have several beneficial effects on the resulting species, by enhancing the biocompatibility, water solubility and selectivity (Warburg Effect). Platinum anticancer drugs are regularly used in clinical therapy, despite the serious issues related to their administration. Therefore, in recent years several efforts were performed for searching valid alternative metallodrugs. In the first part of the PhD, organometallic platinum complexes were studied, by exploring different oxidation states, molecular geometries, and type of glycoconjugate ligands. Particular attention was given to coordinatively saturated Pt(II), by far less represented than square planar Pt(II), and octahedral Pt(IV) species. The synthesis, the structural characterization, and the study of the reactivity in miming-biological conditions were performed, followed by preliminary investigations of the in vitro cytotoxicity and of the mechanism of action. The results allowed to individuate key structural features that influenced the anticancer properties of the designed compounds. The last part of the PhD activity was carried out at the École Polytechnique Fédérale de Lausanne (EPFL, Switzerland) under the supervision of Prof. Paul Dyson. In this frame, glycoconjugation was extended to ruthenium and gold organometallic scaffolds, considered valid alternative to more represented platinum ones. The results obtained during the PhD revealed that coordinatively saturated Pt(II) complexes displayed general high cytotoxicity and, in some cases, enhanced selectivity depending on the sugar fragment. Among the studied species, a trigonal bipyramidal Pt(II) complex with a glucoconjugate N-Heterocyclic Carbene ligand emerged as the most promising candidate drug, displaying an activity 100-fold higher than cisplatin and being 180-fold more selective on the cell lines explored. Preliminary investigations of the in vitro mechanism of action were performed, laying the foundations for further studies on the application of this compound as anticancer drug.

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