DEVELOPMENT OF TARGET-SPECIFIC AND TUMOR-SELECTIVE METALLODRUGS

The clinical use of cisplatin, the milestone of metal-based anticancer drugs, is limited by several side effects, including severe nephrotoxicity. In addition, cisplatin is not orally bioavailable, and both inherited and acquired resistance seriously limit its applications. These problems have motivated great efforts in the research and development of new antitumour metallodrugs with more favourable properties in terms of a wider spectrum of activity, reduced toxicity, and better aqueous solubility. Bioinorganic medicinal chemistry offers many opportunities in this field, and the development of metal-based drugs has moved on from serendipitous discovery to a more rational drug design during the past decade. In this field, this PhD project was aimed at identifying novel metal complexes targeting cancer-specific molecular determinants in order to develop new potential therapeutic strategies endowed with an improved pharmacological profile, both in terms of a higher selectivity towards cancer cells and of a reduced systemic toxicity with respect to platinum-based chemotherapeutics. In particular, the attention was focused on the development of Ag(I), Au(I), Cu(I/II) and Fe(III) complexes coordinated with different classes of ligands. Their in vitro antitumor profiles were evaluated against a series of human tumor cell lines derived from different solid tumors, by means of both 2D and 3D cell viability studies. The interactions with the target(s) were deeply investigated either in cell-free systems and in cell cultures, trying to draw specific assumption about SARs. In addition, the anticancer activity as well as the preliminary biodistribution profile of the most promising derivatives were also evaluated in suitably developed in vivo models.