Exploring new frontiers in cancer drug discovery: G-quadruplex ligands, antiproliferative agents for ovarian and gastro-intestinal tumors, and novel synthetic methodologies.

Cancer remains one of the most complex and pressing challenges to human health, largely due to the heterogeneity of the molecular pathways involved in its pathogenesis. In this context, medicinal chemistry plays a central role in the discovery of innovative therapeutic strategies through the design of small molecules with antiproliferative potential. Through its five main chapters, this PhD thesis explores multiple aspects of this field, combining rational molecular design with innovative synthetic methodologies to advance the development of novel anticancer agents. A first contribution focuses on the targeting of G-quadruplex DNA structures, non-canonical nucleic acid conformations implicated in the regulation of oncogene expression. Guided by a rational design strategy, diversified series of compounds were synthesized and evaluated through biophysical studies, leading to the identification of the benzo[d]imidazo[2,1-b]thiazole scaffold as an effective G4 stabilizer. This finding opens new opportunities for the development of G4 binders with improved drug-like properties. In parallel, G4-binding derivatives functionalized with azide or propargyl groups were prepared to enable future conjugation strategies, paving the way toward molecular tools for selective targeting of specific G4 structures while reducing off-target effects on undesired genomic regions. Beyond G4-centered research, two additional series of small molecules were developed to address ovarian cancer and gastrointestinal stromal tumors. These compounds exhibited significant antiproliferative activity across several cancer cell lines. Notably, within the GIST-oriented series, one candidate showed nanomolar potency against imatinib-resistant cell lines and promising efficacy in vivo. Mechanistic investigations suggested tubulin as a potential molecular target, further supporting the relevance of this scaffold in anticancer therapy. The final part of this thesis adopts a methodological perspective by exploring photocatalytic transformations in continuous-flow systems. In particular, the activation of C–F bonds in aryl fluorides was investigated, providing a basis for future applications of flow photochemistry in the synthesis of bioactive scaffolds.