Design and Synthesis of Novel Metal(loid)-Based Compounds with Pharmacological Potential: From Single Molecules to Smart Nanodelivery Systems

This PhD project focused on the rational design, synthesis, and characterization of novel metal(loid)-based compounds with potential pharmacological applications, as well as on the development of suitable delivery systems. The work was guided by key strategies, including structural modification of known bioactive molecules, repurposing and conjugation of existing drugs with metal fragments, the use of multimetallic frameworks for multiple drug delivery, and the application of polymeric nanocarriers. The main objective was to evaluate how these complementary approaches could be applied to optimize the properties of new metal(loid)-based drugs. Particular emphasis was placed on understanding the behavior and mechanism of action of the synthesized compounds under biologically relevant conditions. Their stability, speciation, and reactivity were investigated in aqueous and organic media to assess their transformation pathways. In addition, interactions with model proteins such as human serum albumin (HSA) were studied using metallomic approaches, providing insight into coordination behavior, binding affinity, and possible transport mechanisms. The first part of the project focused on the modification of known compounds, particularly the tellurium(IV) complex AS101 and its halido derivatives. Combined experimental and computational studies revealed an increase in hydrolytic reactivity along the halogen series from chloride to iodide. These results clarified how ligand substitution modulates activation kinetics and stability in aqueous environments, contributing to a deeper understanding of the activation mechanism of AS101 and highlighting the role of rational ligand design. Subsequent work explored drug repurposing strategies using the gold(I) complex auranofin as a scaffold. A series of derivatives was prepared by coordinating bioactive ligands such as acetylcysteine, naproxen, and a TSPO-targeting moiety to the [Au(PEt₃)]⁺ fragment. The results showed that ligand conjugation significantly influences both physicochemical properties and biological activity, supporting the idea that combining multiple pharmacophores within a single complex can lead to enhanced or complementary effects. The study was then extended to dinuclear systems, specifically dimolybdenum(II,II) paddlewheel complexes bearing non-steroidal anti-inflammatory drugs (NSAIDs). These compounds were synthesized and characterized, and their biological activity was evaluated. While overall cytotoxicity was low, some derivatives showed improved activity compared to the free ligands. In particular, the aspirin-based complex demonstrated drug release behavior consistent with a prodrug mechanism, highlighting the importance of balancing stability and reactivity in multimetallic systems. Parallel investigations focused on metal–protein interactions and nanoparticle stability in biological environments. Studies on the interaction of platinum and gold drugs with albumin, as well as on gold nanoparticles functionalized with dithiols, provided insight into protein binding and corona formation. Metallomic techniques such as SEC-ICP-AES and ESI-MS enabled the characterization of these interactions and their impact on biological activity. Finally, the project addressed the development of multifunctional polymeric nanoparticles for drug delivery. PLGA–PEG-based nanoparticles were designed to co-encapsulate a cisplatin-derived Pt(IV) prodrug and docetaxel and were functionalized with an Ang-mimetic peptide for targeted delivery. The resulting nanoparticles exhibited suitable size and distribution for biological applications. Biological studies showed that encapsulation preserved drug activity while improving safety. The combination of the two drugs produced a synergistic effect in prostate cancer cells, with reduced toxicity toward healthy cells. Moreover, the functionalized nanoparticles demonstrated the ability to interact with angiogenesis-related pathways, suggesting a dual therapeutic role. Overall, this work demonstrates that rational design strategies can be effectively applied across different levels of complexity, from small molecules to nanocarriers. The integration of synthetic, computational, and biological approaches provided a comprehensive understanding of the behavior of metal-based compounds in biological environments. These findings contribute to the development of more selective and effective metallodrugs and offer a framework for future research in medicinal inorganic chemistry.