Synthesis and characterization of implants for bone substitutions made of biomedical apatites containing silicon

In the last decades the development of bone substitutes characterized by a superior biomimetism has become of particular interest, owing to the increasing economic and societal impact of the bone diseases. In the present work of research the development of bone substitutes characterized by improved biomimetism, has been faced in a chemical, structural and morphological perspective. From a chemical point of view, it has been developed the synthesis of hydroxyapatite powders, exhibiting multiple ionic substitutions in both cationic and anionic sites, so to simulate the chemical composition of the natural bone. Particular emphasis has been given to the effect of silicon on the chemical-physical and solubility properties of the obtained hydroxyapatites. From a structural point of view, it has been developed the synthesis of ceramic composite materials, based on hydroxyapatite and calcium silicates, employed both as a reinforcing phase, to raise the mechanical strength of the composite compared to hydroxyapatite, and as a bioactive phase, able to increase the bioactivity properties of the whole ceramic. Finally the unique morphological features of the bone were mimicked by taking inspiration by Nature, so that native wood structures were treated in chemical and thermal way to obtain hydroxyapatite porous materials characterized by the same morphology as the native wood. The results obtained in the present work were positive in all the three different areas of investigation, so to cover the three different aspects of biomimetism, chemical, structural and morphological. Anyway, only at the convergence of the three different fields it is possible to find out the best solutions to develop the ideal bone-like scaffold. Thus, the future activity should be devoted to solve the problems at the borderline between the different research lines, which hamper this convergence and in consequence, the achievement of a bone scaffold able to mimic the various aspects exhibited by the bone tissue

Synthesis of new bioactive β-lactam compounds

New biologically active β-lactams were designed and synthesized, developing novel antibiotics and enzymatic inhibitors directed toward specific targets. Within a work directed to the synthesis of mimetics for RGD (Arg-Gly-Asp) sequence able to interact with αvβ3 and α5β1-type integrins, new activators were developed and their Structure-Activity Relationships (SAR) analysis deepened, enhancing their activity range towards the α4β1 isoform. Moreover, to synthesize novel compounds active both against bacterial infections and pulmonary conditions of cystic fibrosis patients, new β-lactam candidates were studied. Among the abundant library of β-lactams prepared, mainly with antioxidant and antibacterial double activities, it was identified a single lead to be pharmacologically tested in vivo. Its synthesis was optimized up to the gram-scale, and pretreatment method and HPLC-MS/MS analytical protocol for sub-nanomolar quantifications were developed. Furthermore, replacement of acetoxy group in 4-acetoxy-azetidinone derivatives was studied with different nucleophiles and in aqueous media. A phosphate group was introduced and the reactivity exploited using different hydroxyapatites, obtaining biomaterials with multiple biological activities. Following the same kind of reactivity, a small series of molecules with a β-lactam and retinoic hybrid structure was synthesized as epigenetic regulators. Interacting with HDACs, two compounds were respectively identified as an inhibitor of cell proliferation and a differentiating agent on steam cells. Additionally, in collaboration with Professor L. De Cola at ISIS, University of Strasbourg, some new photochemically active β-lactam Pt (II) complexes were designed and synthesized to be used as bioprobes or theranostics. Finally, it was set up and optimized the preparation of new chiral proline-derived α-aminonitriles through an enantioselective Strecker reaction, and it was developed a chemo-enzymatic oxidative method for converting alcohols to aldehydes or acid in a selective manner, and amines to relative aldehydes, amides or imines. Moreover, enzymes and other green chemistry methodologies were used to prepare Active Pharmaceutical Ingredients (APIs).