Synthesis of new bioactive β-lactam compounds

Soldati, Roberto (2015) Synthesis of new bioactive β-lactam compounds, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Chimica, 27 Ciclo. DOI 10.6092/unibo/amsdottorato/6974.
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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).

Tipologia del documento
Tesi di dottorato
Soldati, Roberto
Dottorato di ricerca
Scuola di dottorato
Scienze chimiche
Settore disciplinare
Settore concorsuale
Parole chiave
β-Lactams, Integrins, Peptidomimetics, Agonists, Cell adhesion, Azetidinones, Antibacterial, Antioxidants, Polyphenols, Cystic fibrosis, Bioconjugates, Retinoids, HDAC inhibitors, Epigenetic regulation, Bioprobes, Theranostics, Bioimaging, Luminescence, Multicomponent reactions, Strecker, Laccase, TEMPO, sustainability, oxidation, profens
Data di discussione
9 Aprile 2015

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