TOOLS AND STRATEGIES FOR THE SYNTHESIS OF PHARMACEUTICAL ACTIVE COMPOUNDS

This dissertation presents an overview of three years of research aimed at applying novel tools and strategies for the synthesis of potential pharmaceutical active compounds. In this context, I commenced my research at the University of Milano under the supervision of Professor Daniele Passarella. My work centered on two main projects involving the design, synthesis, and characterization of new pharmaceutical compounds with potential therapeutic applications. These projects focus on convenience and cost-effective synthetic strategies, as detailed in Chapters 1 and 2. I also had the opportunity to spend six months abroad at ICIQ (Tarragona, Spain) in the laboratory of Professor Arjan Kleij. During this time, I worked on the enantioselective synthesis of chiral γ-amino alcohols, which is presented in Chapter 3, as well as the utilization of carbon dioxide as a green starting material to create novel drug-containing macromolecules for future drug-delivery applications, outlined in Chapter 4. In the final part of my Ph.D. program, I moved to Indena SpA (Settala, Italy) to complete my industrial internship, which was a part of my Ph.D. funding. The research conducted during this period focused on the extraction and purification of a component of vaccine adjuvant mixtures, discussed in Chapter 5. Chapter 1 explores the safracin family, a class of alkaloids known for their significant antibacterial and antitumor properties, which were first isolated from bacteria such as Pseudomonas species. This chapter begins with a detailed NMR characterization of Safracin B, an important intermediate in the synthesis of commercially available anticancer drugs. We then report on the synthetic conversion of Safracin B into Cyanosafracin B and Safracin A, two additional components of the safracin family, along with their structural elucidation achieved through NMR spectroscopy. The findings presented will enhance the overall understanding of the chemical profile of safracins and provide a foundation for further chemical and structural investigations into their biological activities and potential applications in drug discovery. Chapter 2 focuses on the design and synthesis of novel tubulin binders in the frame of the European Joint Doctorate TubInTrain program, which examines microtubule dynamics and their relationship to neurodegenerative diseases. The designed scaffolds, created using time- and cost-efficient synthetic methods, feature an amide core with various warheads intended for covalent targeting of tubulin. Biochemical evaluations and X-ray crystallography structure determinations have revealed promising candidates that can covalently bind to the Todalam site. These encouraging results motivate us to continue optimizing these molecules. Chapter 3 discusses the first project I undertook at ICIQ in the laboratory of Professor Arjan Kleij. Specifically, we present the first general enantioselective synthesis of γ-amino alcohols that contain a tertiary carbon center through a Cu-based propargylic amination reaction. Our protocol features user-friendly reaction conditions for the initial oxidation step, and we have established a reasonable scope for both alkynyl oxetanes and functional aromatic amines. Furthermore, the further derivatization of selected γ-amino alcohols demonstrates the synthetic potential of these chiral building blocks, which could diversify the range of chiral intermediates valuable for future drug discovery and development programs. Chapter 4 deals with the development of an effective method for synthesizing drug-modified six-membered cyclic carbonates. These can subsequently be advanced to polycarbonates through organocatalytic ring-opening polymerization (ROP), allowing for a controllable amount of the drug in the resulting polymer-drug conjugates. Preliminary depolymerization studies conducted by Arjan Kleij’s research group indicate that the free acid form of the drug can be released at elevated temperatures, while the polycarbonate selectively degrades into a bicyclic triol. These encouraging results lead us to further investigate this area for future drug release applications. Finally, Chapter 5 addresses a project aimed at the extraction and purification of squalene from vegetable sources. Squalene is a natural triterpene used as an adjuvant in vaccine formulations. In this context, we aimed to develop an efficient and scalable extraction method that could be applied in an industrial setting to yield the desired target quantitatively.