Methods and strategies for the synthesis of biologically active oligopeptides and small molecules for potential applications in the field of drug delivery

Abstract

My PhD research activity focused on the development of novel methods and strategies for synthesizing biologically active short-chain peptides and piperazine-based small molecules, as well as designing mesoporous silica-based nanocarriers capable of incorporating and transporting these compounds, with the aim of enhancing their therapeutic potential. The main activities carried out during my PhD research were as follows: • Development of a novel peptide synthesis method for the production of small peptides in the solution phase. This approach combines TiCl4 as a condensing agent with microwave heating, enabling the rapid and efficient formation of dipeptide systems with urethane protecting groups on the N-terminal amino group. • Design and synthesis of a new cyclic somatostatin analog, c(-FWKTE-), using microwave-assisted solid-phase peptide synthesis (SPPS) and Fmoc chemistry. This cyclic pentapeptide includes the biologically active 7-10 sequence of somatostatin and glutamic acid at the C-terminus. Preliminary in vitro tests were carried out to explore its antiproliferative activity against breast cancer cell lines. • Design and synthesis of a novel class of piperazine-based molecules as potential inhibitors of the NS2B/NS3 protease in Flaviviridae viruses, including Zika and Dengue. These compounds, incorporating urea, sulfonamide, and acyl functional groups, were evaluated for antiviral activity through live-virus assays in human hepatoma cells. Furthermore, the anticancer potential of these piperazine derivatives was investigated in breast cancer cell lines. • Development of mesoporous silica-based (MSN) nanodevices with a dual architecture. featuring targeting molecules on their external surface and linkers within the pores for subsequent drug anchoring via covalent and non-covalent interactions. These nanocarriers are designed to enhance the therapeutic efficacy of the synthesized compounds by improving their delivery and bioavailability. The surface properties of these systems were analyzed to assess the impact of different modifications on the nanoparticle surface structure and their potential for novel applications. This thesis includes published works, studies ready for submission, and ongoing research that requires further investigation before completion and publication.