SYNTHESIS, STRUCTURAL INVESTIGATION AND BIOLOGICAL EVALUATION OF CONFORMATIONALLY CONSTRAINED PEPTIDOMIMETICS

This Ph.D. thesis is located in the medicinal chemistry research field. Peptides are among the most studied entities as potential drug candidates, due to their natural abundance and biological implications. However, as drugs they possess several disadvantages because of low bioavailability and short half-life. Peptidomimetics try to overcome such drawbacks, maintaining meanwhile the biological activity. These mimics can also be useful to define bioactive forms of natural peptides, for instance through insertion of conformational constrictions able to reduce the peptide inherent flexibility. Thus, I explored the synthesis and the evaluation of some conformationally constrained peptidomimetics which potentially could be employed into different scientific fields and pharmaceutical contexts. Once prepared these scaffolds, I evaluated their secondary structure by means of spectroscopic methods including NMR and IR techniques. After insertion into more complex structures, strictly related to biologically active compounds, I verified their therapeutic potential. In some cases I could achieve very interesting biological results, in the range of activity of the natural corresponding peptides or of the reference lead compounds. I also tried to rationalize the biological activity outcomes, by joining them with molecular mechanics and docking-based structural investigation.