Application of the cyclobutane scaffold to the preparation and study of new foldamers, cell penetrating peptides and mri contrast agents

Abstract

In this thesis, different systems containing a - or -substituted cyclobutane scaffold have been synthesized and studied as foldamers, as cell penetrating peptides (CPP) or as contrast agents. Despite having different structures not directly related between them, the same synthetic strategies and techniques have been used to prepare the different compounds. The thesis has been structured with a general introduction with some precedents from our research group, followed by the general objectives (Chapter 2). The results of the present thesis are presented in three different chapters (Chapters 3-5), which are divided in different sections. General conclusions are reported in Chapter 6 and the experimental methodologies can be found in Chapter 7. Chapter 3. Six families of peptides with different stereochemistry built with a cyclobutane containing amino acid (CBAA) in combination with -amino-L-proline were synthesized. The study of their folding ability was carried out by using high resolution NMR techniques in order to detect the formation of hydrogen bonds that could induce secondary structures. The information obtained in this chapter was very useful to design new cell penetrating peptides. Chapter 4. Different new peptides were synthesized by solid phase synthesis techniques and studied as potential penetrating agents in two biological systems: HeLa cells and Leishmania parasites. The best cell penetrating peptides were conjugated with a drug to study their effect in Leishmania parasites. Chapter 5. A new linear ligand containing a cyclobutane-based diamine was synthesized and complexed with different metal ions. The thermodynamic stability and the hydration number of these complexes were studied by means of different techniques. Their potential as new contrast agents for magnetic resonance imaging (MRI) was studied by different NMR methodologies.