Multicomponent and catalytic methods for the modification of peptides and peptidomimetics

The covalent modification of peptides is an active research area today. This PhD thesis demonstrates the broad applicability of modern methods relying on transition metal catalysis and isonitrile-based multicomponent reactions for the derivatization of peptides, peptoids and aminoacid mimetics. In the first part, and after a brief introduction to the state of the art in the field, we report two methodologies relying on the capability of transition metals to promote C-H activation. We demonstrate that N-benzoyl peptides, peptoids or aminomethyl-tetrazoles (i.e. aminoacid isosteres) undergo addition of functionalized acetylenes under ruthenium or rhodium catalysis. Both methods prove high-yields, high chemo- and regioselectivity, and display a broad scope under mild conditions, rendering privileged amphiphilic scaffolds with florescent properties. The rhodium(III)-catalyzed modification of aminomethyltetrazoles allows the creation of a plethora of novel isoquinolone/pyridone heterocyclic hybrids, including naphthalenes, pyridines, furanes, thiofenes and their benzene-fused counterparts. Ruthenium(II)-catalyzed annulation of oligopeptides permits backbone diversification through ligation and conjugation with commercial drugs and natural products. The second part is devoted to the development of novel domain-selective inhibitors of the Angiotensin I Converting Enzyme, which has a central role in the control of the blood pressure in humans. Taking the molecular structure of the inhibitor keto-ACE as starting point, we created a small library of peptoids through a combinatorial procedure involving the Ugi reaction, deprotections and peptide coupling steps. The multicomponent process allows to introduce diverse substituents, able to interact with the relevant catalytic subsites. Preliminary molecular docking, conformational studies and NMR results show the potential of the products to exert the desired biological activity, while ongoing inhibition experiments will assess the validity of our hypothesis. Finally, we stress that all the procedures developed during this thesis possess easy set-up and scalability, making them amenable for industrial applications.