Cyclopeptide Analogs for Generating New Molecular and 3D Diversity

Luca      Gentilucci; Giuliana      Cardillo; Alessandra      Tolomelli; Federico      Squassabia; Rossella      De Marco; Gianpaolo      Chiriano

Abstract

Cyclic peptides have been often utilized as metabolically stable, conformationally restricted mimics of different kinds of biologically active peptides, including peptide antibiotics, endogenous opioid peptides, integrin inhibitors, peptide hormones, anticancer peptides, and so on. And in particular, cyclic compounds which can mimic important secondary structure elements such as β-turns are of outstanding importance. Since greater chemical and structural diversity are primary features to pursue for finding novel leads for pharmacological and biotechnological applications, we explored the potential utility of the retro-inverso modification. We introduced this modification into the sequence of 13- membered cyclotetrapeptides, which can be regarded as easily available, conformationally stable analogs of cyclotetrapeptides composed of all α-residues. In this paper we describe the synthesis of a selected mini-library of partially modified retro-inverso cyclic peptides as conformationally homogeneous scaffolds for medicinal chemistry applications. The different compounds have been obtained by simple scramble of the same residues. Finally, we discuss the conformational features of such molecules as turn mimics. The comparison suggests that the retro-inverso modification allows a higher degree of three-dimensional diversity than normal peptides.

Keywords: Cyclotetrapeptide, peptide library, scaffold, retro-inverso

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