Cyclotetrapeptide Mimics based on a 13-Membered, Partially Modified Retro-Inverso Structure

Cyclic tetrapeptides (CTP) incorporating a distinct -amino acid represent realistic, conformationally homogeneous CTP analogues, which can find application in medicinal chemistry as turn mimics and scaffolds. In this respect, we synthesized a small library of CTP-mimics based on a 13-membered, partially modified retro-inverso (PMRI) structure, containing a 1,2-diamine as -amino acid mimetic and malonic acid as glycine surrogate. Conformational analysis revealed that the PMRI-CTP models containing a unsubstituted diamine (1, 2) exhibited a certain flexibility. On the contrary, the introduction of a chiral, substituted 1,2-diamine rendered the backbone more rigid (3, 4), and induced type I β-turn structures. The comparison with a -amino acid-containing CTP revealed that the PMRI-CTPs can be regarded as alternative -turn scaffolds. To validate the structural deductions based on conformational analysis, we synthesized a couple of diastereomeric RGD analogues (5, 6) as integrin inhibitors, and we found a clear relationship between the 3D display of the pharmacophores and biological activity. In particular, 6 showed a good efficacy in inhibiting fibronectin adhesion to the v3 integrin-expressing human melanoma cells SK-MEL-24 (EC50 3.7 10-7 ).