Gentilucci Luca, Cardillo Giuliana, Tolomelli Alessandra, Squassabia Federico, De Marco Rossella, Chiriano Gianpaolo
Department of Chemistry G. Ciamician, University of Bologna, 40126 Bologna, Italy.
Comb Chem High Throughput Screen. 2009 Dec;12(10):929-39. doi: 10.2174/138620709789824754.
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 beta-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 alpha-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.
环肽常被用作多种生物活性肽的代谢稳定、构象受限的模拟物，包括肽抗生素、内源性阿片肽、整合素抑制剂、肽激素、抗癌肽等。特别是，能够模拟重要二级结构元件（如β-转角）的环状化合物具有突出的重要性。由于更大的化学和结构多样性是寻找药理学和生物技术应用新先导物的主要追求特征，我们探索了逆序-反转修饰的潜在效用。我们将这种修饰引入到13元环四肽序列中，13元环四肽可被视为由所有α-残基组成的环四肽的易于获得、构象稳定的类似物。在本文中，我们描述了一个选定的部分修饰的逆序-反转环肽小型文库的合成，作为用于药物化学应用的构象均一的支架。不同的化合物通过相同残基的简单打乱获得。最后，我们讨论了此类分子作为转角模拟物的构象特征。比较表明，逆序-反转修饰比正常肽允许更高程度的三维多样性。
