Mendive-Tapia Lorena, Preciado Sara, García Jesús, Ramón Rosario, Kielland Nicola, Albericio Fernando, Lavilla Rodolfo
1] Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10-12, 08028 Barcelona, Spain [2] Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain [3] CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine.
Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain.
Nat Commun. 2015 May 21;6:7160. doi: 10.1038/ncomms8160.
Natural peptides show high degrees of specificity in their biological action. However, their therapeutical profile is severely limited by their conformational freedom and metabolic instability. Stapled peptides constitute a solution to these problems and access to these structures lies on a limited number of reactions involving the use of non-natural amino acids. Here, we describe a synthetic strategy for the preparation of unique constrained peptides featuring a covalent bond between tryptophan and phenylalanine or tyrosine residues. The preparation of such peptides is achieved in solution and on solid phase directly from the corresponding sequences having an iodo-aryl amino acid through an intramolecular palladium-catalysed C-H activation process. Moreover, complex topologies arise from the internal stapling of cyclopeptides and double intramolecular arylations within a linear peptide. Finally, as a proof of principle, we report the application to this new stapling method to relevant biologically active compounds.
天然肽在其生物作用中表现出高度的特异性。然而，它们的治疗特性受到其构象自由度和代谢不稳定性的严重限制。环肽构成了解决这些问题的一种方法，而获得这些结构依赖于有限数量的涉及使用非天然氨基酸的反应。在此，我们描述了一种合成策略，用于制备具有色氨酸与苯丙氨酸或酪氨酸残基之间共价键的独特受限肽。此类肽的制备可通过分子内钯催化的C-H活化过程，在溶液中和固相上直接从具有碘芳基氨基酸的相应序列实现。此外，复杂的拓扑结构源于环肽的内部环化和线性肽内的双分子内芳基化。最后，作为原理验证，我们报告了将这种新的环化方法应用于相关生物活性化合物的情况。
