School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street Campus, L3 3AF, Liverpool, UK.
EaStCHEM, School of Chemistry, The University of Edinburgh, Joseph Black Building, David Brewster Road, EH9 3FJ, Edinburgh, UK.
Chemistry. 2023 Oct 2;29(55):e202301410. doi: 10.1002/chem.202301410. Epub 2023 Sep 6.
Polyfluorinated aromatic reagents readily react with thiolates via nucleophilic aromatic substitution (S Ar) and provide excellent scaffolds for peptide cyclisation. Here we report a robust and versatile platform for peptide stapling and multicyclisation templated by 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, opening the door to the next generation of functional scaffolds for 3D peptide architectures. We demonstrate that stapling and multicyclisation occurs with a range of non-protected peptides under peptide-compatible conditions, exhibiting chemoselectivity and wide-applicability. Peptides containing two cysteine residues are readily stapled, and the remaining perfluoroaryl groups permit the introduction of a second peptide in a modular fashion to access bicyclic peptides. Similarly, peptides with more than two cysteine residues can afford multicyclic products containing up to three peptide 'loops'. Finally, we demonstrate that a porphyrin-templated stapled peptide containing the Skin Penetrating and Cell Entering (SPACE) peptide affords a skin cell penetrating conjugate with intrinsic fluorescence.
多氟芳烃试剂可通过亲核芳香取代（S Ar）与硫醇盐快速反应，为肽环化提供了极好的支架。在这里，我们报告了一个通过 5,10,15,20-四（五氟苯基）卟啉模板化的肽 stapling 和多环化的强大而通用的平台，为 3D 肽结构的下一代功能支架开辟了道路。我们证明，在肽相容条件下，一系列非保护肽可以进行 stapling 和多环化，表现出化学选择性和广泛适用性。含有两个半胱氨酸残基的肽很容易 stapling，并且剩余的全氟芳基基团允许以模块化方式引入第二个肽，以获得双环肽。同样，具有两个以上半胱氨酸残基的肽可以得到含有多达三个肽“环”的多环化产物。最后，我们证明含有皮肤穿透和细胞进入（SPACE）肽的卟啉模板 stapled 肽提供了具有内在荧光的皮肤穿透共轭物。
