5,10,15,20‐Tetrakis(pentafluorophenyl)porphyrin as a Functional Platform for Peptide Stapling and Multicyclisation

• Published in: Chemistry : a European journal Vol. 29; no. 55; pp. e202301410 - n/a
• Main Authors: Dognini, Paolo, Chaudhry, Talhat, Scagnetti, Giulia, Assante, Michele, Hanson, George S. M., Ross, Kehinde, Giuntini, Francesca, Coxon, Christopher R.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 02.10.2023; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: aromatic substitution; Chemistry; Chemistry, Multidisciplinary; Cyclization; Cysteine; Fluorescence; fluorine; peptide multicyclisation; peptide stapling; Peptides; Peptides - chemistry; Physical Sciences; Porphyrins; Porphyrins - chemistry; porphyrins strapping; Reagents; Residues; Scaffolds; Science & Technology; Skin; THERAPEUTICS; porphyrins strapping; MACROCYCLES; peptides; porphyrins; DELIVERY; peptide multicyclisation; ROBUST; peptide stapling; SIRNA; SKIN; aromatic substitution; BINDING; CYCLIZATION; fluorine
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202301410

Polyfluorinated aromatic reagents readily react with thiolates via nucleophilic aromatic substitution (SNAr) 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. We introduce 5,10,15,20‐tetrakis(pentafluorophenyl)porphyrin as a widely applicable scaffold for the stapling and multicyclisation of cysteine‐containing peptides. A robust and peptide‐compatible Nucleophilic Aromatic Substitution between aromatic fluorides and cysteine thiols was performed with a library of peptides, leading to different cyclic species – one of which was biologically tested – and offering relevant synthetic insights.