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

Abstract

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.

Synthesis of new representatives of A3B-type carboranylporphyrins based on meso-tetra(pentafluorophenyl)porphyrin transformations

“…Nucleophilic substitution reactions of the four p-fluorine atoms in 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (1) are well studied [15][16][17][18][19][20][21][22][23][24][25][26][27]. In order to prepare boronated PSs of A 3 B-type the employed synthetic strategy included the preparation of monoazido-substituted tris(pentafluorophenyl)porphyrin 2 by the reaction of porphyrin 1 with sodium azide (molar ratio 1:1.9) in DMF at ambient temperature for 4 h. Under these reaction conditions, monoazide derivative 2 was obtained in 40% yield along with a mixture of porphyrin 1, di-and triazido-substituted derivatives.…”

“…Exploring the reactivity of the p-fluorine atom similar nucleophilic substitution reactions of porphyrin 6 were carried out with 1,8-diamino-3,6-dioxaoctane (21) and 1,13-diamino-4,7,10-trioxatridecane (22) in DMSO at 70 °C for 30 min to form amino-conjugates 23 and 24 in 71 and 84% yield, respectively, containing ethylene glycol linkers with terminal primary amino groups (Scheme 6). The presence of ethylene glycol residues in bioactive molecules is known to enhance the aqueous solubility and tumor selectivity of hydrophobic drugs through the enhanced permeability and retention effect [46].…”

“…Pentafluorophenyl-substituted porphyrin systems are especially useful for the connection of various functionalities capable for coupling with biomolecules via the nucleophilic aromatic (S N Ar) substitution reactions [15,16]. A variety of nucleophiles such as amines [17,18], alcohols [18][19][20], thiols [17,19,[21][22][23], and carboranes [17,[24][25][26][27] have been studied in selective S N Ar substitution reactions of the p-fluorine atoms in meso-pentafluorophenyl-substituted porphyrins. Carboranes, due to their unique physical and chemical properties such as high chemical and biological stability [28,29], three-dimensional aromaticity [30,31], low toxicity [28], high hydrophobicity, and enriched boron content [32,33] are perspective compounds in drug development [34][35][36][37].…”