Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains

Abstract

A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki-Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta-meta, meta-ortho, and ortho-meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation. Suzuki-Miyaura macrocyclizations were successfully achieved both in solution and on solid phase for all three sizes of peptide. This approach constitutes a means of constraining peptide conformation via direct carbogenic fusion of side chains of naturally occurring amino acids such as phenylalanine and tyrosine, and so is complementary to strategies involving non-natural, for example, hydrocarbon, bridges.

Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

“…When constrained into rigid α-helical conformations, short peptides can mimic protein binding surfaces and exhibit greater resistance against metabolizing enzymes11. Developing methodologies to predictably induce α-helices in short peptides is therefore of considerable interest for peptide-based drug development1213141516. Over the past several decades, various approaches, spanning non-covalent and covalent strategies, to reinforcing the bioactive helical conformation were developed17.…”

“…These so-called stapled peptides have been extensively studied in recent years and have been the subjects of numerous reviews242526. In general, these stapled peptides have different cross-links, such as aryl, alkenyl, disulphide, “click” triazole, amide, and thioether connectors162728293031323334. Besides, while we know that peptides are composed of chiral L-amino acids, the effect of stereocenters within the cross-links in peptide secondary structure has not been extensively studied.…”

The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

“…The peptidyl resin containing protected 3-iodotyrosine was first borylated; and, after extension of the peptide chain, either protected 4-iodophenylalanine or 3-iodotyrosine was added to synthesize the p,m-and m,m-crosslinked biaryl peptides (not shown). Meyer et al report the preparation of additional combinations of biaryl-bridged peptides [174]. Either a solid-or solution-phase approach allowed m,m-, o,m-, and m,o-bridged cyclic peptides, for example, 115 and 117, through regiochemical variation of the aryl halide and arylboronate ( Figure 16B).…”

Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues

“…The final analogue was prepared via ring-closing macrocyclization 28,29 to afford a rare steroidal macrocycle (Scheme 5). 30,31 Thus, bis-acylation of withalongolide monoacetate 3 with 4-pentenoic anhydride afforded 23 .…”

“…Interestingly, macrocycle 24 exhibited increased potency compared to its acyclic analogue 23 across all cell lines tested with IC 50 values in the range of 0.205–0.965 µM. 28,29 Most of the active analogues were moderately selective towards cancer cells compared to normal fibroblast cells.…”