Highly Efficient Cyclization Approach of Propargylated Peptides via Gold(I)-Mediated Sequential C–N, C–O, and C–C Bond Formation

Abstract

A rapid and efficient cyclization of unprotected N-propargylated peptides using the Au(I) organometallic complex is reported. The method relies on the activation of the propargyl functionality using gold(I) to produce a new linkage with the N-terminus amine at the cyclization site. The presented method features a fast reaction rate (within 20 min), mild conditions, chemoselectivity, wide sequence scope, and high yields (up to 87%). The strategy was successfully tested on a wide variety of 30 unprotected peptides having various sequences and lengths, thus providing access to structurally distinct cyclic peptides. The practical usefulness of this method was demonstrated in producing peptides that bind efficiently to Lys48-linked di- and tetra-ubiquitin chains. The new cyclic peptide modulators exhibited high permeability to living cells and promoted apoptosis via binding with the endogenous Lys48-linked ubiquitin chains.

Handcuffing Peptides by a Key of Gold

“…In this issue of ACS Central Science, the Brik group discloses a gold(I)-catalyzed macrocyclization between the primary amine of the peptide N-terminus or lysine side chain and a backbone amide N-propargyl group. 1 …”

“…In this issue of ACS Central Science, the Brik group discloses a gold(I)-catalyzed macrocyclization between the primary amine of the peptide N-terminus or lysine side chain and a backbone amide N-propargyl group. 1 The 20 proteogenic amino acids are the most fascinating molecular building blocks of life. The biological activities of proteins such as enzymes, antibodies, receptors, oxygen transporters, keratin fibers, as well as peptide hormones have nothing in common, other than that these biomolecules are made from the same set of amino acid building blocks.…”

“…As a consequence, there is a continuous need for powerful reactions that are compatible with fully unprotected peptides. In this issue of ACS Central Science, the Brik group discloses a gold­(I)-catalyzed macrocyclization between the primary amine of the peptide N-terminus or lysine side chain and a backbone amide N-propargyl group …”

Gold-Mediated Multiple Cysteine Arylation for the Construction of Highly Constrained Bicycle Peptides

“…constrained bioactive peptides remains an area of interest to peptide medicinal chemists. 8,9 Direct cysteine arylation has been demonstrated as a potential method for generating Bicycle peptides with a high degree of constraint. 10 The Spokoyny group reported a method for selective gold mediated cysteine arylation under mild conditions, to form a Bicycle in 50% reported yield (Figure 1B).…”

Structured cyclic peptide mimics by chemical ligation

“…However, the synthesis of cyclic peptides is not always straightforward, usually requiring the manipulation of additional protecting groups, or cyclisation through comparatively labile disulfide bonds. [6][7][8][9][10] Perhaps more significantly, simply cyclising a peptide does not necessarily restrict it to one specific conformation. Therefore, the design of cyclic peptides with a specific, targeted conformation is an outstanding challenge in peptide science.…”