Head‐to‐Tail Peptide Cyclodimerization by Copper‐Catalyzed Azide–Alkyne Cycloaddition

Abstract

Cyclic peptides and related structures have received attention in a variety of fields pertinent to drug discovery and biochemistry.[1] Peptide cyclization [2] has been managed most commonly by the formation of amide, [3] ester, [4] disulfide, [3b, 5] olefin, [6] and CÀC [7] bonds. Most methods include cyclization as part of solid-phase peptide synthesis, with ring closure performed on the resin support.[8] Olefin metathesis is particularly attractive for ring closure, because terminal alkenes and the transition-metal catalysts used to manipulate them are generally unreactive with protein functional groups.[6] Thus, the "handles" for cyclization can be installed and ignored until the time comes for their connection. We report herein a conceptually similar approach with different chemistry-the copper(i)-catalyzed azide-alkyne cycloaddition reaction [9] -and describe the propensity of this process to give selective dimerization in the ring-closure step.In the course of constructing linear and cyclic versions of the same peptide sequence for display on supramolecular protein scaffolds, we needed a cyclization method compatible with the requirements of side-chain protection/deprotection and with the installation of a reactive group to enable subsequent bioconjugation. The 11-mer and 19-mer Arg-GlyAsp (RGD)-containing peptides 1 and 2 (Scheme 1) contain sequences taken from an adenovirus serotype that binds several a v integrins.[10] They were synthesized by standard 9-fluorenylmethyloxycarbonyl (Fmoc) methods, starting with Fmoc-Phe-Wang resin and l-propargylglycine as the second residue installed. The end of each chain was terminated with side-chain Boc-protected Fmoc-lysine (Boc = tert-butoxycarbonyl), followed by Fmoc deprotection and capping of the N terminus with 5-azidopentanoic acid. The syntheses were also performed with a standard Boc-based protocol, starting[*] Dr.

Discovery of Potent Inhibitors for Breast Cancer Multidrug Resistance

“…Many other commercially available chiral α-or β-hydroxy acids with hydrophobic branches will be explored as well during the synthesis of the library. Furthermore, a variation of click chemistry (Section D3.2) can also be applied in the cyclic peptide synthesis, which has been confirmed in a head-to-tail peptide dimerization process (Punna et al, 2005). The heterocyclic triazole structure is mimetic to those of thiazole and oxazole, and it could be unique in the MsbA inhibitor design.…”

Click Chemistry: A Powerful Tool to Create Polymer‐Based Macromolecular Chimeras

“…Many examples stemming from the de novo cyclic oligopeptide design field validated the applicability of the click chemistry orthogonal approach. [40][41][42] In one such ground-breaking investigation by the Finn laboratories, the selective production of large cyclic dimers of an 11-mer and a 19-mer Arg-Gly-Asp (RGD) peptide containing sequence that was taken from an adenovirus serotype which binds several a v integrins, was reported ( Figure 1B). [40] The dimer synthesis was performed using precursor resin-tethered peptides containing azide and alkyne functions at the appropriate linking ends.…”

“…[40][41][42] In one such ground-breaking investigation by the Finn laboratories, the selective production of large cyclic dimers of an 11-mer and a 19-mer Arg-Gly-Asp (RGD) peptide containing sequence that was taken from an adenovirus serotype which binds several a v integrins, was reported ( Figure 1B). [40] The dimer synthesis was performed using precursor resin-tethered peptides containing azide and alkyne functions at the appropriate linking ends. Due to the chemoselectivity of the click chemistry reaction itself and the inertness of the azide or alkyne functionalities, the functional ''handles'' for the final cycloaddition reaction could be installed at early stages of the synthesis and ignored until the appropriate time for their connection.…”

“…Such precaution is theoretically not necessary as other studies indicated that unprotected peptides can be directly used in click chemistry coupling reactions, as also expected from the high chemoselectivity of CuAAC. [40,55] In their studies, van Hest and coworkers [56] utilized a conceptionally different approach to synthesize peptidic biopolymers ( Figure 2B). Following a straightforward experimental protocol, the labeling of the C-terminus of peptides with any desired moiety bearing a primary amine (such as polymers and long alkyl chains) could be achieved.…”

Synthesis and Characterization of a New Polytriazole Resin Derived from N,N-Dipropargyl-p-propargyloxyaniline

“…The cycloaddition results in the formation of 1, 2, 3-triazole heterocycle and has been used as a universal ligation tool in polymer and material science. [1][2][3][4][5][6] The Huisgen reaction of azide and alkyne compounds always takes place at a low temperature (lower than 100 C), and produces mixtures of 1, 4-and 1, 5-regioisomers (Scheme 1) without a catalyst, showing the possibility of developing a curable resin at low temperature from multifunctional azides and alkynes.…”