Solid-phase synthesis of “head-to-tail” cyclic peptides via lysine side-chain anchoring

Alsina, Jordi; Rabanal, Francesc; Giralt, Ernest; Alberício, Fernando

doi:10.1016/0040-4039(94)88531-1

Cited by 74 publications

(34 citation statements)

References 36 publications

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“…Most frequently, this has been accomplished through a side-chain carboxyl function of Asp or Glu, which provides access to peptides that contain Asx or Glx, [2][3][4][5][11][12][13][14][15][16] depending on the handle used. More recently, there have been reports of sidechain anchoring via lysine, 5,17 ornithine, 5 arginine, 18,19 serine, 5 threonine, 20 tyrosine, 5,21,22 and cysteine. 23, 24 The present work introduces a novel S-XAL side chain anchoring strategy for Cys (Scheme 1; featuring key preformed handle intermediate 6 shown in box at bottom of Scheme 2) that circumvents previously described side reactions, i.e., racemization [25][26][27][28][29][30][31][32][33][34][35] and 3-(1-piperidinyl)alanine formation, 35 associated with anchoring C-terminal cysteine for solid-phase peptide synthesis, and further provides effective access to a range of free cysteine and cystine (disulfide-bridged) intermediates and products.…”

Section: Introductionmentioning

confidence: 98%

Side‐chain anchoring strategy for solid‐phase synthesis of peptide acids with C‐terminal cysteine

et al. 2003

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Many naturally occurring peptide acids, e.g., somatostatins, conotoxins, and defensins, contain a cysteine residue at the C-terminus. Furthermore, installation of C-terminal cysteine onto epitopic peptide sequences as a preliminary to conjugating such structures to carrier proteins is a valuable tactic for antibody preparation. Anchoring of N(alpha)-Fmoc, S-protected C-terminal cysteine as an ester onto the support for solid-phase peptide synthesis is known to sometimes occur in low yields, has attendant risks of racemization, and may also result in conversion to a C-terminal 3-(1-piperidinyl)alanine residue as the peptide chain grows by Fmoc chemistry. These problems are documented for several current strategies, but can be circumvented by the title anchoring strategy, which features the following: (a). conversion of the eventual C-terminal cysteine residue, with Fmoc for N(alpha)-amino protection and tert-butyl for C(alpha)-carboxyl protection, to a corresponding S-xanthenyl ((2)XAL(4)) preformed handle derivative; and (b). attachment of the resultant preformed handle to amino-containing supports. This approach uses key intermediates that are similar to previously reported Fmoc-XAL handles, and builds on earlier experience with Xan and related protection for cysteine. Implementation of this strategy is documented here with syntheses of three small model peptides, as well as the tetradecapeptide somatostatin. Anchoring occurs without racemization, and the absence of 3-(1-piperidinyl)alanine formation is inferred by retention of chains on the support throughout the cycles of Fmoc chemistry. Fully deprotected peptides, including free sulfhydryl peptides, are released from the support in excellent yield by using cocktails containing a high concentration (i.e., 80-90%) of TFA plus appropriate thiols or silanes as scavengers. High-yield release of partially protected peptides is achieved by treatment with cocktails containing a low concentration (i.e., 1-5%) of TFA. In peptides with two cysteine residues, the corresponding intramolecular disulfide-bridged peptide is obtained by either (a). oxidation, in solution, of the dithiol product released by acid; (b). simultaneous acidolytic cleavage and disulfide formation, achieved by addition of the mild oxidant DMSO to the cleavage cocktail; or (c). concomitant cleavage/cooxidation (involving a downstream S-Xan protected cysteine), using reagents such as iodine or thallium tris(trifluoroacetate) in acetic acid.

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Section: Introductionmentioning

confidence: 98%

Side‐chain anchoring strategy for solid‐phase synthesis of peptide acids with C‐terminal cysteine

et al. 2003

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“…Alternative linkers used in this approach include thioesters [46], 'safety-catch' linkers based on sulfonamide [47], or the most recent catechol example [48] summarized in Scheme 4. A totally on-resin approach has been developed by linking the side chain of a trifunctional amino acid to the resin, and through use of three levels of orthogonal protection, a protocol such as the one depicted in Scheme 5 [49,50] has proved successful. Many aspects of this on-resin approach have been reviewed authoritatively by Spatola and Romanovskis [25].…”

Section: On-resin Cyclizationsmentioning

confidence: 99%

The cyclization of peptides and depsipeptides

Davies

2003

Journal of Peptide Science

413

241

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Constricting the peptide backbone into a more defined conformational form through cyclization is an activity evolved in nature and in synthetic work, the latter straddling only the most recent decades. The resulting conformational constraints increase the probability of an optimum response with bio-receptors. The purpose of this review is to highlight developments that have proved to be reasonably efficient in the macrocyclization of linear precursors into cyclic peptides and depsipeptides.

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“…Once chain elongation is finished, the deprotection of both ends and subsequent cyclization and cleavage delivers the final cyclized product. Numerous amino acids have been used for side-chain anchoring, including Asx/Glx [220][221][222][223][224][225][226], Lys/Orn [220,227], Ser/Thr [220,228], Tyr [220,224,229], His [230,231], and Cys [232,233], on the usual supports and linkers for peptide synthesis. BAL anchoring: The original concept of the BAL linker [234,235] involves the attachment of a backbone amide nitrogen to an appropriate handle.…”

Section: Cyclic Peptidesmentioning

confidence: 99%