Problems in the synthesis of cyclic peptides through use of the Dmab protecting group †

Johnson, Tony; Liley, Mark; Cheeseright, Timothy J.; Begum, Farida

doi:10.1039/b001694m

Cited by 21 publications

(21 citation statements)

References 17 publications

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“…This suggests that a threshold density of azides or alkynes is required on the solid support, and that the dimeric pathway is favored even when two chains are difficult to bring together. Cyclodimerization was neither favored by the peptide sequence itself nor by the presence of copper ions, as shown by the attempted ring closure with amide bond formation shown in Scheme . HBTU‐mediated cyclization of resin‐ 3 , incorporating orthogonally‐protected aspartic acid in place of propargyl glycine, gave poor results, and no compounds of dimeric molecular weight were observed 14. The expected monocyclic peptide cyclo ‐ 3 was detected by mass spectrometry, but the material was impossible to isolate by HPLC owing to the presence of many impurities.…”

Section: Methodsmentioning

confidence: 99%

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

Punna¹,

Kuzelka²,

Wang³

et al. 2005

Angew Chem Int Ed

202

138

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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.

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Section: Methodsmentioning

confidence: 99%

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

Punna¹,

Kuzelka²,

Wang³

et al. 2005

Angew Chem Int Ed

202

138

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“…This encouraged us to try a second approach where not only the coupling and Fmoc-removal conditions were stronger to avoid deletions observed in the previous approach, but also, and more relevantly, the Dmab/ivDde removal cycle with hydrazine was carried out with additional precautions to ensure complete removal of the Dmab group. This group is removed in a two-step reaction where hydrazine firstly cleaves the ivDde moiety, which is released as an indazole by-product that can be detected at 290 nm, after which the p-amino benzyl ester suffers spontaneous cleavage to give the free carboxyl group (Scheme 2) (Chan et al 1995;Chhabra et al 1998;Johnson et al 2000).…”

Section: Resultsmentioning

confidence: 99%

“…Once Bocpz-OH was incorporated in the peptidyl-resin, this was repeatedly treated with 2% hydrazine in DMF until no increase on absorption at 290 nm, due to the indazole byproduct arising from protecting group removal, was detected (cf. Results and Discussion) (Johnson et al 2000). The resin was then washed with 20% DIEA in DMF/water 90:10 to overcome eventual problems with sluggish cleavage of the aminobenzyl moiety in the course of Dmab removal (cf.…”

Section: Peptide Synthesismentioning

confidence: 99%

Comparative Study of Chemical Approaches to the Solid-Phase Synthesis of a Tumor-Seeking α-MSH Analogue

Valldosera

Monsò

Xavier

et al. 2008

Int J Pept Res Ther

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The synthesis of a cyclic melanocortin analogue (H-pz-bAla-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH 2), where the Boc-protected derivative of a metal-chelating pyrazolyl ligand (pz) was inserted as N-terminal residue, was addressed by several different Fmoc/tBu and Boc/Bzl solid-phase strategies. On-resin cyclization was achieved immediately following incorporation of Asp, by condensation of the Asp side chain carboxyl with the Lys side chain primary amine after selective and simultaneous removal of side chain protecting groups. The success of the synthesis was highly dependent on the chemical strategy employed, with Boc/Bzl chemistry giving the best results. On the light of our findings, Fmoc/tBu strategies are not advantageous for the solid-phase synthesis of this particular type of lactam-bridged peptides. Last, but not least, the target peptide was recently found to have promising tumorseeking properties (

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“…There are various cyclization methods of dipeptides leading to DKP derivatives, including cyclization of dipeptides bearing C‐terminal methyl esters or active esters …”

Section: Introductionmentioning

confidence: 99%

“…In our recent publication, 1 we described the synthesis and hemoregulatory activity of a series of Glu-Trp (Thymogen) analogs 1 to 5 contained at the N-terminus a 2,5-diketopiperazine moiety which protects the peptides from rapid proteolysis and endows oral bioavailability to the peptides 1, 4, and 5 (Figure 1 There are various cyclization methods of dipeptides leading to DKP derivatives, including cyclization of dipeptides bearing C-terminal methyl esters or active esters. [2][3][4][5] In our preceding work, the cyclopeptides 1 to 5 were prepared via direct cyclization of the linear peptides H-Xaa-Glu(Trp)-OH by refluxing in pyridine, whereby as Xaa residues Ala, Val, Trp, Glu(Ile), or Lys(Boc) were used. 1 In the latter case, acidolytic removal of the Boc protecting group was required to obtain the lysine derivative 4.…”

Section: Introductionmentioning

confidence: 99%

Novel side reaction accompanying cyclization of Glu(R1)‐Glu(R2) dipeptides via lactamization of the Glu(R1) residue

Дейгин

Ksenofontova

Yatskin

et al. 2018

Journal of Peptide Science

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A series of linear peptides with the general formula H-Glu(R1)-Glu(R2)-OH was subjected to cyclization under standard conditions. Formation of respective 2,5-diketopiperazines was accompanied by transformation of the N-terminal Glu(R1) to pyroglutamic acid residue. Even in the case R1 is an amino acid residue attached to the N-terminal γ-carboxyl group, lactamization leads to its elimination. The observed reaction has not been reported so far in the literature. Correspondingly, an alternative route to Glu(R1)-Glu(R2)-containing 2,5-diketopiperazines was applied to improve the overall yields.

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Problems in the synthesis of cyclic peptides through use of the Dmab protecting group †

Cited by 21 publications

References 17 publications

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

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

Comparative Study of Chemical Approaches to the Solid-Phase Synthesis of a Tumor-Seeking α-MSH Analogue

Novel side reaction accompanying cyclization of Glu(R1)‐Glu(R2) dipeptides via lactamization of the Glu(R1) residue

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