A Novel and Versatile Silicon-Derived Linkage Agent, 4-[1-Hydroxy-2-(trimethylsilyl)ethyl]benzoic Acid, Compatible with the Fmoc/t-Bu Strategy for Solid Phase Synthesis of C-Terminal Peptide Acids

Chao, Hann-Guang; Bernatowicz, Michael S.; Reiss, Paul D.; Klimas, Clifford E.; Matsueda, Gary R.

doi:10.1021/ja00084a016

Cited by 33 publications

(10 citation statements)

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“…Although TBAF and BTAF are the most powerful fluoride sources, their use is mandatory to cleave specific handles and protecting groups [15,16]. Furthermore, the addition of 18-crown-6/KF in DMF at 25 °C can be applied to selectively remove the Fmoc group in 70-100% yield, without provoking 03-rearrangement in Gluand Asp-containing peptides as reported by Joulli6 et al [20].…”

Section: Discussionmentioning

confidence: 95%

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Rearrangement of Glu(OtBu)- and Asp(OtBu)-containing peptides upon fluoride treatment in solid-phase synthesis

Kates

Alberício

1995

Lett Pept Sci

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Although fluoride-labile protecting groups and linkers have been developed in solid-phase peptide synthesis to add an extra level of orthogonality, fluoride ions were found to convert ~x-peptides to their corresponding ~/-or 13-peptides in Glu(OtBu)-and Asp(OtBu)-containing peptidyl resins. Different peptide sequences and fluoride reagents were examined to determine the scope of this side reaction. CZE analysis was found to be a useful analytical technique to characterize peptides with respect to this phenomenon.

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Section: Discussionmentioning

confidence: 95%

“…Recently, 4-[1-[N-(9-fluorenylmethyloxycarbonyl)amino]-2-(trimethylsilyl)ethyl]-phenoxyacetic acid and 4-[1-hydroxy-2-(trimethylsilyl)ethyl]benzoic acid were introduced to prepare C-terminal amides and acids, respectively [15,16]. Peptides could be obtained either by treatment with TFA solutions or by fluoride ions.…”

Section: Introductionmentioning

confidence: 99%

Rearrangement of Glu(OtBu)- and Asp(OtBu)-containing peptides upon fluoride treatment in solid-phase synthesis

Kates

Alberício

1995

Lett Pept Sci

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“…The entire solution of crude product thus obtained was purified by loading directly onto a preparative HPLC system with a C-18 column using a linear gradient of increasing acetonitrile in water containing 0.1% TFA for elution as previously detailed. 32 Fractions shown by HPLC to be >95% pure were pooled and lyophilized to provide, with a few exceptions, 25-45 mg of peptide products (ca. 30-50% overall yield) as white powder TFA salts that in general were >98% pure as determined by HPLC (YMC C18 column, detection at 215 and 280 nm using several gradients and solvent systems).…”

Section: Methodsmentioning

confidence: 99%

Development of Potent Thrombin Receptor Antagonist Peptides

et al. 1996

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A peptide-based structure-activity study is reported leading to the discovery of novel potent thrombin receptor antagonists. Systematic substitution of nonproteogenic amino acids for the second and third residues of the human thrombin receptor "tethered ligand" sequence (SFLLR) led to a series of agonists with enhanced potency. The most potent pentapeptide agonist identified was Ser-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2, 9 (EC50 approximately 0.04 microM for stimulation of human platelet aggregation, approximately 10-fold more potent than the natural pentapeptide). Systematic substitution of the NH2-terminal Ser in 9 with neutral hydrophobic NH2-acyl groups led to partial agonists and eventually antagonists with unprecedented potency (greater than 1000-fold increase over the previously reported antagonist 3-mercaptopropionyl-Phe-Cha-Cha-Arg-Lys-Pro-Asn-Asp-Lys-NH2). In the series of NH2-acyl tetrapeptide antagonists, N-transcinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH 2, 41 (BMS-197525), was identified as the tightest binding (IC50 approximately 8 nM) and most potent with an IC50 approximately 0.20 microM for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. Systematic single substitutions in 41 indicated that, in addition to the NH2-terminal acyl group, the side chains at the second and third positions were also responsible for important and specific receptor interactions. The p-fluoroPhe and p-guanidinoPhe residues in the second and third positions of 41 were observed to be optimal in both the agonist and antagonist series. In the case of antagonists, however, an appropriately positioned positively charged group (i.e., protonated base) at the third residue was required. In contrast, such a substitution was not required for potent agonist activity. An even more potent antagonist resulted when 41 was extended at the C-terminus by a single Arg residue giving rise to analog 90 (BMS-200261) which had an IC50 approximately 20 nM for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. When the C-terminal Arg of 90 was replaced by an Orn-(Ndelta-propionyl) residue, the resulting antagonist 91 (BMS-200661) was suitable for use in radioligand binding assays (Kd = 10-30 nM). Antagonist activity observed for selected compounds was verified through secondary assays in that these analogs prevented SFLLRNP-NH2-stimulated GTPase activity in platelet membranes and Ca2+ mobilization in cultured human smooth muscle cells and mouse fibroblasts. Furthermore, this inhibition occurred at concentrations that had no effect on thrombin catalytic activity indicating a specific activity attributable to receptor binding and not enzyme inhibition.

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“…A change in the stereochemistry of the prevailing trans-amide bond is required for reaction (Fischer 2003), which is, on the contrary, favoured by alkylation of the peptide bond of the dipeptide (as with an N-terminal proline residue). Specific procedures involving a replacement of the alkyl ester moieties with hindered groups or alternative structures have been introduced to suppress this side-reaction (Akaji et al 1990;Chao et al 1994;Kochansky and Wagner 1992;Sola et al 1996;Anne et al 1998;Chiva et al 1999;Gothe et al 1999;Lundquist and Pelletier 2001;Sakamoto et al 2002). On the other hand, a facilitated cleavage into diketopiperazines can constitute an advantage as for example by allowing the release of specific derivatives from a solid support under mild conditions (Burgess et al 1997;Hulme et al 1998;Orain and Bradley 2001;Chitku et al 2001).…”

Section: Introductionmentioning

confidence: 99%

The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

Beaufils

Jepaul

Liu

et al. 2015

Orig Life Evol Biosph

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The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

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A Novel and Versatile Silicon-Derived Linkage Agent, 4-[1-Hydroxy-2-(trimethylsilyl)ethyl]benzoic Acid, Compatible with the Fmoc/t-Bu Strategy for Solid Phase Synthesis of C-Terminal Peptide Acids

Cited by 33 publications

References 0 publications

Rearrangement of Glu(OtBu)- and Asp(OtBu)-containing peptides upon fluoride treatment in solid-phase synthesis

Rearrangement of Glu(OtBu)- and Asp(OtBu)-containing peptides upon fluoride treatment in solid-phase synthesis

Development of Potent Thrombin Receptor Antagonist Peptides

The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

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