Trimethoxyphenylthio as a Highly Labile Replacement for <i>tert</i>-Butylthio Cysteine Protection in Fmoc Solid Phase Synthesis

Postma, Tobias M.; Giraud, Matthieu; Alberício, Fernando

doi:10.1021/ol3025499

Cited by 49 publications

(69 citation statements)

References 16 publications

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“…39 Thus, this study using a CCa 2 X library paves the way for the use of such libraries to probe palmitoylation specificity. For this, a CCa 2 X library could be prenylated chemically using orthogonally protected Cys 40,41 or enzymatically with PFTase or PGGTase-I and then screened for enzymatic palmitoylation using an alkyne-containing palmitoyl-CoA analogue. 42 …”

Section: Resultsmentioning

confidence: 99%

Rapid Analysis of Protein Farnesyltransferase Substrate Specificity Using Peptide Libraries and Isoprenoid Diphosphate Analogues

et al. 2014

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Protein farnesytransferase (PFTase) catalyzes the farnesylation of proteins with a carboxy-terminal tetrapeptide sequence denoted as a Ca1a2X box. To explore the specificity of this enzyme, an important therapeutic target, solid-phase peptide synthesis in concert with a peptide inversion strategy was used to prepare two libraries, each containing 380 peptides. The libraries were screened using an alkyne-containing isoprenoid analogue followed by click chemistry with biotin azide and subsequent visualization with streptavidin-AP. Screening of the CVa2X and CCa2X libraries with Rattus norvegicus PFTase revealed reaction by many known recognition sequences as well as numerous unknown ones. Some of the latter occur in the genomes of bacteria and viruses and may be important for pathogenesis, suggesting new targets for therapeutic intervention. Screening of the CVa2X library with alkyne-functionalized isoprenoid substrates showed that those prepared from C10 or C15 precursors gave similar results, whereas the analogue synthesized from a C5 unit gave a different pattern of reactivity. Lastly, the substrate specificities of PFTases from three organisms (R. norvegicus, Saccharomyces cerevisiae, and Candida albicans) were compared using CVa2X libraries. R. norvegicus PFTase was found to share more peptide substrates with S. cerevisiae PFTase than with C. albicans PFTase. In general, this method is a highly efficient strategy for rapidly probing the specificity of this important enzyme.

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Section: Resultsmentioning

confidence: 99%

Rapid Analysis of Protein Farnesyltransferase Substrate Specificity Using Peptide Libraries and Isoprenoid Diphosphate Analogues

et al. 2014

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“…8 In this case, we use the reaction between NCS and an excess of 2,5-dimethoxythiophenol to make a calibration curve to determine the loading of the resin based on the formation of 2,5-dimethoxyphenyl disulfide using UV spectroscopy at 300 nm.…”

Section: Methodsmentioning

confidence: 99%

“…Initially, we used NCS to form a disulfide bond between Cys and trimethoxythiophenol to make the Cys protecting group S -Tmp. 8 The reaction between the thiol and NCS proceeds by the formation of a sulfenyl chloride, which is highly reactive toward other thiols. In this regard, we observed a rapid, clean, and efficient reaction (Scheme 1).…”

mentioning

confidence: 99%

Immobilized N-Chlorosuccinimide as a Friendly Peptide Disulfide-Forming Reagent

Postma

Alberício

2014

ACS Comb. Sci.

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A novel immobilized N-chlorosuccinimide resin was developed for peptide disulfide bond formation in combinatorial libraries. The resin is prepared in a simple two-step process from commercial starting materials. Disulfide formation is initiated by adding a peptide solution to the resin, and excess reagent is removed by a convenient filtration upon completion of disulfide formation. Completion of disulfide formation is rapid and clean, as demonstrated by the oxidation of a small nonapeptide library. This immobilized reagent allows a wider scope for the use of N-chlorosuccinimide-based disulfide formation in combinatorial chemistry.

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“…[12] This synthetic strategy led to the expected macrocycles in high purities and overall yields (Supporting Information, Scheme S4, Figure S5, S6). [12] This synthetic strategy led to the expected macrocycles in high purities and overall yields (Supporting Information, Scheme S4, Figure S5, S6).…”

Section: Angewandte Chemiementioning

confidence: 99%

A Solid‐Phase Approach to Accessing Bisthioether‐Stapled Peptides Resulting in a Potent Inhibitor of PRC2 Catalytic Activity

et al. 2018

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Stapled peptides have emerged as an ew class of therapeutics to effectively target intractable protein-protein interactions.Thus,efficient and versatile methods granting easy access to this class of compounds and expanding the scope(s) of the currently available ones are of great interest. Now,asolid phase approach is described for the synthesis of bisthioether stapled peptides with multiple architectures,i ncluding singleturn, double-turn, and double-stapled macrocycles.T his method allows for ligation with all-hydrocarbon linkers of various lengths,avoiding the use of unnatural amino acids and expensive catalysts,and affords cyclopeptides with remarkable resistance to proteolytic degradation. The potential of this procedure is demonstrated by applying it to generate astapled peptide that shows potent in vitro inhibition of methyltransferase activity of the polycomb repressive complex 2( PRC2) of proteins.

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Trimethoxyphenylthio as a Highly Labile Replacement for tert-Butylthio Cysteine Protection in Fmoc Solid Phase Synthesis

Cited by 49 publications

References 16 publications

Rapid Analysis of Protein Farnesyltransferase Substrate Specificity Using Peptide Libraries and Isoprenoid Diphosphate Analogues

Rapid Analysis of Protein Farnesyltransferase Substrate Specificity Using Peptide Libraries and Isoprenoid Diphosphate Analogues

Immobilized N-Chlorosuccinimide as a Friendly Peptide Disulfide-Forming Reagent

A Solid‐Phase Approach to Accessing Bisthioether‐Stapled Peptides Resulting in a Potent Inhibitor of PRC2 Catalytic Activity

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