Electron‐Deficient Alkynes as Cleavable Reagents for the Modification of Cysteine‐Containing Peptides in Aqueous Medium

Shiu, Hoi Yan; Chan, Tak Chung; Ho, Chi Ming; Liu, Yungen; Wong, Man Leung; Ming, Chi

doi:10.1002/chem.200800669

Cited by 116 publications

(114 citation statements)

References 46 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…As an alternative protective moiety we decided to use 1,2-double substituted vinyl-sulfides which may be efficiently synthesized from corresponding electron-deficient alkynes and unprotected free-cysteine containing peptides in aqueous media 16 (Figure 1). Notably, similar cysteine-protecting/labeling synthetic schemes employing, both mono- 17;18 and double-substituted alkynes 17–19 , were recently reported. Analogous reaction(s) employing allenes were also successfully used to create vinylthioether-linkage 20;21 .…”

mentioning

confidence: 78%

“…Notably, PR73SH appears also to be remarkably stable in mildly oxidizing conditions as prolonged storage of the compound in DMSO (10 mM solution) at room temperature for 30 days shows very limited levels of decomposition or sulfide oxidation (99.5±0.5% of stability, determined by LC/MS/MS experiments). Interestingly, compounds containing similar functional group(s) described to date 17–19 show diverse bio-stability levels.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Thiol-derivatized minihepcidins retain biological activity

Fung

Chua

Ganz

et al. 2015

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Minihepcidins are small peptides that mimic biological activity of the iron-regulatory hormone hepcidin. Structurally, they contain thiol-free-cysteine residue in position 7 which is crucial for their bioactivity. Nonetheless, free sulfhydryl group is not desirable in pharmaceutical entities as it may lead to dermatological side effects. Moreover free thiol moiety is quite reactive and depending on conditions/reagents may be alkylated and/or oxidized giving various Cys-derivatives: S-alkyl cysteines, sulfoxides, sulfones, disulfides, cysteinesulfinic and cysteic acids. To limit such reactivity and maintain bioactivity of minihepcidin(s) we used thiol-protection strategy based on activated vinyl thioethers. Novel S-protected analogs of physiologically active minihepcidin PR73 were synthesized and tested in vitro showing activity comparable to parental molecule. The most active compound, PR73SH was also tested in vivo showing activity profile analogous to PR73. Collectively, our findings suggest that S-vinyl-derivatization of minihepcidin(s) may be a suitable approach in the development of physiologically active agonists of hepcidin.

show abstract

mentioning

confidence: 78%

mentioning

confidence: 99%

Thiol-derivatized minihepcidins retain biological activity

Fung

Chua

Ganz

et al. 2015

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

show abstract

“…The 2 nd -order rate constant of the conjugate addition of a model cysteine-containing peptide to N -phenylpropiolamide can be estimated as approximately 0.13 M −1 s −1 (pH 7.0). 17 The reaction rates of maleimide 18 and oxanorbornadiene reagents 19,20 with thiols are more than 500 times greater.…”

mentioning

confidence: 99%

Relative Performance of Alkynes in Copper-Catalyzed Azide–Alkyne Cycloaddition

et al. 2013

View full text Add to dashboard Cite

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) has found numerous applications in a variety of fields. We report here only modest differences in the reactivity of various classes of terminal alkynes under typical bioconjugative and preparative organic conditions. Propargyl compounds represent an excellent combination of azide reactivity, ease of installation, and cost. Electronically activated propiolamides are slightly more reactive, at the expense of increased propensity for Michael addition. Certain alkynes, including tertiary propargyl carbamates, are not suitable for bioconjugation due to copper-induced fragmentation. A fluorogenic probe based on such reactivity is available in one step from rhodamine 110 and can be useful for optimization of CuAAC conditions.

show abstract

“…This explains why when even stronger EWGs are present the heterobisthioether cannot be isolated. 33,34 A similar phenomenon has been reported with geminal doubly activated vinyl compounds and has been exploited to prepare covalent yet reversible small molecule enzyme inhibitors. 40 To assess the reactivity of trans and cis regioisomers, observed rate constants for the addition of 4 to ΔUb-VME (trans) and ΔUb-VME* (cis) were determined.…”

Section: Acs Chemical Biologymentioning

confidence: 77%

Orthogonal Thiol Functionalization at a Single Atomic Center for Profiling Transthiolation Activity of E1 Activating Enzymes

et al. 2015

View full text Add to dashboard Cite

Transthiolation is a fundamental biological reaction and is utilized by many enzymes involved in the conjugation of ubiquitin and ubiquitin-like proteins. However, tools that enable selective profiling of this activity are lacking. Transthiolation requires cysteine-cysteine juxtaposition; therefore a method that enables irreversible "stapling" of proximal thiols would facilitate the development of novel probes that could be used to profile this activity. Herein, we characterize biocompatible chemistry that enables sequential functionalization of cysteines within proteins at a single atomic center. We use our method to develop a new class of activity-based probe that profiles transthiolation activity of human E1 activating enzymes. We demonstrate use in vitro and in situ and compatibility with competitive activity-based protein profiling. We also use the probe to gain insight into the determinants of transthiolation between E2 and a RING-in-between-RING (RBR) E3 ligase. Furthermore, we anticipate that this method of thiol functionalization will have broad utility by enabling simple redox-stable cross-linking of proximal cysteines in general.

show abstract

Electron‐Deficient Alkynes as Cleavable Reagents for the Modification of Cysteine‐Containing Peptides in Aqueous Medium

Cited by 116 publications

References 46 publications

Thiol-derivatized minihepcidins retain biological activity

Thiol-derivatized minihepcidins retain biological activity

Relative Performance of Alkynes in Copper-Catalyzed Azide–Alkyne Cycloaddition

Orthogonal Thiol Functionalization at a Single Atomic Center for Profiling Transthiolation Activity of E1 Activating Enzymes

Contact Info

Product

Resources

About