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A hydrophilic azacyclooctyne for Cu-free click chemistry.

Sletten EM, Bertozzi CR - Org. Lett. (2008)

Bottom Line: Here, we report the synthesis and evaluation of a novel azacyclooctyne, 6,7-dimethoxyazacyclooct-4-yne (DIMAC).Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes.However, its superior polarity and water solubility reduced nonspecific binding, thereby improving the sensitivity of azide detection.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, California, USA.

ABSTRACT
Biomolecules labeled with azides can be detected through Cu-free click chemistry with cyclooctyne probes, but their intrinsic hydrophobicity can compromise bioavailability. Here, we report the synthesis and evaluation of a novel azacyclooctyne, 6,7-dimethoxyazacyclooct-4-yne (DIMAC). Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes. However, its superior polarity and water solubility reduced nonspecific binding, thereby improving the sensitivity of azide detection.

Show MeSH
Cu-free click chemistry with (A) cyclooctyne reagents or (B) 6,7-dimethoxyazacyclooct-4-yne (DIMAC) reagents.
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fig1: Cu-free click chemistry with (A) cyclooctyne reagents or (B) 6,7-dimethoxyazacyclooct-4-yne (DIMAC) reagents.

Mentions: A growing area of reaction methodology focuses on the development of chemical transformations with the selectivity, kinetics, and biocompatibility required to proceed in living systems.(1) Several efforts in this area have converged on the azide as a reagent. Its small size, diverse modes of reactivity, and bioorthogonality make the azide an ideal chemical reporter group for biomolecules.(2) Azides can be incorporated into glycans, lipids, and proteins using metabolic machineries,2a–2d covalent inhibitors,(2e) or enzymatic transfers.(2f)Staudinger ligation with phosphines,(2a) Cu-catalyzed cycloaddition with terminal alkynes (often referred to as click chemistry),(3) or strain-promoted cycloaddition with cyclooctynes(4) allow for modification of the azido biomolecules with diverse probes. The latter reaction, also termed Cu-free click chemistry (Figure 1A), was designed to eliminate the cytotoxic metal catalyst required for conventional click chemistry. Incorporating the alkyne into a strained eight-membered ring system promoted the cycloaddition with azides without compromising selectivity in biological systems.(4) Since the initial report, fluorination(5) and fused phenyl rings(6) have improved the reaction kinetics, and a difluorinated analogue has been employed to image glycans in developing zebrafish.(7)


A hydrophilic azacyclooctyne for Cu-free click chemistry.

Sletten EM, Bertozzi CR - Org. Lett. (2008)

Cu-free click chemistry with (A) cyclooctyne reagents or (B) 6,7-dimethoxyazacyclooct-4-yne (DIMAC) reagents.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2664610&req=5

fig1: Cu-free click chemistry with (A) cyclooctyne reagents or (B) 6,7-dimethoxyazacyclooct-4-yne (DIMAC) reagents.
Mentions: A growing area of reaction methodology focuses on the development of chemical transformations with the selectivity, kinetics, and biocompatibility required to proceed in living systems.(1) Several efforts in this area have converged on the azide as a reagent. Its small size, diverse modes of reactivity, and bioorthogonality make the azide an ideal chemical reporter group for biomolecules.(2) Azides can be incorporated into glycans, lipids, and proteins using metabolic machineries,2a–2d covalent inhibitors,(2e) or enzymatic transfers.(2f)Staudinger ligation with phosphines,(2a) Cu-catalyzed cycloaddition with terminal alkynes (often referred to as click chemistry),(3) or strain-promoted cycloaddition with cyclooctynes(4) allow for modification of the azido biomolecules with diverse probes. The latter reaction, also termed Cu-free click chemistry (Figure 1A), was designed to eliminate the cytotoxic metal catalyst required for conventional click chemistry. Incorporating the alkyne into a strained eight-membered ring system promoted the cycloaddition with azides without compromising selectivity in biological systems.(4) Since the initial report, fluorination(5) and fused phenyl rings(6) have improved the reaction kinetics, and a difluorinated analogue has been employed to image glycans in developing zebrafish.(7)

Bottom Line: Here, we report the synthesis and evaluation of a novel azacyclooctyne, 6,7-dimethoxyazacyclooct-4-yne (DIMAC).Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes.However, its superior polarity and water solubility reduced nonspecific binding, thereby improving the sensitivity of azide detection.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, California, USA.

ABSTRACT
Biomolecules labeled with azides can be detected through Cu-free click chemistry with cyclooctyne probes, but their intrinsic hydrophobicity can compromise bioavailability. Here, we report the synthesis and evaluation of a novel azacyclooctyne, 6,7-dimethoxyazacyclooct-4-yne (DIMAC). Generated in nine steps from a glucose analogue, DIMAC reacted with azide-labeled proteins and cells similarly to cyclooctynes. However, its superior polarity and water solubility reduced nonspecific binding, thereby improving the sensitivity of azide detection.

Show MeSH