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Synthesis of an azido-tagged low affinity ratiometric calcium sensor.

Caldwell ST, Cairns AG, Olson M, Chalmers S, Sandison M, Mullen W, McCarron JG, Hartley RC - Tetrahedron (2015)

Bottom Line: The synthesis of a dual excitation, ratiometric calcium ion sensor with a K d of 90 μM, is described.It is tagged with an azido group for bioconjugation, and absorbs in the blue/green and emits in the red region of the visible spectrum with a large Stokes shift.The thiohydantoin unit has to be protected with an acetoxymethyl (AM) caging group to allow CuAAC click reaction and incorporation of the KDEL peptide endoplasmic reticulum (ER) retention sequence.

View Article: PubMed Central - PubMed

Affiliation: WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.

ABSTRACT

Changes in high localised concentrations of Ca(2+) ions are fundamental to cell signalling. The synthesis of a dual excitation, ratiometric calcium ion sensor with a K d of 90 μM, is described. It is tagged with an azido group for bioconjugation, and absorbs in the blue/green and emits in the red region of the visible spectrum with a large Stokes shift. The binding modulating nitro group is introduced to the BAPTA core prior to construction of a benzofuran-2-yl carboxaldehyde by an allylation-oxidation-cyclisation sequence, which is followed by condensation with an azido-tagged thiohydantoin. The thiohydantoin unit has to be protected with an acetoxymethyl (AM) caging group to allow CuAAC click reaction and incorporation of the KDEL peptide endoplasmic reticulum (ER) retention sequence.

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Mentions: Selective formylation of the more electron rich ring gave aldehyde 10, which was deprotected by hydrogenolysis to yield phenol 11. Construction of the benzofuran unit by alkylation with the diethyl acetal of bromoacetaldehyde followed by acid-induced cyclisation34 proved capricious, so we decided to investigate allylation of the phenol, followed by oxidative cleavage and cyclisation. This route to benzofuran-2-ylcarboxaldehydes is new and there was only one literature example35 of an allyl group being cleaved in the presence of a tertiary amine. The literature example employed ozonolysis, but the use of osmium tetroxide/sodium periodate followed by acid proved satisfactory. Nitration of the A ring has to be carried out after construction of the BAPTA unit and deactivation of the B ring by the aldehyde to take advantage of the directing effect of the amino group,14, 29, 36 and experimentation showed that it was best performed on the allyl ether 12. Oxidation of the nitrated compound 13 and cyclisation then gave the desired benzofuran 14 in modest yield over the two steps (Scheme 1).


Synthesis of an azido-tagged low affinity ratiometric calcium sensor.

Caldwell ST, Cairns AG, Olson M, Chalmers S, Sandison M, Mullen W, McCarron JG, Hartley RC - Tetrahedron (2015)

© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660056&req=5

Mentions: Selective formylation of the more electron rich ring gave aldehyde 10, which was deprotected by hydrogenolysis to yield phenol 11. Construction of the benzofuran unit by alkylation with the diethyl acetal of bromoacetaldehyde followed by acid-induced cyclisation34 proved capricious, so we decided to investigate allylation of the phenol, followed by oxidative cleavage and cyclisation. This route to benzofuran-2-ylcarboxaldehydes is new and there was only one literature example35 of an allyl group being cleaved in the presence of a tertiary amine. The literature example employed ozonolysis, but the use of osmium tetroxide/sodium periodate followed by acid proved satisfactory. Nitration of the A ring has to be carried out after construction of the BAPTA unit and deactivation of the B ring by the aldehyde to take advantage of the directing effect of the amino group,14, 29, 36 and experimentation showed that it was best performed on the allyl ether 12. Oxidation of the nitrated compound 13 and cyclisation then gave the desired benzofuran 14 in modest yield over the two steps (Scheme 1).

Bottom Line: The synthesis of a dual excitation, ratiometric calcium ion sensor with a K d of 90 μM, is described.It is tagged with an azido group for bioconjugation, and absorbs in the blue/green and emits in the red region of the visible spectrum with a large Stokes shift.The thiohydantoin unit has to be protected with an acetoxymethyl (AM) caging group to allow CuAAC click reaction and incorporation of the KDEL peptide endoplasmic reticulum (ER) retention sequence.

View Article: PubMed Central - PubMed

Affiliation: WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.

ABSTRACT

Changes in high localised concentrations of Ca(2+) ions are fundamental to cell signalling. The synthesis of a dual excitation, ratiometric calcium ion sensor with a K d of 90 μM, is described. It is tagged with an azido group for bioconjugation, and absorbs in the blue/green and emits in the red region of the visible spectrum with a large Stokes shift. The binding modulating nitro group is introduced to the BAPTA core prior to construction of a benzofuran-2-yl carboxaldehyde by an allylation-oxidation-cyclisation sequence, which is followed by condensation with an azido-tagged thiohydantoin. The thiohydantoin unit has to be protected with an acetoxymethyl (AM) caging group to allow CuAAC click reaction and incorporation of the KDEL peptide endoplasmic reticulum (ER) retention sequence.

No MeSH data available.


Related in: MedlinePlus