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Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer

[Image: see text] The use of coumarin caged molecules has been well documented in numerous photocaging applications including for the spatiotemporal control of Cre-estrogen receptor (Cre-ERT2) recombinase activity. In this article, we report that 4-hydroxytamoxifen (4OHT) caged with coumarin via a c...

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Autores principales: Wong, Pamela T., Roberts, Edward W., Tang, Shengzhuang, Mukherjee, Jhindan, Cannon, Jayme, Nip, Alyssa J., Corbin, Kaitlin, Krummel, Matthew F., Choi, Seok Ki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2017
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404426/
https://www.ncbi.nlm.nih.gov/pubmed/28191924
http://dx.doi.org/10.1021/acschembio.6b00999
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author Wong, Pamela T.
Roberts, Edward W.
Tang, Shengzhuang
Mukherjee, Jhindan
Cannon, Jayme
Nip, Alyssa J.
Corbin, Kaitlin
Krummel, Matthew F.
Choi, Seok Ki
author_facet Wong, Pamela T.
Roberts, Edward W.
Tang, Shengzhuang
Mukherjee, Jhindan
Cannon, Jayme
Nip, Alyssa J.
Corbin, Kaitlin
Krummel, Matthew F.
Choi, Seok Ki
author_sort Wong, Pamela T.
collection PubMed
description [Image: see text] The use of coumarin caged molecules has been well documented in numerous photocaging applications including for the spatiotemporal control of Cre-estrogen receptor (Cre-ERT2) recombinase activity. In this article, we report that 4-hydroxytamoxifen (4OHT) caged with coumarin via a conventional ether linkage led to an unexpected photo-Claisen rearrangement which significantly competed with the release of free 4OHT. The basis for this unwanted reaction appears to be related to the coumarin structure and its radical-based mechanism of uncaging, as it did not occur in ortho-nitrobenzyl (ONB) caged 4OHT that was otherwise linked in the same manner. In an effort to perform design optimization, we introduced a self-immolative linker longer than the ether linkage and identified an optimal linker which allowed rapid 4OHT release by both single-photon and two-photon absorption mechanisms. The ability of this construct to actively control Cre-ERT2 mediated gene modifications was investigated in mouse embryonic fibroblasts (MEFs) in which the expression of a green fluorescent protein (GFP) reporter dependent gene recombination was controlled by 4OHT release and measured by confocal fluorescence microscopy and flow cytometry. In summary, we report the implications of this photo-Claisen rearrangement in coumarin caged compounds and demonstrate a rational linker strategy for addressing this unwanted side reaction.
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spelling pubmed-54044262018-02-13 Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer Wong, Pamela T. Roberts, Edward W. Tang, Shengzhuang Mukherjee, Jhindan Cannon, Jayme Nip, Alyssa J. Corbin, Kaitlin Krummel, Matthew F. Choi, Seok Ki ACS Chem Biol [Image: see text] The use of coumarin caged molecules has been well documented in numerous photocaging applications including for the spatiotemporal control of Cre-estrogen receptor (Cre-ERT2) recombinase activity. In this article, we report that 4-hydroxytamoxifen (4OHT) caged with coumarin via a conventional ether linkage led to an unexpected photo-Claisen rearrangement which significantly competed with the release of free 4OHT. The basis for this unwanted reaction appears to be related to the coumarin structure and its radical-based mechanism of uncaging, as it did not occur in ortho-nitrobenzyl (ONB) caged 4OHT that was otherwise linked in the same manner. In an effort to perform design optimization, we introduced a self-immolative linker longer than the ether linkage and identified an optimal linker which allowed rapid 4OHT release by both single-photon and two-photon absorption mechanisms. The ability of this construct to actively control Cre-ERT2 mediated gene modifications was investigated in mouse embryonic fibroblasts (MEFs) in which the expression of a green fluorescent protein (GFP) reporter dependent gene recombination was controlled by 4OHT release and measured by confocal fluorescence microscopy and flow cytometry. In summary, we report the implications of this photo-Claisen rearrangement in coumarin caged compounds and demonstrate a rational linker strategy for addressing this unwanted side reaction. American Chemical Society 2017-02-13 2017-04-21 /pmc/articles/PMC5404426/ /pubmed/28191924 http://dx.doi.org/10.1021/acschembio.6b00999 Text en Copyright © 2017 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Wong, Pamela T.
Roberts, Edward W.
Tang, Shengzhuang
Mukherjee, Jhindan
Cannon, Jayme
Nip, Alyssa J.
Corbin, Kaitlin
Krummel, Matthew F.
Choi, Seok Ki
Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer
title Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer
title_full Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer
title_fullStr Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer
title_full_unstemmed Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer
title_short Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer
title_sort control of an unusual photo-claisen rearrangement in coumarin caged tamoxifen through an extended spacer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404426/
https://www.ncbi.nlm.nih.gov/pubmed/28191924
http://dx.doi.org/10.1021/acschembio.6b00999
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