cb6b00999_si_001.pdf (1.73 MB)
Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer
journal contribution
posted on 2017-02-13, 00:00 authored by Pamela
T. Wong, Edward W. Roberts, Shengzhuang Tang, Jhindan Mukherjee, Jayme Cannon, Alyssa J. Nip, Kaitlin Corbin, Matthew F. Krummel, Seok Ki ChoiThe 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.