Tetrahedron Letters
Synthesis of novel dansyl-labeled Celecoxib derivatives
Andreas Lill a, Klaus Scholich b, Holger Stark a,c,
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a Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany
b Johann Wolfgang Goethe University, Institute of Clinical Pharmacology, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
c Heinrich-Heine-Universität Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitätsstraße 1, 40225 Düsseldorf, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2013
Revised 5 September 2013
Accepted 10 September 2013
Available online 19 September 2013
Four novel dansyl-labeled derivatives of Celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, were
designed and synthesized. To realize the fluorophore-linker-approach divergent and convergent
synthetic strategies were applied. Therefore Celecoxib p-benzoic acid, 8, was synthesized in a new and
convenient way. The yield and the synthetic route to Celecoxib, 1, its pyrazolylic acid, 7, and its pyrazol-
ylic methyl ester, 6, were improved. Through a convenient synthesis 1,11-diamino-3,6,9-trioxundecane,
19, was obtained in high yield and purity and used as a linker for the dansyl moiety.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Fluorescence labeling
Celecoxib
Dansyl
COX
NSAR
Linker
Introduction
The visualization of COX-2 by molecular imagining has been
shown by Marnett et al.11 The unselective COX inhibitor indometh-
Visualization of molecules can help to understand the interac-
tions and molecular pathways of pharmacologically active sub-
stances. Labeled substances are tools to identify unknown
binding partners and to clarify the details of the mechanism of ac-
tion. They can be used as a diagnostic or therapeutic marker to de-
sign assay systems for distinct binding partners as well, for
example an enzyme or receptor associated with a disease. Aside
from radiolabels or imaging agents for complex optical photon
techniques, the introduction of a fluorescence moiety is the easiest
method to visualize a molecule.1,2
acin has been derivatized to a diagnostic and therapeutic fluores-
cent marker for COX-2.12–14 Other groups have studied
radiolabeled Celecoxib derivatives that are suitable for molecular
imaging—for example introduction of 123I and fluorination.11,15,16
Recently Marnett et al. described Celecoxib derivatives that are
linked to a fluorophore.12,13 Here we report the synthesis of novel
fluorescent labeled Celecoxib derivatives with a different design
approach. The final compounds were tested for their COX-2 inhib-
itory activity and absorptions and emission spectra in different sol-
vents were recorded.
It is well known that cyclooxygenase 2 (COX-2), the inducible
form of two isoenzymes that catalyze the conversion of arachi-
donic acid to prostaglandin PGH2, is overexpressed in inflamed
and tumerous tissue, distinct from most normal tissue. Through
the produced prostaglandins, COX-2 is a major contributor in can-
cer progression and might also be important in some neurological
diseases.3–6
Celecoxib, 1, a nonsteroidal anti-inflammatory drug (NSAID), is
a selective COX-2 inhibitor. COX-2-dependent and independent
anti-carcinogenic effects are observed independent of its concen-
tration, but they are far from being understood.7–9 Visualization
of COX-2 and/or Celecoxib is one way to get better insights in
the molecular actions involving Celecoxib.6,10
Results
Modeling
For the design of fluorescence-labeled Celecoxib derivatives a
linker approach was chosen to maintain the pharmacophore and
introduce the labeling element (Fig. 1).
Known structure–activity-relationship (SAR) studies,17 X-ray
structure of COX-2 with bond ligands18 and molecular docking-
experiments on Celecoxib and its derivatives19,20 revealed that
the sulfonamide moiety is essential for biological activities.
Whereas the trifluoromethyl group at the heterocycle points to-
ward the entry tunnel of the active site and should not alter the
affinity. The SAR showed that a pyrazole-3-carboxamide is still ac-
tive on COX-2.17 Derivatization of the tolyl group could serve as an
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Corresponding author. Tel.: +49 211 81 10478; fax: +49 211 81 13359.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.