ACS Medicinal Chemistry Letters
Letter
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introduction of smaller substituents at the flurbiprofen α-
carbon. Yet, there is a trade-off between potency and selectivity.
Comparing the RAW cell data of 3a and 7a suggests that
reducing the steric bulk at the α-carbon (i.e., converting the α-
methyl group of 7a into the hydrogen present in 3a) increases
potency for 2-AG and AA inhibition, resulting in less substrate
selectivity. There appear to be favorable interactions promoting
substrate selectivity that the more sterically demanding 7a can
utilize, but are unavailable to the smaller 3a. The identity of
these interactions remains unclear.
The data presented here lead us to several conclusions about
achiral profen COX-2 inhibitors. First, achiral profens
demonstrate substrate-selective behavior in vitro and in a
cellular setting. Second, smaller α-carbon substituents (i.e.,
hydrogens) result in more potent but less selective inhibitors
than more sterically demanding groups (i.e., dimethyl, cyclo-
propyl). Finally, inhibitor potency and selectivity are dependent
on the profen’s aryl scaffold, with some scaffolds (e.g.,
flurbiprofen) offering superior behavior relative to others
(e.g., ibuprofen). In addition, our most potent compound,
desmethylflurbiprofen (3a), possesses metabolic stability on par
with that of ibuprofen. These results indicate that achiral
profens can act as lead molecules for further development
toward in vivo probes of substrate-selective COX-2 inhibition.
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degradation of the endocannabinoid 2-arachidonoylglycerol. BioFactors
2011, 37 (1), 1−7.
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete assay and synthetic procedures, crystallization data,
and analytical and spectral characterization of synthesized
compounds. This material is available free of charge via the
(12) Kozak, K. R.; Crews, B. C.; Ray, J. L.; Tai, H.-H.; Morrow, J. D.;
Marnett, L. J. Metabolism of Prostaglandin Glycerol Esters and
Prostaglandin Ethanolamides in Vitro and in Vivo. J. Biol. Chem. 2001,
276 (40), 36993−36998.
(13) Prusakiewicz, J. J.; Duggan, K. C.; Rouzer, C. A.; Marnett, L. J.
Differential Sensitivity and Mechanism of Inhibition of COX-2
Oxygenation of Arachidonic Acid and 2-Arachidonoylglycerol by
Ibuprofen and Mefenamic Acid. Biochemistry 2009, 48 (31), 7353−
7355.
(14) Dong, L.; Vecchio, A. J.; Sharma, N. P.; Jurban, B. J.; Malkowski,
M. G.; Smith, W. L. Human Cyclooxygenase-2 Is a Sequence
Homodimer That Functions as a Conformational Heterodimer. J. Biol.
Chem. 2011, 286 (21), 19035−19046.
(15) Rimon, G.; Sidhu, R. S.; Lauver, D. A.; Lee, J. Y.; Sharma, N. P.;
Yuan, C.; Frieler, R. A.; Trievel, R. C.; Lucchesi, B. R.; Smith, W. L.
Coxibs interfere with the action of aspirin by binding tightly to one
monomer of cyclooxygenase-1. Proc. Natl. Acad. Sci. 2010, 107 (1),
28−33.
(16) Duggan, K. C.; Hermanson, D. J.; Musee, J.; Prusakiewicz, J. J.;
Scheib, J. L.; Carter, B. D.; Banerjee, S.; Oates, J. A.; Marnett, L. J. (R)-
Profens are substrate-selective inhibitors of endocannabinoid oxygen-
ation by COX-2. Nat. Chem. Biol. 2011, 7 (11), 803−809.
(17) Leipold, D. D.; Kantoci, D.; Murray, E. D.; Quiggle, D. D.;
Wechter, W. J. Bioinversion of (R)-flurbiprofen to (S)-flurbiprofen at
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379−387.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: 615-343-7329. Fax: 615-343-7534. E-mail: larry.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
This work was supported by grants from the U.S. National
Institutes of Health, the National Center for Research
Resources, the National Institute of General Medical Sciences,
the Department of Energy and the Canadian Institutes of
Health Research. See the Supporting Information for grant
numbers and additional funding information.
Notes
The authors declare no competing financial interest.
(18) Woodman, T. J.; Wood, P. J.; Thompson, A. S.; Hutchings, T. J.;
Steel, G. R.; Jiao, P.; Threadgill, M. D.; Lloyd, M. D. Chiral inversion
of 2-arylpropionyl-CoA esters by human alpha-methylacyl-CoA
racemase 1A (P504S) - a potential mechanism for the anti-cancer
effects of ibuprofen. Chem. Commun. 2011, 47, 7332−7334.
(19) Ossipov, M. H.; Jerussi, T. P.; Ren, K.; Sun, H.; Porreca, F.
Differential effects of spinal (R)-ketoprofen and (S)-ketoprofen
against signs of neuropathic pain and tonic nociception: evidence for
a novel mechanism of action of (R)-ketoprofen against tactile
allodynia. Pain 2000, 87 (2), 193−199.
ACKNOWLEDGMENTS
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We are grateful to Kebreab Ghebreselasie for generating the
enzyme used for in vitro assays.
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