Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 5, Issue 11, Pages 1254-1258Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml500344j
Keywords
Cyclooxygenase-1 (COX-1); rofecoxib; furanone; structure-activity relationship; imaging
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Funding
- National Institutes of Health [CA89450, CA136465, S10 RR019022]
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We report the design and synthesis of fluorine-containing cyclooxygenase-1 (COX-1)-selective inhibitors to serve as prototypes for the development of a COX-1-targeted imaging agent. Deletion of the SO2CH3 group of rofecoxib switches the compound from a COX-2- to a COX-1-selective inhibitor, providing a 3,4-diarylfuran-2(5H)-one scaffold for structureactivity relationship studies of COX-1 inhibition. A wide range of fluorine-containing 3,4-diarylfuran-2(5H)-ones were designed, synthesized, and tested for their ability to selectively inhibit COX-1 in purified protein and human cancer cell assays. Compounds containing a fluoro-substituent on the C-3 phenyl ring and a methoxy-substituent on the C-4 phenyl ring of the 3,4-diarylfuran-2(5H)-one scaffold were the best COX-1-selective agents of those evaluated, exhibiting IC(50)s in the submicromolar range. These compounds provide the foundation for development of an agent to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX-1.
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