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ACS Med Chem Lett. 2014 Jan 23;5(4):446-50. doi: 10.1021/ml400485g. eCollection 2014.

Trifluoromethyl fluorocoxib a detects cyclooxygenase-2 expression in inflammatory tissues and human tumor xenografts.

Author information

  • 1A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.

Abstract

Fluorocoxib A is an effective COX-2-targeted optical imaging agent, used for in vivo detection of inflammatory tissues and premalignant and malignant tumors that express elevated levels of COX-2 (Uddin et al. Cancer Res. 2010, 70, 3618-3627). In an effort to discover novel optical probes for COX-2, a trifluoromethyl analogue of fluorocoxib A (CF3-fluorocoxib A) was synthesized and evaluated for its ability to inhibit COX-2 in vitro purified enzyme and human cancer cell lines. Kinetic analysis revealed that CF3-fluorocoxib A is a slow, tight binding inhibitor of COX-2 that exhibits low nanomolar inhibitory potency. While CF3-fluorocoxib A and fluorocoxib A are similar in structure, CF3-fluorocoxib A shows improved potency in inhibition of wtCOX-2 and with a series of site-directed COX-2 mutants. After intraperitoneal injection, selective uptake of CF3-fluorocoxib A is detected in inflamed mouse paws compared to noninflamed contralateral paws by optical imaging, and uptake is blocked by pretreatment with the COX-2 inhibitor, celecoxib. Selective uptake is also detected in the COX-2-positive human tumor xenografts (1483 HNSCC) as compared with the COX-2-negative tumor xenografts (HCT116) in an in vivo nude mouse tumor model. These in vitro and in vivo studies suggest that binding to COX-2 is the major determinant of uptake of CF3-fluorocoxib A into the inflamed tissues and tumor xenografts. Thus, this new COX-2-targeted imaging probe should find utility in the detection and evaluation of COX-2 status in naturally occurring malignancies.

KEYWORDS:

CF3-fluorocoxib A; CF3-indomethacin; Cyclooxygenase-2 (COX-2); cancer; inflammation; optical imaging

PMID:
24900856
[PubMed]
PMCID:
PMC4027729
Free PMC Article
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