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

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.

SUBMITTER: Uddin MJ

PROVIDER: S-EPMC4027729 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Uddin Md Jashim MJ Crews Brenda C BC Huda Imran I Ghebreselasie Kebreab K Daniel Cristina K CK Marnett Lawrence J LJ

ACS medicinal chemistry letters 20140123 4

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 re ...[more]

PMID: 24900856

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Dataset Information

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

Publications

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

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