Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology

Andrew S. Felts, Chuan Ji, Jennifer B. Stafford, Brenda C. Crews, Philip J. Kingsley, Carol A. Rouzer, Mary Kay Washington, Kotha Subbaramaiah, Brianna S. Siegel, Shiu M. Young, Andrew J. Dannenberg, Lawrence J. Marnett

    Research output: Contribution to journalArticlepeer-review

    22 Scopus citations

    Abstract

    Cyclooxygenases (COX) have been implicated in the etiology of a number of diseases, but defining the precise contribution of COXs to these diseases is challenging. Potent COX inhibitors exist, but they display off-target effects. 2′-Desmethyl derivatives of indomethacin and sulindac sulfide were synthesized that demonstrated reduced COX inhibitory activity but were inducers of peroxisome proliferator-activated receptor γ-dependent transcription, adipocyte differentiation, or apoptosis of colon cancer cell lines. 2′-Desmethylindomethacin demonstrated gastrointestinal toxicity lower than that of indomethacin in C57BL6 mice, highlighting the importance of COX activity in maintaining gastrointestinal homeostasis and establishing that COX inhibition contributes to gastrointestinal toxicity by nonsteroidal antiinflammatory drugs. These compounds serve as useful probes of COX-dependent biology and may represent leads for antidiabetic and anticancer drugs.

    Original languageEnglish (US)
    Pages (from-to)479-483
    Number of pages5
    JournalACS Chemical Biology
    Volume2
    Issue number7
    DOIs
    StatePublished - Jul 2007

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine

    Fingerprint

    Dive into the research topics of 'Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology'. Together they form a unique fingerprint.

    Cite this