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

doi:10.1021/cb700077z

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 Institute

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19 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 language	English (US)
Pages (from-to)	479-483
Number of pages	5
Journal	ACS Chemical Biology
Volume	2
Issue number	7
DOIs	https://doi.org/10.1021/cb700077z
State	Published - Jul 2007

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/cb700077z

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Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology. / Felts, Andrew S.; Ji, Chuan; Stafford, Jennifer B.; Crews, Brenda C.; Kingsley, Philip J.; Rouzer, Carol A.; Washington, Mary Kay; Subbaramaiah, Kotha; Siegel, Brianna S.; Young, Shiu M.; Dannenberg, Andrew J.; Marnett, Lawrence J.

In: ACS Chemical Biology, Vol. 2, No. 7, 07.2007, p. 479-483.

Research output: Contribution to journal › Article › peer-review

Felts, Andrew S. ; Ji, Chuan ; Stafford, Jennifer B. ; Crews, Brenda C. ; Kingsley, Philip J. ; Rouzer, Carol A. ; Washington, Mary Kay ; Subbaramaiah, Kotha ; Siegel, Brianna S. ; Young, Shiu M. ; Dannenberg, Andrew J. ; Marnett, Lawrence J. / Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology. In: ACS Chemical Biology. 2007 ; Vol. 2, No. 7. pp. 479-483.

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title = "Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology",

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.",

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AU - Ji, Chuan

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AU - Kingsley, Philip J.

AU - Rouzer, Carol A.

AU - Washington, Mary Kay

AU - Subbaramaiah, Kotha

AU - Siegel, Brianna S.

AU - Young, Shiu M.

AU - Dannenberg, Andrew J.

AU - Marnett, Lawrence J.

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AB - 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.

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

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