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 journalArticle

17 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Sulindac
Prostaglandin-Endoperoxide Synthases
Indomethacin
Derivatives
Toxicity
Peroxisome Proliferator-Activated Receptors
Cyclooxygenase Inhibitors
Transcription
Hypoglycemic Agents
Adipocytes
Pharmaceutical Preparations
Colonic Neoplasms
Homeostasis
Anti-Inflammatory Agents
Cells
5-hydroxyindomethacin
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Felts, A. S., Ji, C., Stafford, J. B., Crews, B. C., Kingsley, P. J., Rouzer, C. A., ... Marnett, L. J. (2007). Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology. ACS Chemical Biology, 2(7), 479-483. https://doi.org/10.1021/cb700077z

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 journalArticle

Felts, AS, Ji, C, Stafford, JB, Crews, BC, Kingsley, PJ, Rouzer, CA, Washington, MK, Subbaramaiah, K, Siegel, BS, Young, SM, Dannenberg, AJ & Marnett, LJ 2007, 'Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology', ACS Chemical Biology, vol. 2, no. 7, pp. 479-483. https://doi.org/10.1021/cb700077z
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.
@article{7fac4be98da048d4bb70ba34ea0ae424,
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.",
author = "Felts, {Andrew S.} and Chuan Ji and Stafford, {Jennifer B.} and Crews, {Brenda C.} and Kingsley, {Philip J.} and Rouzer, {Carol A.} and Washington, {Mary Kay} and Kotha Subbaramaiah and Siegel, {Brianna S.} and Young, {Shiu M.} and Dannenberg, {Andrew J.} and Marnett, {Lawrence J.}",
year = "2007",
month = "7",
doi = "10.1021/cb700077z",
language = "English (US)",
volume = "2",
pages = "479--483",
journal = "ACS Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology

AU - Felts, Andrew S.

AU - Ji, Chuan

AU - Stafford, Jennifer B.

AU - Crews, Brenda C.

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.

PY - 2007/7

Y1 - 2007/7

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=34548630613&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548630613&partnerID=8YFLogxK

U2 - 10.1021/cb700077z

DO - 10.1021/cb700077z

M3 - Article

VL - 2

SP - 479

EP - 483

JO - ACS Chemical Biology

JF - ACS Chemical Biology

SN - 1554-8929

IS - 7

ER -