Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs

Komba Thomas, Terry W. Moody, Robert T. Jensen, Jason Tong, Cassie L. Rayner, Nigel L. Barnett, Kathryn E. Fairfull-Smith, Lisa A. Ridnour, David A. Wink, Steven E. Bottle

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Dual-acting hybrid anti-oxidant/anti-inflammatory agents were developed employing the principle of pharmacophore hybridization. Hybrid agents were synthesized by combining stable anti-oxidant nitroxides with conventional non-steroidal anti-inflammatory drugs (NSAIDs). Several of the hybrid nitroxide-NSAID conjugates displayed promising anti-oxidant and anti-inflammatory effects on two Non-Small Cell Lung Cancer (NSCLC) cells (A549 and NCI-H1299) and in ameliorating oxidative stress induced in 661 W retinal cells. One ester-linked nitroxide-aspirin analogue (27) delivered better anti-inflammatory effects (cyclooxygenase inhibition) than the parent compound (aspirin), and also showed similar reactive oxygen scavenging activity to the anti-oxidant, Tempol. In addition, a nitroxide linked to the anti-inflammatory drug indomethacin (39) significantly ameliorated the effects of oxidative stress on 661 W retinal neurons at efficacies greater or equal to the anti-oxidant Lutein. Other examples of the hybrid conjugates displayed promising anti-cancer activity, as demonstrated by their inhibitory effects on the proliferation of A549 NSCLC cells.

Original languageEnglish
Pages (from-to)34-47
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume147
DOIs
Publication statusPublished - 10 Mar 2018
Externally publishedYes

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Oxidants
Anti-Inflammatory Agents
Pharmaceutical Preparations
Oxidative stress
Cells
Non-Small Cell Lung Carcinoma
Aspirin
Oxidative Stress
Retinal Neurons
Lutein
Scavenging
Prostaglandin-Endoperoxide Synthases
Indomethacin
Neurons
Esters
Oxygen
Neoplasms

Cite this

Thomas, Komba ; Moody, Terry W. ; Jensen, Robert T. ; Tong, Jason ; Rayner, Cassie L. ; Barnett, Nigel L. ; Fairfull-Smith, Kathryn E. ; Ridnour, Lisa A. ; Wink, David A. ; Bottle, Steven E. / Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 147. pp. 34-47.
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abstract = "Dual-acting hybrid anti-oxidant/anti-inflammatory agents were developed employing the principle of pharmacophore hybridization. Hybrid agents were synthesized by combining stable anti-oxidant nitroxides with conventional non-steroidal anti-inflammatory drugs (NSAIDs). Several of the hybrid nitroxide-NSAID conjugates displayed promising anti-oxidant and anti-inflammatory effects on two Non-Small Cell Lung Cancer (NSCLC) cells (A549 and NCI-H1299) and in ameliorating oxidative stress induced in 661 W retinal cells. One ester-linked nitroxide-aspirin analogue (27) delivered better anti-inflammatory effects (cyclooxygenase inhibition) than the parent compound (aspirin), and also showed similar reactive oxygen scavenging activity to the anti-oxidant, Tempol. In addition, a nitroxide linked to the anti-inflammatory drug indomethacin (39) significantly ameliorated the effects of oxidative stress on 661 W retinal neurons at efficacies greater or equal to the anti-oxidant Lutein. Other examples of the hybrid conjugates displayed promising anti-cancer activity, as demonstrated by their inhibitory effects on the proliferation of A549 NSCLC cells.",
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Thomas, K, Moody, TW, Jensen, RT, Tong, J, Rayner, CL, Barnett, NL, Fairfull-Smith, KE, Ridnour, LA, Wink, DA & Bottle, SE 2018, 'Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs' European Journal of Medicinal Chemistry, vol. 147, pp. 34-47. https://doi.org/10.1016/j.ejmech.2018.01.077

Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs. / Thomas, Komba; Moody, Terry W.; Jensen, Robert T.; Tong, Jason; Rayner, Cassie L.; Barnett, Nigel L.; Fairfull-Smith, Kathryn E.; Ridnour, Lisa A.; Wink, David A.; Bottle, Steven E.

In: European Journal of Medicinal Chemistry, Vol. 147, 10.03.2018, p. 34-47.

Research output: Contribution to journalArticleResearchpeer-review

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