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*

*Corresponding author for this work

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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.

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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    Thomas, K., Moody, T. W., Jensen, R. T., Tong, J., Rayner, C. L., Barnett, N. L., Fairfull-Smith, K. E., Ridnour, L. A., Wink, D. A., & Bottle, S. E. (2018). Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs. European Journal of Medicinal Chemistry, 147, 34-47. https://doi.org/10.1016/j.ejmech.2018.01.077