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

doi:10.1016/j.ejmech.2018.01.077

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

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

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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 language	English
Pages (from-to)	34-47
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	147
DOIs	https://doi.org/10.1016/j.ejmech.2018.01.077
Publication status	Published - 10 Mar 2018
Externally published	Yes

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Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugsAccepted author manuscript, 529 KBLicence: CC BY-NC-ND

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@article{0ee3b745e53445ff831dfc8cdc93637a,

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

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.",

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

year = "2018",

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day = "10",

doi = "10.1016/j.ejmech.2018.01.077",

language = "English",

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journal = "European Journal of Medicinal Chemistry",

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AU - Thomas, Komba

AU - Moody, Terry W.

AU - Jensen, Robert T.

AU - Tong, Jason

AU - Rayner, Cassie L.

AU - Barnett, Nigel L.

AU - Fairfull-Smith, Kathryn E.

AU - Ridnour, Lisa A.

AU - Wink, David A.

AU - Bottle, Steven E.

PY - 2018/3/10

Y1 - 2018/3/10

N2 - 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.

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

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