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Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine-2,3-dioxygenase (IDO) as Potential Target for Anticancer Activity

Blunt, Christopher E.; Blunt, Christopher; Torcuk, Canan; Liu, Yang; Lewis, William; Siegel, David; Ross, David; Moody, Christopher J.

Authors

Christopher E. Blunt

Christopher Blunt

Canan Torcuk

Yang Liu

William Lewis

David Siegel

David Ross

Christopher J. Moody



Abstract

Natural quinones, often linked with cellular oxidation processes, also exhibit pronounced biological activity. In particular, the structurally unique isothiazolo-naphthoquinone, aulosirazole, isolated from blue-green alga, possesses selective antitumor cytotoxicity, although its mechanism of action is unknown. The first synthesis of aulosirazole is now described, using a route centered upon a late stage regioselective Diels-Alder reaction. The structurally related natural product pronqodine A, an inhibitor of prostaglandin release, and analogues thereof, were also prepared for comparison. Biological evaluation of the compounds identified one potential target as the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). The isothiazolo-quinones are also efficient substrates for the human quinone reductase NQO1, and undergo intracellular NQO1-dependent redox cycling resulting in the generation of reactive oxygen species, and at lower doses have the potential to alter the ratio of intracellular oxidized to reduced pyridine nucleotides.

Journal Article Type Article
Publication Date Jul 20, 2015
Journal Angewandte Chemie International Edition
Print ISSN 1433-7851
Electronic ISSN 1521-3773
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 54
Issue 30
Pages 8740-8745
APA6 Citation Blunt, C. E., Blunt, C., Torcuk, C., Liu, Y., Lewis, W., Siegel, D., …Moody, C. J. (2015). Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine-2,3-dioxygenase (IDO) as Potential Target for Anticancer Activity. Angewandte Chemie International Edition, 54(30), 8740-8745. https://doi.org/10.1002/anie.201503323
DOI https://doi.org/10.1002/anie.201503323
Publisher URL http://onlinelibrary.wiley.com/doi/10.1002/anie.201503323/abstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This is the peer reviewed version of the following article: Blunt, C. E., Torcuk, C., Liu, Y., Lewis, W., Siegel, D., Ross, D. and Moody, C. J. (2015), Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine-2,3-dioxygenase (IDO) as Potential Target for Anticancer Activity. Angew. Chem. Int. Ed., 54: 8740–8745. doi:10.1002/anie.201503323 which has been published in final form at http://onlinelibrary.wi...anie.201503323/abstract
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