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.

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.

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

• Journal Article Type: Article
• Online Publication Date: Jun 10, 2015
• Publication Date: Jul 20, 2015
• Deposit Date: Nov 17, 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
• DOI: https://doi.org/10.1002/anie.201503323
• Public URL: https://nottingham-repository.worktribe.com/output/754723
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1002/anie.201503323/abstract
• 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.wiley.com/doi/10.1002/anie.201503323/abstract