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ChemMedChem. 2019 Nov 28. doi: 10.1002/cmdc.201900548. [Epub ahead of print]

Monocyclic Quinone Structure-Activity Patterns: Synthesis of Catalytic Inhibitors of Topoisomerase II with Potent Antiproliferative Activity.

Author information

1
Department of Chemistry, University College London Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H OAJ, UK.
2
Prostate Cancer Research Centre Research Department of Urology Charles Bell House, University College London, 67-75 Riding House Street, London, W1 W 7EJ, UK.

Abstract

The monocyclic 1,4-benzoquinone, HU-331, the direct oxidation product of cannabidiol, inhibits the catalytic activity of topoisomerase II but without inducing DNA strand breaks or generating free radicals, and unlike many fused-ring quinones exhibits minimal cardiotoxicity. Thus, monocyclic quinones have potential as anticancer agents, and investigation of the structural origins of their biological activity is warranted. New syntheses of cannabidiol and (±)-HU-331 are here reported. Integrated synthetic protocols afforded a wide range of polysubstituted resorcinol derivatives; many of the corresponding novel 2-hydroxy-1,4-benzoquinone derivatives are potent inhibitors of the catalytic activity of topoisomerase II, some more so than HU-331, whose monoterpene unit replaced by a 3-cycloalkyl unit conferred increased antiproliferative properties in cell lines with IC50 values extending below 1 mM, and greater stability in solution than HU-331. The principal pharmacophore of quinones related to HU-331 was identified. Selected monocyclic quinones show potential for the development of new anticancer agents.

KEYWORDS:

Frémy's salt; HU-331; anticancer agents; cannabidiol; monocyclic quinones; structure-activity relationships

PMID:
31778038
DOI:
10.1002/cmdc.201900548

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