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Monocyclic Quinone Structure‐Activity Patterns: Synthesis of Catalytic Inhibitors of Topoisomerase II with Potent Antiproliferative Activity
Author(s) -
Waugh Thomas M.,
Masters John,
Aliev Abil E.,
Marson Charles M.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900548
Subject(s) - pharmacophore , chemistry , topoisomerase , stereochemistry , quinone , benzoquinone , combinatorial chemistry , enzyme , biochemistry
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 IC 50 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.