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

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 anti-cancer 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 anti-proliferative 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. Financial support from the Engineering and Physical Sciences Research Council for a PhD studentship to T. D.W. is gratefully acknowledged.

Cannabinoid Quinones—A Review and Novel Observations

“…The effect of HU-331 as inhibitor of topoisomerase IIα seemed very selective [19]. This finding was later also supported by Dewesee's group [20] and Marson's group [21]. In addition, we found it to possess anti-angiogenic effects [22], and unlike most other quinones, HU-331 was not cardiotoxic [23,24].…”

“…Recently, Marson's group added an additional piece to the puzzle of cannabinoid quinones and their action on topoisomerase II, by synthesizing about 15 derivatives related to HU-331, and assaying them for topoisomerase inhibition and cancer cell growth inhibition (mostly DU-145 prostate carcinoma) [21]. The most active derivatives were those with cyclohexyl and cyclopentyl substitution at the place of limonene in HU-331, with no substituent in position 2 of the quinone ring, and with pentyl or methyl groups in position 3 (Compounds 6 and 7).…”

Cannabidiol oxidation product HU-331 is a potential anticancer cannabinoid-quinone: a narrative review

“…Further, HU-331 has also been tested in several cancer cell lines and mouse model systems (Kogan et al 2004;Kogan et al 2007a;Kogan et al 2007b;Waugh et al 2020). Evidence from these studies, which will be detailed further below, indicates that HU-331 has promising anticancer properties and may have less off-target toxicity.…”

“…It was noted in the literature as early as the 1960s as being formed by oxidation of cannabidiol by potassium hydroxide resulting in the violet color that serves as the basis for the Beam test, which is used to identify the presence of cannabis (Mechoulam et al 1968). CBD can also be oxidized by exposure to air and oxidizing agents, forming HU-331 and possibly other oxidized products (Watanabe et al 1991;Kogan et al 2004;Wilson et al 2018;Waugh et al 2020). Studies by Watanabe et al examined the impact of HU-331 (CBDHQ) on mouse liver microsomes and demonstrated that HU-331 was isolated from a chloroform solution from CBD that stood at room temperature for 10 months (Watanabe et al 1991).…”

A review on the syntheses of Dronabinol and Epidiolex as classical cannabinoids with various biological activities including those against SARS-COV2

“…Marson et al have proposed a new method to synthesize CBD [99]. Olivetol was condensed with the diol under optimized Friedel-Crafts conditions and the triol has been achieved in 73% yield.…”