Abstract
A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo grafts of human tumors in nude mice. The main mechanism was topoisomerase IIα catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series.
Highlights
Quinones of various chemical families have biological activities [1,2,3], and both natural and synthetic quinones are widely used as drugs [4,5]
We report the syntheses of additional compounds in the cannabinoid quinone series, which presumably may help to shed more light on the structure-activity relationship (SAR) and the mechanism of action of HU-331 and related compounds
In our original reports [15,18], the oxidation of cannabidiol (CBD) by air in petroleum ether in the presence of 5% aqueous potassium hydroxide in ethanol over 3 h at 0 ◦C led to the formation of the HU-331 in about a 20% yield
Summary
Quinones of various chemical families have biological activities [1,2,3], and both natural and synthetic quinones are widely used as drugs [4,5]. 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]. In an additional neurodegenerative disease model with SOD1G93A mutant mice (a model of Amyotrophic Lateral Sclerosis, ALS), treatment with VCE-003.2 improved most of the neuropathological signs such as weight loss and neurological deterioration, which was associated with a marked loss of spinal cholinergic motor neurons and glial reactivity, indicating the effectiveness of this compound for ALS treatment [40] This molecule, which is being developed by Emerald Health Pharmaceuticals, is named EHP-102, and was granted both FDA and EMA orphan designation for the treatment of Huntington’s disease. We report the syntheses of additional compounds in the cannabinoid quinone series, which presumably may help to shed more light on the SAR and the mechanism of action of HU-331 and related compounds
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