Cannabizetol, a Novel Cannabinoid: Chemical Synthesis, Anti-inflammatory Activity and Extraction from Cannabis sativa L

Abstract

We report the first isolation of a previously unknown cannabinoid, cannabizetol (CBGD, 7), from Cannabis sativa extracts, representing the third member of the rare class of methylene-bridged dimeric cannabinoids. The availability of a chemically synthesized standard was crucial for its unequivocal identification, thus confirming the natural occurrence of this new compound. In addition to this structural discovery, we demonstrate that cannabizetol exhibits remarkable antioxidant and skin anti-inflammatory activity, significantly higher than that observed for the known dimeric cannabinoid cannabitwinol (CBDD, 6). These results highlight cannabizetol as a promising bioactive metabolite with potential dermatological applications. To further enable its study, we developed a continuous flow approach to optimize the preparation of these dimers, achieving a substantial reduction in reaction times.

1

Chemical structure of Δ⁹-THC, CBD, CBG, and CBC.

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Chemical structure of cannabisol, cannabitwinol (CBDD) ,and cannabizetol (CBGD).

1. Synthesis of Cannabizetol 7

2. Best Experimental Condition Identified for the Continuous Synthesis Cannabizetol (7)

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Effect of cannabinoids 6 (A) and 7 (B), on IL-8 release in HaCaT cells cotreated with the molecules and TNFα for 6 h. EGCG (20 μM) was used as reference compound. Data are reported as percentage in comparison to the stimulated control (mean ± SEM), which was arbitrarily assigned 100% value. * p < 0.05, *** p < 0.001 versus TNFα; on right, effect of cannabinoids 6 (C) and 7 (D), on NF-κB driven transcription in HaCaT cells cotreated with pure compounds and TNFα for 6 h. EGCG (20 μM) was used as reference compound. Data are reported as percentage in comparison to the stimulated control (mean ± SEM), which was arbitrarily assigned 100% value. * p < 0.05, *** p < 0.001 versus TNFα.