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

Phytocannabinoids are a family of more than 150 natural products isolated from Cannabis sativa L. extracts. While the biological activity of the four “major cannabinoids” (Δ9-THC, CBD, CBG, and CBC) has been extensively investigated, information on the “minor cannabinoids” is still limited, mainly due to their presence in trace amounts in plant extracts. Recent efforts have led to the identification of two new cannabinoids characterized by a particular methylene-bridged homodimeric structure: cannabisol and cannabitwinol (CBDD), the homodimers of Δ9-THC and CBD respectively. In this work we report the discovery of the third member of this rare class of cannabinoids, cannabizetol (CBGD), the homodimer of CBG (Figure 1). The availability of a chemically synthesized standard was crucial for its unequivocal identification, thus confirming the natural occurrence of this new compound. In addition, the skin anti-inflammatory activity of cannabizetol was evaluated in HaCaT keratinocytes, demonstrating a remarkable inhibitory effect on NF-κB signaling and IL-8 secretion. These results highlight cannabizetol as a promising bioactive metabolite with potential dermatological applications. Motivated by these results, we developed a synthetic strategy based on continuous flow chemistry technology, achieving a substantial reduction in reaction times