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Background: Phytochemicals derived from the plant Cannabis sativa hold promise in terms of medicinal value. Cannabinoids such as Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are arguably the best characterized and known to possess wide-ranging therapeutic benefits. The mechanism of action for these therapeutic effects remains to be fully elucidated, however, the anti-inflammatory actions are of particular interest. Maximizing therapeutic effects while limiting adverse effects is crucial in pharmaceutical development. Fluorination of natural products often yields molecules with enhanced biological properties and provides opportunities for intellectual property protection not available to the natural product., Methods: Herein, we describe four novel cannabinoids (a deoxy trifluoroCBN analog (F 3 CBN), the racemic cis-deoxy-trifluoro-THC (F 3 THC), and truncated pyridine analogs of an intermediate in route to the THC and CBN, SG126 and SG154. Importantly, we provide the initial assessment of the biologic activity of these molecules, by investigating the in vitro effects on metabolic activity (via 3-[4,5-dimethylthiazol-2-yl]-2,5,-diphenyltetrazolium bromide, MTT assay) and cytokine expression (via enzyme linked immunosorbent assay, ELISA) in human C20 microglial cells., Results: The cannabinoids examined had minimal to no effect on metabolic activity up to 10 µM. Notably, F 3 CBN and F 3 THC potentiated interleukin-1 β (IL-1β)-induced expression of interferon-γ inducible protein 10 (CXCL10) and IL-6 expression whereas, SG126 and SG154 were inhibitory., Conclusions: These findings are foundational for new lines of investigation into the therapeutic potential of four novel fluorinated cannabinoids., Competing Interests: Declarations. Conflicts of interest: Some authors, JDW, BK, and SG have filed a patent application covering some of the chemical structures (18/547251, pending). RLD declares no conflicts of interest., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Within the framework of discovery chemistry, polyfluorination remains a synthetic challenge despite its ability to provide useful characteristics, such as a reduction in the number of hydrogen bond donors and metabolic stability. Coupling a reversal of this methodology with photocatalysis has been demonstrated to allow the rapid synthesis of previously difficult or impossible targets by starting with fluorines everywhere and selectively removing or functionalizing them. Herein, we demonstrate a novel method to synthesize 1,4-cyclohexadienes through a dearomative photocatalytic C-C coupling reaction. This allows for access to materials that are orthogonal to the selectivity of the Birch reaction and are more functional-group-tolerant. The reaction also allows the efficient synthesis of polyfluorinated cannabinoids. While the yields are modest, the access to the new chemical space provided by the reaction is unprecedented by any means. The trifluorinated analog of THC, 1-deoxy-1,2,4-trifluoro-THC, is synthesized, demonstrating the importance of discovery chemistry and the ability to explore otherwise unknown structure-activity relationships.