Bioactive products from singlet oxygen photooxygenation of cannabinoids.

Photooxygenation of Δ⁸ tetrahydrocannabinol (Δ⁸-THC), Δ⁹ tetrahydrocannabinol (Δ⁹-THC), Δ⁹tetrahydrocannabinolic acid (Δ⁹-THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides. Testing these compounds for their modulatory effect on cannabinoid receptors CB₁ and CB₂ led to the identification of 7 and 21 as CB₁ partial agonists with Ki values of 0.043 μM and 0.048 μM, respectively and 23 as a cannabinoid with high binding affinity for CB₂ with Ki value of 0.0095 μM, but much less affinity towards CB₁ (Ki 0.467 μM). The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC₅₀ values ranging from 4.2 to 8.5 μg/mL. Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens.