Aromatisation-based extract engineering of Cannabis sativa L. Unveils rare cannabinoids with anticancer potential

Cancer remains a major global health challenge, necessitating new, effective therapies. Phytocannabinoids from Cannabis sativa L. show significant anticancer potential, yet their natural scarcity limits research and development. This study presents an innovative extract engineering approach to generate rare varin-type cannabinoids from abundant precursors. Through this strategy, nine cannabinoid analogues were synthesised, including four rare varin-type compounds, and screened against five human cancer cell lines. Among them, cannabinovarin (CBNV) and Δ^6a,10a-THCV exhibited potent cytotoxicity against breast (MCF-7) and colon (HCT-116) cancer cells, with IC₅₀ values of 15-30 µM. Mechanistic investigations revealed apoptosis induction via mitochondrial membrane disruption and reactive oxygen species generation. These findings establish extract engineering as a rapid and efficient route to access rare cannabinoids, highlighting CBNV and Δ^6a,10a-THCV as promising anticancer leads for further mechanistic and in vivo evaluation.