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

Cancer remains a major global health challenge, necessitating new, effective therapies. Phytocannabinoids from <i>Cannabis sativa</i> 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 <i>via</i> 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 <i>in vivo</i> evaluation.