Discovery\nof Ring-Annulated Analogues of Cannabidiol\nas Potential Anticancer Agents: Synthesis and Biological Evaluation

Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived\nfrom <i>Cannabis sativa</i> and its potential therapeutic\neffects extend\nbeyond its well-known antiepileptic properties. Exploring CBD and\nits analogues as anticancer agents has gained significant attention\nin recent years. In this study, a series of novel ring-annulated analogues\nof CBD with oxazinyl moiety were synthesized and evaluated for their\nantiproliferative effect. The analogues <b>4d</b> and <b>4h</b> demonstrate promising activity against breast and colorectal\ncancer. Furthermore, mechanistic insights revealed that the identified\ncandidates arrest the G1 phase of the cell cycle and induce apoptosis\nvia the mitochondrial pathway in breast cancer cell lines. Notably,\nCBD ring-annulated analogues <b>4d</b> or <b>4h</b> exhibit\nenhanced solubility, better metabolic stability, and lowered cytochrome\nP450 (CYP) inhibition liability compared to CBD. These multifaceted\nattributes highlight the potential of cannabinoid-based candidates\nfor further preclinical development.