Selective, Nontoxic CB<sub>2</sub> Cannabinoid <i>o</i>‑Quinone with in Vivo Activity against Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. Here, we report the synthesis and evaluation of a potent antitumor agent in vivo for this type of breast cancer designed as a combination of quinone/cannabinoid pharmacophores. This new compound (<b>10</b>) has been selected from a series of chromenopyrazolediones with full selectivity for the nonpsychotropic CB<sub>2</sub> cannabinoid receptor and with efficacy in inducing death of human TNBC cell lines. The dual concept quinone/cannabinoid was supported by the fact that compound <b>10</b> exerts antitumor effect by inducing cell apoptosis through activation of CB<sub>2</sub> receptors and through oxidative stress. Notably, it did not show either cytotoxicity on noncancerous human mammary epithelial cells nor toxic effects in vivo, suggesting that it may be a new therapeutic tool for the management of TNBC.