Selective, nontoxic CB(2) cannabinoid o-quinone with in vivo activity against triple-negative breast cancer

J Med Chem. 2015 Mar 12;58(5):2256-64. doi: 10.1021/acs.jmedchem.5b00078. Epub 2015 Feb 20.


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 (10) has been selected from a series of chromenopyrazolediones with full selectivity for the nonpsychotropic CB2 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 10 exerts antitumor effect by inducing cell apoptosis through activation of CB2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Benzoquinones / chemistry*
  • Blotting, Western
  • Breast / cytology
  • Breast / drug effects*
  • Cannabinoids / chemistry*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • 7-(1',1'-dimethylheptyl)-1-ethyl-1,4-dihydro-4,4-dimethylchromeno(4,3-c)pyrazole-8,9-dione
  • Antineoplastic Agents
  • Benzopyrans
  • Benzoquinones
  • Cannabinoids
  • Pyrazoles
  • RNA, Messenger
  • Receptor, Cannabinoid, CB2
  • quinone