Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging

  • J Med Chem. 2019 Feb 14;62(3):1657-1668. doi: 10.1021/acs.jmedchem.8b01994.
Laura Fási ,  Florent Di Meo  1 ,  Ching-Ying Kuo  2 ,  Sonja Stojkovic Buric  3 ,  Ana Martins  4 ,  Norbert Kúsz ,  Zoltán Béni ,  Miklós Dékány ,  György Tibor Balogh ,  Milica Pesic  3 ,  Hui-Chun Wang  2 ,  Patrick Trouillas  1  5 ,  Attila Hunyadi
Affiliations
  • 1. INSERM UMR 1248 IPPRITT, Université Limoges, Faculty of Pharmacy , 2 rue du Dr Marcland , F-87000 Limoges , France.
  • 2. Graduate Institute of Natural Products , Kaohsiung Medical University , Shih-Chuan 1st Rd. 100 , Kaohsiung 807 , Taiwan , ROC.
  • 3. Department of Neurobiology, Institute for Biological Research , University of Belgrade , Bulevar Despota Stefana 142 , 11060 Belgrade , Serbia.
  • 4. Institute of Medical Microbiology and Immunobiology, Faculty of Medicine , University of Szeged , Dóm tér 10 , H-6720 Szeged , Hungary.
  • 5. RCPTM, Faculty of Sciences , Palacký University , tr. 17. listopadu 12 , 771 46 Olomouc , Czech Republic.
PMID: 30615450 DOI: 10.1021/acs.jmedchem.8b01994
Abstract

Cancer cells generally possess higher levels of Reactive Oxygen Species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone. Graviquinone bypassed ABCB1-mediated resistance, induced DNA damage in lung carcinoma cells but exerted DNA protective activity in normal keratinocytes, and modulated DNA damage response in MCF-7 cells. The cytotoxic effect of pcm in MCF-7 cells was potentiated under H2O2-induced oxidative stress, and the formation of graviquinone was confirmed by Fenton's reaction on pcm. In silico density functional theory calculations suggested graviquinone as a kinetic product of pcm-scavenging •OH radicals. Our results demonstrate the pharmacological value of an in situ-formed, oxidative stress-related metabolite of an antioxidant. This might be of particular importance for designing new strategies for antioxidant-based drug discovery.

Products