A synthetic chalcone as a potent inducer of glutathione biosynthesis.

Abstract

Chalcones continue to attract considerable interest due to their anti-inflammatory and antiangiogenic properties. We recently reported the ability of 2',5'-dihydroxychalcone (2',5'-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure-activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F and Cl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4',6'-dimethoxy-2'-hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements.

• Authors: Remy Kachadourian, Brian J Day, Subbiah Pugazhenti, Christopher C Franklin, Estelle Genoux-Bastide, Gregory Mahaffey, Charlotte Gauthier, Attilio Di Pietro, Ahcène Boumendjel
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 3 Pg. 1382-8 (Feb 09 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22239485 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 2-chloro-4',6'-dimethoxy-2'-hydroxychalcone
• Antioxidants
• Chalcones
• Holoenzymes
• NF-E2 Transcription Factor, p45 Subunit
• NFE2 protein, human
• Luciferases
• Glutamate-Cysteine Ligase
• Glutathione

Topics

• Antioxidants (metabolism)
• Cell Line, Tumor
• Chalcones (chemical synthesis, chemistry, pharmacology)
• Genes, Reporter
• Glutamate-Cysteine Ligase (biosynthesis, genetics)
• Glutathione (biosynthesis)
• Holoenzymes (biosynthesis, genetics)
• Humans
• Intracellular Space (metabolism)
• Luciferases (genetics, metabolism)
• NF-E2 Transcription Factor, p45 Subunit (genetics, metabolism)
• Response Elements
• Structure-Activity Relationship
• Transcription, Genetic