title: Unraveling curcumin degradation: autoxidation proceeds through spiroepoxide and vinylether intermediates en route to the main bicyclopentadione.
abstract: Curcumin is a dietary anti-inflammatory and chemopreventive agent consisting of two methoxyphenol rings connected by a conjugated heptadienedione chain. Curcumin is unstable at physiological pH and rapidly degrades in an autoxidation reaction to a major bicyclopentadione product in which the 7-carbon chain has undergone oxygenation and double cyclization. Early degradation products (but not the final bicyclopentadione) mediate topoisomerase poisoning and possibly many other activities of curcumin, but it is not known how many and what autoxidation products are formed, nor their mechanism of formation. Here, using [(14)C2]curcumin as a tracer, seven novel autoxidation products, including two reaction intermediates, were isolated and identified using one- and two-dimensional NMR and mass spectrometry. The unusual spiroepoxide and vinylether reaction intermediates are precursors to the final bicyclopentadione product. A mechanism for the autoxidation of curcumin is proposed that accounts for the addition and exchange of oxygen that have been determined using (18)O2 and H2(18)O. Several of the by-products are formed from an endoperoxide intermediate via reactions that are well precedented in lipid peroxidation. The electrophilic spiroepoxide intermediate formed a stable adduct with N-acetylcysteine, suggesting that oxidative transformation is required for biological effects mediated by covalent adduction to protein thiols. The spontaneous autoxidation distinguishes curcumin among natural polyphenolic compounds of therapeutic interest; the formation of chemically diverse reactive and electrophilic products provides a novel paradigm for understanding the polypharmacological effects of curcumin.
authors.affiliation: Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232 and.
authors.forename: Odaine N
authors.initials: ON
authors.lastname: Gordon
authors.affiliation: Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232 and.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Luis
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742.
authors.forename: Herman O
authors.initials: HO
authors.lastname: Sintim
authors.affiliation: Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232 and. Electronic address: claus.schneider@vanderbilt.edu.
authors.forename: Claus
authors.initials: C
authors.lastname: Schneider
mesh_terms: D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D010103:Oxygen Isotopes / Q000737:chemistry; D013141:Spiro Compounds / Q000737:chemistry*
chemical_list: D010103:Oxygen Isotopes; D013141:Spiro Compounds; D003474:Curcumin
keywords: Analytical Chemistry; Isotopic Tracer; Mass Spectrometry (MS); Metabolism; Natural Product; Nuclear Magnetic Resonance (NMR); Polyphenol; Quinone; Radical