Accueil > Événements > Séminaires

Séminaire Chimie ED459/IBMM

Chemical biology of curcumin

Prof. Claus Schneider (Department of Pharmacology, Vanderbilt University Medical School, Nashville, TN, USA)

publié le , mis à jour le

Le Lundi 02 Juin 2014 à 11h
Institut de Botanique, Amphithéâtre Flahault (163 rue Auguste Broussonnet, Montpellier)

The diphenol curcumin is recognized for its antioxidant, anti-inflammatory, and antitumorigenic bioactivities. It is currently tested in more than 90 clinical trials for the prevention or treatment of a broad range of diseases, including intestinal cancers, inflammatory, and neurodegenerative diseases. A large number of in vitro cellular targets of curcumin have been identified but the precise chemical-molecular mechanisms by which curcumin affects its biological targets have not been conclusively elucidated. We have discovered a novel, previously unrecognized transformation of curcumin : a spontaneous, rapid, and prominent autoxidation reaction gives rise to a dioxygenated cyclopentadione derivative of curcumin as the major product [1]. We hypothesize that oxidative transformation is the biochemical basis underlying some, if not most, of the biological effects of curcumin.

Using 14C2 curcumin as a tracer a total of 10 autoxidation products, including two reaction intermediates, were isolated and identified using 1D and 2D NMR and mass spectrometry. We propose a mechanism in which autoxidation is initiated by H-abstraction from a phenolic hydroxyl. Delocalization of the phenoxyl radical into the heptadienedione chain enables 5-exo cyclization to a cyclopentadione ring, oxygen addition to form a peroxyl radical and endoperoxide formation followed by SHi carbon radical attack on the peroxide. The resulting spiroepoxide intermediate undergoes water exchange during transformation to a vinylether intermediate en route to the final bicyclopentadione. Oxygen incorporation from 18O2 and H2 18O was used to determine the sites and reaction steps of oxygen addition and water exchange [2].

Scheme 1 (click to enlarge)

We have shown that an early reactive intermediate of oxidative transformation of curcumin is responsible for poisoning of human topoisomerase, a major mechanism of its anti-tumorigenic activity [3]. The spontaneous and rapid autoxidation distinguishes curcumin among natural polyphenolic compounds of therapeutic interest. The chemically diverse products we have identified exhibit a range of electrophilic and nucleophilic moieties that may be involved in mediating biological effects of curcumin.

References

1. M. Griesser, et al. (2011) J. Biol. Chem. 286, 1114.
2. O. N. Gordon, C. Schneider (2014) submitted.
3. A.C. Ketron, et al. (2013) Biochemistry 52, 221.

This work is supported by NIH awards CA159382 and AT006896.

Contact local IBMM : Dr. Thierry Durand (équipe Lipides bioactifs)

Agenda

Ajouter un événement iCal