Gordon Odaine N, Luis Paula B, Sintim Herman O, Schneider Claus
Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232 and.
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742.
J Biol Chem. 2015 Feb 20;290(8):4817-4828. doi: 10.1074/jbc.M114.618785. Epub 2015 Jan 6.
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.
姜黄素是一种具有抗炎和化学预防作用的膳食成分，由两个通过共轭庚二烯二酮链连接的甲氧基酚环组成。姜黄素在生理pH值下不稳定，会在自氧化反应中迅速降解为一种主要的双环戊二酮产物，其中7碳链发生了氧化和双环化。早期降解产物（而非最终的双环戊二酮）介导拓扑异构酶中毒以及姜黄素的许多其他可能活性，但目前尚不清楚形成了多少种以及哪些自氧化产物，也不清楚它们的形成机制。在此，我们以[(14)C2]姜黄素作为示踪剂，利用一维和二维核磁共振以及质谱技术分离并鉴定了七种新型自氧化产物，包括两种反应中间体。不同寻常的螺环氧化物和乙烯基醚反应中间体是最终双环戊二酮产物的前体。我们提出了一种姜黄素自氧化的机制，该机制解释了利用(18)O2和H2(18)O所确定的氧的添加和交换情况。几种副产物是由内过氧化物中间体通过脂质过氧化中常见的反应形成的。亲电螺环氧化物中间体与N - 乙酰半胱氨酸形成了稳定的加合物，这表明由与蛋白质硫醇的共价加合介导的生物学效应需要氧化转化。姜黄素的自发自氧化使其在具有治疗意义的天然多酚化合物中独树一帜；化学性质多样的反应性和亲电产物的形成，为理解姜黄素的多药理学效应提供了一种新的范例。
