Department of Pharmacology, Division of Clinical Pharmacology, and Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Org Biomol Chem. 2018 May 2;16(17):3273-3281. doi: 10.1039/c8ob00639c.
The efficacy of the curry spice compound curcumin as a natural anti-inflammatory agent is limited by its rapid reductive metabolism in vivo. A recent report described a novel synthetic derivative, 2,6-dimethyl-curcumin, with increased stability against reduction in vitro and in vivo. It is also known that curcumin is unstable at physiological pH in vitro and undergoes rapid autoxidative transformation. Since the oxidation products may contribute to the biological effects of curcumin, we tested oxidative stability of 2,6-dimethyl-curcumin in buffer (pH 7.5). The rate of degradation was similar to curcumin. The degradation products were identified as a one-carbon chain-shortened alcohol, vanillin, and two isomeric epoxides that underwent cleavage to vanillin and a corresponding hydroxylated cleavage product. 2,6-Dimethyl-curcumin was more potent than curcumin in inhibiting NF-κB activity but less potent in inhibiting expression of cyclooxygenase-2 in LPS-activated RAW264.7 cells. 2,6-Dimethyl-curcumin and some of its degradation products covalently bound to a peptide that contains the redox-sensitive cysteine of IKKβ kinase, the activating kinase upstream of NF-κB, providing a mechanism for the anti-inflammatory activity. In RAW264.7 cells vanillin, the chain-shortened alcohol, and reduced 2,6-dimethyl-curcumin were detected as major metabolites. These studies provide new insight into the oxidative transformation mechanism of curcumin and related compounds. The products resulting from oxidative transformation contribute to the anti-inflammatory activity of 2,6-dimethyl-curcumin in addition to its enhanced resistance against enzymatic reduction.
咖喱香料化合物姜黄素作为一种天然抗炎剂的功效受到其在体内快速还原代谢的限制。最近的一份报告描述了一种新型合成衍生物，2,6-二甲基姜黄素，其在体外和体内对还原的稳定性增加。已知姜黄素在生理 pH 值下不稳定，在体外会迅速发生自动氧化转化。由于氧化产物可能有助于姜黄素的生物学效应，我们测试了 2,6-二甲基姜黄素在缓冲液（pH 7.5）中的氧化稳定性。降解速度与姜黄素相似。降解产物被鉴定为一个一碳链缩短的醇、香草醛和两个异构环氧化物，它们经历裂解生成香草醛和相应的羟基裂解产物。2,6-二甲基姜黄素在抑制 NF-κB 活性方面比姜黄素更有效，但在抑制 LPS 激活的 RAW264.7 细胞中环氧化酶-2 的表达方面效果较差。2,6-二甲基姜黄素及其一些降解产物与包含 IKKβ激酶的还原敏感半胱氨酸的肽共价结合，IKKβ激酶是 NF-κB 的上游激活激酶，为抗炎活性提供了一种机制。在 RAW264.7 细胞中，香草醛、缩短链的醇和还原的 2,6-二甲基姜黄素被检测为主要代谢物。这些研究为姜黄素和相关化合物的氧化转化机制提供了新的见解。氧化转化产生的产物除了增强对酶还原的抵抗力外，还为 2,6-二甲基姜黄素的抗炎活性做出了贡献。
