Department of Biochemistry, Bose Institute, Centenary Campus, P-1/12 CIT Scheme VIIM, Kolkata 700054, India.
J Med Chem. 2011 Sep 22;54(18):6183-96. doi: 10.1021/jm2004046. Epub 2011 Aug 29.
Although curcumin is known for its anticarcinogenic properties, the exact mechanism of its action or the identity of the target receptor is not completely understood. Studies on a series of curcumin analogues, synthesized to investigate their tubulin binding affinities and tubulin self-assembly inhibition, showed that: (i) curcumin acts as a bifunctional ligand, (ii) analogues with substitution at the diketone and acetylation of the terminal phenolic groups of curcumin are less effective, (iii) a benzylidiene derivative, compound 7, is more effective than curcumin in inhibiting tubulin self-assembly. Cell-based studies also showed compound 7 to be more effective than curcumin. Using fluorescence spectroscopy we show that curcumin binds tubulin 32 Å away from the colchicine-binding site. Docking studies also suggests that the curcumin-binding site to be close to the vinblastine-binding site. Structure-activity studies suggest that the tridented nature of compound 7 is responsible for its higher affinity for tubulin compared to curcumin.
虽然姜黄素以其抗癌特性而闻名，但它的确切作用机制或靶受体的身份尚不完全清楚。对一系列姜黄素类似物的研究，旨在研究它们与微管蛋白的结合亲和力和微管蛋白自组装抑制作用，表明：(i)姜黄素作为双功能配体起作用，(ii)在姜黄素的二酮和末端酚羟基乙酰化位置进行取代的类似物的效果较差，(iii)一种亚苄基衍生物，化合物 7，在抑制微管蛋白自组装方面比姜黄素更有效。基于细胞的研究也表明化合物 7 比姜黄素更有效。使用荧光光谱法，我们发现姜黄素与微管蛋白的结合距离离秋水仙碱结合位点有 32Å。对接研究还表明，姜黄素结合位点靠近长春碱结合位点。结构活性研究表明，与姜黄素相比，化合物 7 的三叉结构特性使其对微管蛋白具有更高的亲和力。
