Identification of nitric oxide-releasing derivatives of oleanolic acid as potential anti-colon cancer agents
Identification of nitric oxide-releasing derivatives of oleanolic acid as potential anti-colon cancer agents
复制标题
鉴定释放一氧化氮的齐墩果酸衍生物作为潜在的抗结肠癌药物
DOI：
10.1039/c5ra00270b
复制
发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Zhang, Yihua
中科院分区：
文献类型：
--
作者：
Fu, Junjie;Zou, Yu;Zhang, Yihua
设计、合成了一组齐墩果酸(OA)的一氧化氮(NO)释放衍生物(5-13)，并对其抗结肠癌活性进行了生物活性评价。研究发现，最有效的化合物6最好在结肠癌细胞中释放高水平的NO，而在正常细胞中不释放，从而对结肠癌细胞产生强大的细胞毒作用。此外，与GSTA相比，6更容易被GSTp催化产生NO。此外，6还显著抑制了小鼠异种移植瘤的生长。最后，6诱导线粒体蛋白中酪氨酸残基的硝化，下调Wnt/b-catenin通路，抑制COX-2为中心的结肠癌细胞信号转导环。总而言之，我们的发现表明，6可能是一种有希望的结肠癌干预候选药物。
A group of nitric oxide (NO)-releasing derivatives of oleanolic acid (OA) (5-13) were designed, synthesized and biologically evaluated for their anti-colon cancer activity. It was found that the most potent compound 6 preferably released high levels of NO in colon cancer cells but not in normal cells, leading to potent cytotoxicity against colon cancer cells. In addition, 6 was more prone to produce NO catalyzed by GSTp relative to GSTa. Furthermore, 6 significantly inhibited the tumor growth in a mouse xenograft model. Finally, 6 induced nitration of tyrosine residues in mitochondrial protein, down-regulated Wnt/b-catenin pathway, and inhibited COX-2 centered signaling loop in colon cancer cells. Collectively, our findings suggested that 6 could be a promising candidate for the intervention of colon cancer.