靶向Nrf2的萝卜硫素衍生物的设计、合成及其抗癌活性研究

Chemical prevention which can reduce the incidence of tumor has become one of the hot research areas. Nrf2/ARE pathway plays an important role in chemical prevention. It is of great significance to develop new Nrf2 targeted inducers for preventive treatment of tumor and multi-organs diseases. Sulforaphane is found to be the strongest natural Nrf2 inducer. It exerts the effect of chemical preventing cancer through inducing phase II detoxifying enzymes, antioxidant enzymes and drug transport protein expression via the Nrf2/ARE signaling pathway. Sulforaphane has shown both cancer-prevention and anti-cancer properties. In the present proposal, sulforaphane is taken as a lead compound to design and synthesize a series of novel derivatives; and Nrf2 is regarded as a target to screen more potent Nrf2 inducers via Nrf2/ARE pathway; While the in vitro anti-cancer activities of the new derivatives are evaluated by MTT assay in various types of cancer cells line and normal cell lines; Anti-cancer mechanism of highly potent compounds is to be explored through the mitochondrial apoptosis pathway. The proposed research would be very helpful for developing novel cancer-prevention and anti-cancer drugs with high potency and low toxicity.

肿瘤的发病率日益增高，化学预防能降低肿瘤发病率，近而成为研究的热点。Nrf2/ARE 通路在化学预防中发挥重要作用，Nrf2靶向开发新的诱导剂对于肿瘤和多组织器官多种疾病的预防治疗均具有重要意义。萝卜硫素是迄今发现的最强的天然Nrf2诱导剂，通过Nrf2/ARE 信号通路诱导II 相解毒酶、抗氧化酶类及药物转运蛋白的表达，发挥其化学预防肿瘤的作用及其机制。萝卜硫素既有预防癌症也有抗癌作用。本课题以萝卜硫素为先导化合物，设计并合成一系列新的衍生物；以Nrf2为靶点，Nrf2/ARE通路为研究对象，筛选更强的Nrf2诱导剂并对其机制进行研究；同时选取多种癌症细胞线和正常细胞线进行体外细胞毒活性检测，测定其抗癌活性；从细胞凋亡途径探讨新合成化合物的抗癌作用机制，为开发更有潜力的防治癌症的药物提供参考。

萝卜硫素既有预防癌症也有抗癌作用。本项目以萝卜硫素为先导化合物，设计并合成22个新颖的衍生物；以5-Fu和SFN做对照，选取SH-SY5Y 细胞（人神经母细胞瘤细胞）、HCT-116（结肠癌）、A549(人非小细胞肺癌细胞)、HepG2 细胞（人肝癌细胞）、MCF-7 细胞（人乳腺癌细胞）等肿瘤细胞株测定所合成化合物的抗癌活性，实验结果表明，大部分萝卜硫素衍生物表现出比萝卜硫素更高的细胞毒活性。接下来主要调查了活性较好的化合物BSFN和先导化合物SFN对HepG2细胞和SH-SY5Y细胞的抗癌及防癌作用机制，结果表明它们均能通过线粒体依赖的PI3K/AKT途径诱导细胞凋亡。同时细胞中Nrf2蛋白表达、核转运和转录活性均被增加，表明其激活Nrf2/ARE信号通路。且全部结果均显示BSFN作用优于SFN。因此BSFN可能成为癌症预防和治疗的有潜力的实体。