Petasin衍生物的合成及其抗神经母细胞瘤作用机制研究

Petasin是菊科蜂斗菜属植物的活性成分之一。据报道它有抑制胃肠道平滑肌痉挛，镇痛和抗炎等药理学活性。我们研究中意外发现，Petasin对神经母细胞瘤SK-N-SH细胞系有很高的抑制活性（作用72小时后IC50值为0.8μM），并发现其对SK-N-SH抑制有着完全不同于传统化疗药物的机制，不能诱导神经母细胞瘤细胞的凋亡，仅能抑制其增殖；能抑制转染前动力蛋白受体（Prokineticin Receptor）的CHO细胞的ERK磷酸化，但对未转染该蛋白的CHO无此作用，结果提示其可能是前动力蛋白受体的抑制剂。本研究拟对petasin结构上两个部位衍生合成，并进行活性筛选，筛选出活性高，有专利保护的新型抗神经母细胞瘤药物。同时，通过蛋白质二维电泳技术以及分子水平的筛选和研究，对蜂斗菜素的分子药理机制做深入的研究。本研究的完成，为新型抗神经母细胞瘤药物提供新的思路、方法和理论依据。

Petasin is the active component of Petasites hybridus (Petasites Tricholobus, Compositae), which has been reported to possess many bioactivities including analgesic, anti-inflammation, inhibition of ileum contraction. Recently, researches in our group found that petasin inhibited the proliferation of human neuroblastoma cell lines SK-N-SH with a very low IC50 (0.8μM). Further experiments showed that the mechanisms involved in the antiproliferation effects of petasin were completely different from traditional anti-cancer medicines. Petasin did not induce the apoptosis of the neuroblastoma. Petasin inhibited ERK phosorylation in the CHO cells expressing prokineticin receptors but not in the CHO cells without prokineticin receptors, indicating that petasin might be an inhibitor of Prokineticin Receptors. In the present proposal, we will synthesis the derivatives of petasin and study the molecular mechanisms of petasin. We will analyze their structure-activity relationships and learn the necessary structure of petasin and design better effective chemicals based on the analysis of the structure-activity relationships. We will analysis the binding activity of petasin and PKR and calculation of IC50 of such binding. Then we will perform 2-D gel analysis to compare the proteomics of SK-N-SH cells with or without the treatment with petasin. The proteins with significant changes between control groups and petasin-treated group will be further analyzed using molecular techniques. With the complement of the present proposal, we will understand more molecular mechanism of petasin and develop new medicine for anti-neuroblastom.