源于广西莪术的β-榄香烯的肝靶向抗肿瘤化合物的设计、合成与生物学评价

Since liver cancer harms human health and most of traditional Chinese medicines are short of tissue and cell selectivities, the investigation on the modification of β-elemene, which is derived from Curcuma Kwangsiensis S.G.Lee et C.F.Liang, into a small molecular antitumor agent with HepDirect ability has become an urgent requirement for treatment of liver cancer and modernization of traditional Chinese medicines. In the preparatory work, we have synthesized a series of "lactose-heterocycles-β-elemene" compounds, and delightedly found that these compounds possessed obvious HepDirect effects. Therefore, structure based drug design (SBDD) and chemical targeting methods are combined to make an intensive study of "lactose-heterocycles-β-elemene" compounds, and illuminate the mechanism of these compounds recognizing asialoglycoprotein receptor (ASGP-R) in the molecular level. The implementation of this project, can not only help to understand which combination between heterocycles and lactose possesses higher selectivity for liver cell, but also obtain a series of small molecular HepDirect antitumor agents with absolute intellectual property rights, and provide a specific research method for traditional Chinese medicines without tissue and cell selectivities.

鉴于肝癌对人类健康的危害及大多数中药有效成分缺乏组织和细胞选择性的特点，将富含于广西莪术的抗肿瘤药β-榄香烯开发为具肝靶向性的小分子抗肿瘤药，是肝癌治疗及中药现代化的迫切要求。我们在前期研究中构建了系列具"乳糖-杂环-β-榄香烯"结构的化合物，并惊喜地发现这些化合物具明显的肝靶向性质。据此，本课题融汇基于结构的药物设计和化学靶向方法，进一步深化"乳糖-杂环-β-榄香烯"类化合物研究，并在分子水平上揭示这些化合物与去唾液酸糖蛋白受体（ASGP-R）作用的机制。项目的实施，不仅可以深入了解糖类识靶端与何种杂环搭配组成的化合物具更高的肝细胞选择性，而且有望获得具全新知识产权的β-榄香烯类小分子肝靶向抗肿瘤药，进而为中药有效成分无组织或细胞选择性提供独特的研究思路。

本课题在广西属肝癌高发区、肝癌治疗缺医少药及β-榄香烯是广西特色中药广西莪术的抗肿瘤有效成分的背景下，通过本课题组全体师生4年的共同努力, 以广西特色中药广西莪术的抗肿瘤有效成分β-榄香烯及具有抗肿瘤活性的萘酰亚胺为抗肿瘤药效端, 以可特异性识别肝细胞膜ASGPR蛋白的乳糖、半乳糖等为肝靶向识别基团, 设计并合成了54个新颖结构的化合物。确定了乳糖、半乳糖与1，2，3-连三唑搭配组成的化合物具较佳的ASGP-R识别效果。分子模拟与激光共聚焦定位等生物学实验阐明了目标化合物的肝靶向识别机制和规律。合成的目标化合物药理活性优于阳性对照药β-榄香烯，且切实提高了β-榄香烯及萘酰亚胺细胞或者组织选择性，达到了项目的预期效果。迄今已发表SCI收录论文12篇, 核心期刊论文1篇，会议论文4篇。申请专利2项：糖基β-榄香烯衍生物及其制备方法和应用（2016109526100），两/三簇糖基罗丹明衍生物及其制备方法和应用（2016109497254），培养了青年教师2人（王勉、黄爱民），研究生8人， 其中一人获得研究生国家奖学金。