罗汉果皂苷、苷元及其衍生物防癌活性及机制研究

Mogrosides have effective antitumor properties, which have been proved mainly by in vitro tests of saponin. Our ongoing project of the National Science Foundation of China, Study of Luo Han Guo total saponin and characteristics of its components absorption and metabolism, found that any mogrosides which are constructed by more than two sugar residues cannot enter the blood. Majority of mogrosides are absorbed as the aglycone form, named mogrol. Mogroside II is the only natural mogroside can be absorbed into blood. That is to say the antitumor properties of mogrosides in vivo have not been explained correctly so far. Our preliminary tests revealed mogrol has effective anticancer properties. In this project, research on mogroside II, mogrol, and its derivatives will be focused on NF-κB pathway, together with results of metabolism test of metabolites distribution in different organs will reveal the in vivo anticancer mechanism of mogrosides. And we intend to construct a derivatives library of mogroside aglycone by chemical synthesis and acquisition from metabolic experiments. Then we would carry out broad-spectrum anti-cancer activity screening. Base on the structure and anti-cancer activity data, a 3D-QSAR model will be established, and then will be used to forecast and guide subsequent synthesis. Finally, potential compounds for cancer chemoprevention, and structure-activity relationship of mogrol and its derivatives would be obtained. This project would provide the necessary basic data for broadening the application scope of mogrosides, further develop its health and medicinal function.

罗汉果皂苷有较好的防癌效果，但现有的研究结果多是直接通过皂苷的体外试验获得的，而我们正准备完成的国家基金项目“罗汉果总皂苷及其组分的吸收和代谢特点研究”发现：糖残基超过两个的罗汉果皂苷根本不能进入血液，苷元罗汉果醇及其衍生物是体内被吸收的主要分子形式，而在天然罗汉果皂苷中只有苦味的罗汉果皂苷II可以直接入血；体外试验显示苷元及其衍生物具备较好的抗癌活性。本项目承接之前研究结果和工作基础，一方面拟结合罗汉果皂苷代谢产物的体内分布，通过NF-κB通路研究罗汉果皂苷、苷元及其衍生物防癌活性及作用机理。另一方面，利用3D-QSAR、化学修饰等手段设计、合成苷元衍生物，并与皂苷代谢试验中获得的苷元衍生物一起构建化合物库，研究其抗癌防癌活性、构效关系。为拓宽罗汉果皂苷应用范围，深入开发其保健和药用功能提供理论依据，推动罗汉果产业发展壮大。

本项目承接上一个基金项目关于罗汉果皂苷体内代谢研究的成果，通过分离大鼠粪便中的代谢产物和化学合成罗汉果皂苷元（即罗汉果醇）的各种衍生物进一步研究了它们的体外抑制癌细胞活性、分子机制和动物试验。.首先，从罗汉果果实、罗汉果皂苷喂养的大鼠粪便、体外罗汉果皂苷酶水解产物中分离各种罗汉果皂苷及其衍生物，其中包括4个新化合物。开发了一套新型的酶水解和氧化裂解联用的方法制备罗汉果醇，进而以罗汉果醇为起始化合物合成了包括醇类、脂肪胺类、氨基酸酯类、二氢吡啶类、吲哚类以及四氢咔啉类共6大类衍生物。.然后，通过MTT法对以上化合物进行了体外筛选，其中化学合成的四氢咔啉类衍生物表现最佳，其IC50值达到2-9umol的水平，相比于罗汉果醇提高了一个数量级。进一步，发现化合物6和罗汉果醇通过降低survivin的表达并上调Caspase-3的表达，又通过促进Bax的表达，抑制Bcl-2的表达，从而促使肿瘤细胞发生凋亡。为研究罗汉果皂苷在口腔鳞癌中的抑癌作用，我们对罗汉果在口腔鳞癌细胞株中对其增殖能力以及侵袭迁移能力的影响作用进行了研究。结果显示罗汉果醇在口腔鳞癌中抑制增殖及其侵袭迁移能力，其机制可能通过影响细胞周期、凋亡、侵袭迁移相关蛋白表达，抑制肿瘤的发展。.最后，研究了罗汉果醇对Lewis荷瘤小鼠移植瘤的抑制作用并观察罗汉果醇对小鼠免疫器官的影响。

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