帚状香茶菜中具有免疫抑制活性新颖杂二萜的发现、合成及作用机制研究

The incidence of autoimmune disease is high and has a tendency to increase year by year. Studies have shown that finding high efficient and low-toxic immune inhibitors from traditional medicinal plants is an important way to discover innovative immunosuppressive drugs. At the early stage of this project, three unsymmetrical cyclobutane derivatives with novel skeletons were isolated from ethnic medicinal plant Isodon scoparius, and some of them showed remarkable immunosuppressive activity. However, these novel compounds are few and low natural abundance in this plant. To resolve this problem, we have developed an efficient strategy to construct their unsymmetrical cyclobutane core. Furthermore, we have accomplished the semi-synthesis and the preliminary structural modification of scopariusicides using this strategy. Based on these new discoveries, we will initiate this program in three aspects. First, we will majorly study the meroditerpenoids from two I. scoparius, which were distributed in different regions. Secondly, we will develop an approach to the synthesis of isoscopariusins, which exhibited significant immunosuppressive activity, and their structural modification. Thirdly, we will investigate the structure-activity relationship of the natural or synthetic cyclobutane derivatives for immunosuppressive activity, and their mechanism of action (MOA). The main purpose of this program is performed to discover more meroditerpenoid leads with significant immunosuppressive activity by the strategy of phytochemistry combined with organic synthesis and pharmacology. This research may provide a useful exploration for the innovative immunosuppressive agent discovery, and may support an efficient solution for the construction of unsymmetrical cyclobutanes in other molecular settings.

自身免疫性疾病发病率高且有逐年升高的趋势。研究表明，从传统药用植物出发寻找高效低毒免疫抑制剂是研发创新免疫抑制药物的一条重要途径。项目前期，从民族药用植物帚状香茶菜中发现了三种新颖骨架的含不对称环丁烷结构单元的杂二萜，部分化合物显示了较强的免疫抑制活性，同时通过一种高效构建环丁烷片段的方法完成了一种新骨架杂二萜的半合成和结构修饰研究。鉴于以上新的发现，本项目拟从三个方面开展研究：1. 对两种不同产地帚状香茶菜开展针对杂二萜的系统性研究；2. 对活性显著的isoscopariusin骨架杂二萜开展合成及结构修饰研究；3. 对所分离得到的化合物及合成衍生物开展有关免疫抑制活性及作用机制研究。该项目将通过运用天然产物化学、有机合成及药理学相结合的策略，发现具有免疫抑制活性的杂二萜先导化合物，同时为高效构建含不对称环丁烷片段杂二萜提供一定的科学依据，为创新免疫抑制药物的研发提供有益的探索。

由于自身免疫性疾病发病率高且有逐年升高的趋势，使高效、低毒免疫抑制剂的研发成为了研究热点。研究表明，从传统药用植物出发寻找新颖免疫抑制剂是研发创新免疫抑制药物的一条重要途径。前期研究中，我们发现帚状香茶菜中含不对称环丁烷片段的新颖杂二萜类化合物表现出了较强的免疫抑制活性。为了更为深入的开展帚状香茶菜化学成分的研究，从中发现新颖的免疫抑制先导化合物。本项目已对三个不同产地的该种植物开展了化学成分的系统性研究，取得了系列研究成果：不重复分离鉴定了287个化合物，其中新化合物208个（包括26个含环丁烷片段的杂二萜），新颖骨架类型15种；通过单晶X-衍射、化学合成及量子化学计算的方法对多个新颖骨架二萜、二萜二聚体和杂二萜类化合物的绝对构型进行了确证；对两种不同骨架杂二萜类化合物开展了结构修饰研究，合成了衍生物66个；通过对所发现化合物开展了免疫抑制活性筛选，发现部分化合物具有较好的活性；通对衍生物sis-25开展了深入的作用机制和体内效应研究，结果表明该化合物有望成为新颖的免疫抑制先导化合物；在Nat. Prod. Rep.、Org. Chem. Front.、J. Nat. Prod.、Phytochemistry和Cell Chem. Biol.等刊物上发表SCI论文17篇（IF>5的论文4篇）；获授权发明专利5项，包括2项PCT专利。通过该项目的实施，不仅超额完成了既定的考核指标，进一步丰富了帚状香茶菜化学成分的研究内容，为高效构建含不对称环丁烷片段杂二萜及结构修饰研究提供了新的科学依据，同时为新颖免疫抑制药物的研发奠定了坚实的研究基础。