源于吉马烷的倍半萜抗糖尿病构效关系及作用机制的研究

Clinical anti Type 2 Diabetes Mellitus (T2DM) drugs have been found to induce many side effects. In our studies on high performance and low toxicity anti-diabetic new drug candidates, we found that many sesquiterpenoids biogenetically originated from germacrane, which bearing oxygenated or non-oxygenated isopropyl groups, are the effective components of many anti-diabetic medicinal plants. The action mechanisms include promoting insulin secretion, increasing insulin sensitivity, and inhibiting ?-glucosidase. The current project including the preparation of effective fractions and isolation of no less than 100 (including 6 sub-classes) sesquiterpenoids, determine their structures and analysis their content. Subsequently, we will evaluate their anti-diabetic activities on cell and animal level pharmacological models. The Structure-Activity Relationship of these sesquitepenoids will be studied by CoMFA method. The action manchanism of the sesquiterpenoids will be further studied by evaluating their activities on many new targets, such as DPP-4/ GLP-1, PPARs, AR, GK, 11β-HSD, AMPK, GSK-3, and PTPs, by the state of the art molecular pharmacological methods (ELISA/RTPCR/Western blot, etc.). Finally, virtual screening and docking will be carried out to investigate the interaction between 3D structures of sesquiterpenoids and the key targets. The project will lay a solid foundation for new drug leads and action mechanism in type 2 diabetes mellitus therapy.

现有的抗2型糖尿病药物存在不同程度的副作用，临床上迫切需要高效低毒的新型药物。我们前期对菖蒲的研究中发现多种来源于吉马烷型的倍半萜，均含有氧化或非氧化的异丙基基团，通过胰岛素促分泌、胰岛素增敏及α-葡萄糖苷酶抑制等多种途径发挥良好的抗糖尿病作用。本项目拟建立快速分析方法从5 种富含此类倍半萜的天然药物中分离鉴定不少于150 种化合物并完成简单化学修饰转化；然后通过多种细胞、动物水平的抗糖尿病模型分别评价所有单体、总萜的药效；进一步通过分子药理学流行技术研究其对多种抗糖尿病靶点的药效从而阐明作用机制；在实验基础上利用计算化学方法建立化合物CoMFA 模型，进而小分子-大分子相互虚拟筛选及对接、3D-QSAR等研究阐明此类倍半萜的作用靶点、构效关系及其抗糖尿病整体药效的实现，为发现具有前景的药物先导化合物打下坚实基础。

糖尿病是一种由于机体胰岛素分泌绝对或相对不足而引起高血糖的代谢性疾病。我们前期对菖蒲的研究中发现多种来源于吉马烷型的倍半萜，可通过胰岛素促分泌、胰岛素增敏及α-葡萄糖苷酶抑制等多种途径发挥良好的抗糖尿病作用。本项目因此对富含此类倍半萜的郁金Curcuma wenyujin；白术Atractylodes macrocephala；千年健Homalomena occulta；石菖蒲Acorus tatarinowii；新疆一支蒿Artemisia rupestris；菊苣Cichorium intybus；以及民间用于治疗糖尿病的药用植物华泽兰Eupatorium chinense、青钱柳Cyclocarya paliurus等进行了较为详细的研究。从这些植物中，分离得到化合物200余个，其中萜类化合物150余个；此外还发现苯并呋喃类化合物20个。获得新化合物17个，并发现总共20多个倍半萜、三萜及苯并呋喃类化合物显示出较好的抗糖尿病活性，此外还发现部分苯并呋喃类化合物具有较好的抗炎活性。建立了重要倍半萜单体化合物在药材中的含量测定方法。在实验基础上利用计算化学方法进行小分子-大分子相互虚拟筛选及对接、3D-QSAR等研究探索了活性倍半萜的作用靶点、构效关系，发现并初步阐明了多个结构子类型与降糖活性之间的构效关系。通过本项目的实施，基本上明确了倍半萜不同结构类型在构效关系中的重要价值；丰富了萜类及苯并呋喃类化合物结构的多样性；明确了具有开发为抗2型糖尿病药物前景的先导化合物。