基于PTP1B抑制的凹叶厚朴中新型复杂木脂素的发现及其抗糖尿病活性研究

从天然药物中寻找具有抗糖尿病活性的化合物或活性组分是国内外抗糖尿病新药研发的重要途径之一。前期研究发现传统中药凹叶厚朴有降血糖、降血脂及体外蛋白酪氨酸磷酸酶1B（PTP1B）抑制活性，经化学成分的快速识别和发现研究，得到了30个新化合物，包括17个新的萜类-苯丙素类结合的复杂木脂素及13个结构新颖的寡聚木脂素类化合物，其中有8个为新骨架化合物。13个化合物表现出显著的PTP1B抑制活性。受限于前期分离得到化合物的量较少，未对活性化合物的化学和生物学特性进行深入研究。为此，本课题拟对凹叶厚朴中新型复杂木脂素类成分进行研究：以PTP1B为靶点，利用建立的复杂木脂素的快速获取和富集方法，高效获取凹叶厚朴中该类成分，并与多靶点的抗糖尿病活性评价相结合，进行构效关系、计算机虚拟筛选等研究。对活性强且量大的化合物进行作用机制研究，最终得到活性确切的抗糖尿病先导分子。

It is one of the major methods for antidiabetic agents to obtain candidates from natural products by systematic pharmaceutical research. Our previous research showed the stems of Magnolia officinalis had the activities of hypoglycemic, hypolipidemic and in-vitro protein tyrosine phosphatase 1B (PTP1B) inhibition. In quick identification and recognition means of chemical ingredients, we had isolated 30 new compounds, including 17 novel terpene-phenylpropanoid complicated lignans and 13 new oligolignans, eight of which represented the new skeletons. In addition, 13 compounds showed significant inhibitive activity to PTP1B. In-depth activity evaluations of the novel compounds were not performed due to limited amount obtained. Thus, this project will focus on the studies of novel complicated lignanoid derivatives: targeting PTP1B, obtain compounds of the same category effectively by the established fast identification and enrichment methods, and evaluate their antidiabetic activities, carry out structure-activity relationship research and structure-based virtual screening. For those compounds with strong activities, we will make efforts to accumulate enough amounts, so that the mechanism research can be performed, and finally the lead molecules with exact antidiabetic activity could be found.