在我国多发性骨髓瘤的发病率已超过急性白血病，位居血液系统恶性肿瘤发病率的第二位。研究表明抑制IRE1/XBP1信号通路有望成为包括治疗多发性骨髓瘤在内的多种实体瘤的抗肿瘤药物研发新策略。在前期靶向IRE1/XBP1剪切抑制筛选，首次发现中药竹柏中的竹柏内酯类化合物对人骨髓瘤细胞的XBP1剪切具有明显的抑制作用；体外体内实验证实，该类化合物对人骨髓瘤细胞的生长具有显著的抑制作用。. 本项目拟在前期工作的基础上，利用前述IRE1/XBP1信号通路高通量筛选模对中药竹柏中所分离得到的竹柏内酯类化合物的抗多发性骨髓瘤活性进行全面评价，初步总结活性与结构之间的关系；并以此为指导，在完成竹柏内酯骨架全合成的基础上，对该类化合物进行结构优化和改造，总结其结构与活性之间的关系，以期发现具有显著抑制多发性骨髓瘤的先导化合物，为中药竹柏和其中富含的竹柏内酯类化合物的新药开发奠定科学基础。

The incidence rate of multiple myeloma has exceeded the rate of acute leukemia and ranked second in hematological malignant tumor in China. The research results indicated that the inhibition of IRE1/XBP1 signaling pathway is expected to be a new strategy for the treatment of a variety of solid tumors including multiple myeloma. From screening IRE1/XBP1 splicing inhibition, for the first time, we found that nagilactones from Podocarpus nagi showed positive effect on XBP1 splicing inhibition in H929 cell line. Further investigation disclosed that the active nagilactone displayed remarkable inhibition on the growth of human multiple myeloma cell lines in vitro and in vivo. . To explore the anti-tumor activity of nagilacones against multiple myeloma and structure-activity relationship (SAR), natural nagilactones derivatives from P. nagi will be fully evaluated by IRE1/XBP1 splicing inhibition assay and preliminary SAR will be concluded on the basis of screening results. At the same time, two skeletons of nagilactone will be synthesized to break through the limitation of natural products by using geraniol acetate as starting material. Consequently, modification of nagilacones based on above total synthesis will be carried out for systematic evaluation of structure-activity relationship of nagilactones. Additionally, the anti-tumor mechanism of nagilactones against multiple myeloma will be performed in-depth to check the effects of active nagilactone on the ER stress signaling pathway and apoptotic signaling pathway. We expect that lead compounds with pretty bioavailability, high efficacy and low toxicity will be generated from SAR research and our study will supply scientific foundation for the development of anti-tumor effects against multiple myeloma from the medicinal herb of Podocarpus nagi or the nagilactones enriched in P. nagi.