土槿皮乙酸（Pseudolaric acid B，PAB）是中药土槿皮的主要成分，具有独特的二萜结构母核。近来，上海药物所研究人员首次发现该化合物具有显著的抗肿瘤新生血管形成的作用，其作用机制是通过加速蛋白酶体降解新生血管生成关键因子HIF-1，减少其蓄积，从而抑制新生血管生成。肿瘤新生血管系统是目前抗肿瘤药物研究领域的热点和重要靶标。因此，开展PAB的结构修饰和构效关系研究具有重要的学术意义和实际应用价值。PAB由于其独特而复杂的结构使得全合成和结构修饰的难度很大，研究人员通过对土槿皮进行深入的化学研究，获得了一系列结构新颖、多样化、难以通过化学合成或修饰得到的PAB同系物，从而为深入研究该化合物的抗肿瘤活性和构效关系提供了方便。在此基础上，合成了一系列土槿皮乙酸衍生物，并通过深入抗肿瘤活性评价，发现了一系列活性明显提高的PAB衍生物（13c-13k），如针对HMEC-1细胞的抑制活性（PAB衍生物13c，IC50 = 0.199 mM；13d，IC50 = 0.238 mM；13f，IC50 = 0.195 mM；PAB：0.803 mM）。体外细胞迁移实验表明PAB衍生物（13c-13k）具有显著的细胞迁移抑制作用，并建立了清楚的PAB类化合物抗肿瘤作用的构效关系。
本研究为丁健课题组和岳建民课题组共同完成，论文发表在Journal of Medicinal Chemistry 上。本研究为中药土槿皮的深层次的开发和利用提供了理论基础，具有重要的学术和实际应用意义。
Structural Modification of an Angiogenesis Inhibitor Discovered from Traditional Chinese Medicine and a Structure–Activity Relationship Study
Sheng-Ping Yang, Yu-Jun Cai, Bang-Le Zhang, Lin-Jiang Tong, Hua Xie, Yan Wu, Li-Ping Lin, Jian Ding,* and Jian-Min Yue*
Journal of Medicinal Chemistry (IF 5.115)
2008, 51, 77–85
Pseudolaric acid B (1) (PAB), with a unique scaffold, was initially isolated as the major compound from the root and trunk bark of Pseudolarix kaempferi Gordon, which is a well-known TCM. Recently, PAB (1) was initially demonstrated by our research group to inhibit angiogenesis, and to have function of abrogating paracrine stimulation of VEGF from tumor cell due to the reduction of HIF-1a protein by promoting its proteasome-mediated degradation. Due to the unique structural scaffold and the significant anti-angiogenesis activity, PAB (1) has potential value as an anticancer drug or a drug lead. However, there has been very limited study on the structural modification and structure activity relationship (SAR) of PAB analogs related with the anticancer purpose, largely due to the protracted and complex nature of their structures for modification/and synthesis. Fortunately, a series of pseudolaric acids analogs with diversified structures, which were difficult to be synthesized, have been isolated from P. kaempferi in our laboratory, providing a chance to initially outline the gross anticancer SAR. Subsequently, a refined structural modification of PAB (1) and SAR study were conducted after the syntheses of a series of PAB derivatives. The in vitro anticancer activities of the selected naturally occurring pseudolaric acids and the structurally modified PAB derivatives have led to the establishment of a clear structure-activity relationship. Some PAB derivatives, such as 13c-13k, exhibited more potent inhibition (e.g. 13c, IC50 = 0.199 mM; 13d, IC50 = 0.238 mM; 13f, IC50 = 0.195 mM) than PAB (IC50 = 0.803 mM) on the proliferation of HMEC-1 cell, and also displayed strong cytotoxicities against six tumor cell lines.
In conclusion, PAB derivatives represent a novel structural scaffold and possess a unique mode-of-action of anticancer. Their strong inhibitory activity against HMEC-1 cell proliferation, migration and tube formation (only 13d) featuring the antianiogenesis property, and their significant cytotoxic activity against the selected tumor cell lines suggest that these compounds have dual functions, and further investigation into this structure class is warranted. We view the pseudolaric acid B and its derivatives as a promising new class of anticancer leads deserving of further studies.