School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610000, China.
Int J Mol Sci. 2019 Aug 20;20(16):4062. doi: 10.3390/ijms20164062.
There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and . According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.
需要一种高效且低成本的先导化合物发现模式。然而，药物开发仍然缓慢、昂贵且充满风险。本文提出了一种基于中药方剂和药物化学相结合的先导化合物发现策略，以治疗血管生成的川芎嗪-白桦脂酸衍生物（BA-12）为例。抑制血管生成以抑制实体瘤的生长和转移是目前临床上公认的癌症治疗方法之一。首先，基于一个传统的膏药，根据我们之前的研究合成了 BA-12，因为它在人膀胱癌细胞（T24）上表现出比其他衍生物更好的抗肿瘤活性；然后将其上传进行靶标预测。其次，用人脐静脉内皮细胞（HUVEC）、鹌鹑鸡胚绒毛尿囊膜和进行 BA-12 对血管生成的疗效和生物毒性评估。根据预测结果，BA-12 的主要作用机制是代谢途径。因此，应用多种代谢组学方法来揭示 BA-12 的作用机制。最后，通过靶向代谢组学和药理学实验验证了 BA-12 对谷胱甘肽代谢和甘油磷脂代谢激活的预测机制。该策略可能为高效药物发现提供参考，旨在为未满足的临床需求分享中药智慧。
