Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs
Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs
复制标题
新型熊果酸衍生物作为潜在抗癌前药的合成及生物学评价
DOI：
10.1111/cbdd.12608
复制
发表时间：
2015-12-01
影响因子：
3
通讯作者：
Shao, Jingwei
中科院分区：
文献类型：
--
作者：
Yang, Xiang;Li, Yuanfang;Shao, Jingwei
熊果酸（Ursolic acid，UA）是一种天然产物，具有广泛的药理活性，尤其是抗癌活性。本研究设计并合成了13种新型熊果酸衍生物，旨在进一步提高化合物的药效。新合成的化合物的结构用质谱、红外光谱和1H NMR进行了确认。针对各种肿瘤细胞系和非致病性细胞系HELF测定UA衍生物抑制细胞生长的能力。使用OSIRIS对所有衍生物的理论毒性风险进行分析，结果表明大多数化合物的风险为中度至低度。药理实验结果表明，大多数衍生物的生长抑制作用强于UA。特别是，5 b对12种不同的肿瘤细胞系表现出的IC 50值范围为4.09 ± 0.27至7.78 ± 0.43 μm。流式细胞仪分析表明，5 b诱导G 0/G1阻滞在这些细胞系中的三个。这些结果通过结构对接研究得到验证，该研究证实UA可以与细胞周期中G 0/G1转换的关键调节因子细胞周期蛋白D1（Cyc D1）和细胞周期蛋白依赖性激酶（CDK 6）结合，而5 b的哌嗪部分可以与参与癌细胞代谢的主要蛋白葡萄糖激酶（GK），葡萄糖转运蛋白1（GLUT 1）和ATP酶结合。吖啶橙子/溴化乙锭染色证实，5 b能够以剂量依赖性方式诱导细胞凋亡并降低细胞活力。
Ursolic acid (UA) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and 1H NMR. The ability of the UA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non‐pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors than UA. In particular, 5b demonstrated IC50 values ranging from 4.09 ± 0.27 to 7.78 ± 0.43 μm against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin‐dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose‐dependent manner.