Ling Huiping, Li Hong, Chen Meijun, Lai Baolong, Zhou Haiming, Gao Hui, Zhang Jiangye, Huang Yan, Tao Yiwen
Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
Department of Pharmacy, the 7th Affiliated Hospital, Sun Yat-Sen University, ShenZhen, Guangdong 518107, China.
Anticancer Agents Med Chem. 2021;21(9):1110-1119. doi: 10.2174/1871520620666200408080040.
Gambogic Acid (GA), a promising anti-cancer agent isolated from the resin of Garcinia species in Southeast Asia, exhibits high potency in inhibiting a wide variety of cancer cells' growth. Moreover, the fact that it is amenable to chemical modification makes GA an attractive molecule for the development of anti-cancer agents.
Gambogic acid-3-(4-pyrimidinyloxy) propyl ester (compound 4) was derived from the reaction between 4-hydroxypropoxy pyrimidine and GA. Its structure was elucidated by comprehensive analysis of ESIMS, HRESIMS, 1 D NMR data. Anti-tumor activities of compound 4 and GA in vitro against HepG-2, A549 and MCF-7 cells were investigated by MTT assay. FITC/PI dye was used to test apoptosis. The binding affinity difference of compound 4 and GA binding to IKKβ was studied by using Discovery Studio 2016.
Compound 4 was successfully synthesized and showed strong inhibitory effects on HepG-2, A549 and MCF-7 cells lines with an IC value of 1.49±0.11, 1.37±0.06 and 0.64±0.16μM, respectively. Molecular docking study demonstrated that four more hydrogen bonds were established between IKKβ and compound 4, compared with GA.
Our results suggested that compound 4 showed significant effects in inducing apoptosis. Further molecular docking study indicated that the introduction of pyrimidine could improve GA's binding affinity to IKKβ. Compound 4 may serve as a potential lead compound for the development of new anti-cancer drugs.
藤黄酸（GA）是一种从东南亚藤黄属植物树脂中分离出的有前景的抗癌剂，在抑制多种癌细胞生长方面表现出高效力。此外，其易于化学修饰这一特性使GA成为开发抗癌剂的一个有吸引力的分子。
藤黄酸 - 3 -（4 - 嘧啶氧基）丙酯（化合物4）由4 - 羟基丙氧基嘧啶与GA反应制得。通过对电喷雾离子化质谱（ESIMS）、高分辨电喷雾离子化质谱（HRESIMS）、一维核磁共振（1D NMR）数据的综合分析来阐明其结构。采用MTT法研究化合物4和GA体外对肝癌细胞HepG - 2、肺癌细胞A549和乳腺癌细胞MCF - 7的抗肿瘤活性。使用异硫氰酸荧光素/碘化丙啶（FITC/PI）染料检测细胞凋亡。利用Discovery Studio 2016研究化合物4和GA与IKKβ结合亲和力的差异。
成功合成了化合物4，其对HepG - 2、A549和MCF - 7细胞系显示出强烈的抑制作用，IC值分别为1.49±0.11、1.37±0.06和0.64±0.16μM。分子对接研究表明，与GA相比，IKKβ与化合物4之间多形成了四个氢键。
我们的结果表明化合物4在诱导细胞凋亡方面显示出显著效果。进一步的分子对接研究表明，嘧啶的引入可提高GA与IKKβ的结合亲和力。化合物4可能作为开发新型抗癌药物的潜在先导化合物。
