Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, PR China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang City, Hunan Province, PR China.
Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang City, PR China.
Bioorg Chem. 2020 Mar;96:103652. doi: 10.1016/j.bioorg.2020.103652. Epub 2020 Feb 4.
5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC values of 10.26 ± 6.94 μM and 17.17 ± 3.03 μM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f, as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies.
5,6,7-三甲氧基黄酮水杨酸酯衍生物是根据组合原理，将三个重要药效团（TMP、黄酮和 SA）结合在一起设计的。合成了一系列新型的 5,6,7-三甲氧基黄酮水杨酸酯衍生物，并对其体外抗肿瘤活性进行了评价。在这些衍生物中，化合物 7f 对 HGC-27 细胞和 MGC-803 细胞表现出优异的增殖抑制活性，IC 值分别为 10.26 ± 6.94 μM 和 17.17 ± 3.03 μM。随后，测定了化合物 7f 对细胞集落形成（集落形成生存实验）、细胞迁移（划痕愈合实验）、细胞周期分布（PI 染色实验）、细胞凋亡（Hoechst 33258 染色实验和 Annexin V-FITC/PI 双染色实验）、乳酸水平（乳酸测量）、微管排列（免疫荧光染色分析）和对接构象（分子对接模拟）的影响。进一步的 Western blot 分析证实，化合物 7f 能够有效地下调糖酵解相关蛋白 HIF-1α、PFKM 和 PKM2 以及肿瘤血管生成相关蛋白 VEGF 的表达。综上所述，这些研究表明，化合物 7f 可能是一种有前途的治疗胃癌的候选药物，值得进一步研究。
