Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China; State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
Bioorg Chem. 2021 Nov;116:105298. doi: 10.1016/j.bioorg.2021.105298. Epub 2021 Aug 21.
Selaginellins are a type of rare natural products from the genus Selaginella with unusual alkynyl phenol skeletons and extensive biological activities. Previous structural simplification of these natural compounds afforded a series of diaryl acetylene derivatives with hypoxia-inducible factor 1 (HIF-1) inhibitory activity. In this study, we synthesized thirty compounds by stepwise optimization using methyl 3-(4-methoxylphenyl ethynyl)-[4'-methoxyl-1,1'-biphenyl]-2-carboxylate (1a) as a lead compound and evaluated their HIF-1 inhibitory activity by dual luciferase reporter assay. Among them, compound 9i displayed the most potent HIF-1 inhibitory activity (IC = 1.5 ± 0.03 μM) with relatively low cytotoxicity. Under hypoxia, compound 9i showed no effect on the accumulation of HIF-1α protein in western blot analysis, but could down-regulate the expression of VEGF mRNA, the downstream target gene of HIF-1 pathway. Cell-based activity assay demonstrated that compound 9i could inhibit the hypoxia-induced migration, invasion and proliferation of HeLa cells at the concentrations of 1 ~ 5 μM. In mouse breast cancer xenograft model, compound 9i exhibited obvious tumor growth inhibition and very low toxicity at a dose of 15 mg/kg. The results suggested that compound 9i would be a potential antitumor agent via HIF-1 pathway inhibition.
卷柏素是一类来自卷柏属的稀有天然产物，具有不寻常的炔基酚骨架和广泛的生物活性。这些天然化合物的结构简化以前得到了一系列具有缺氧诱导因子 1（HIF-1）抑制活性的二芳基乙炔衍生物。在本研究中，我们使用甲酯 3-(4-甲氧基苯基乙炔基)-[4'-甲氧基-1,1'-联苯]-2-羧酸酯（1a）作为先导化合物，通过逐步优化合成了三十种化合物，并通过双荧光素酶报告基因检测法评估了它们对 HIF-1 的抑制活性。其中，化合物 9i 表现出最强的 HIF-1 抑制活性（IC = 1.5 ± 0.03 μM），且细胞毒性相对较低。在低氧条件下，化合物 9i 对 Western blot 分析中 HIF-1α 蛋白的积累没有影响，但可以下调 HIF-1 通路下游靶基因 VEGF mRNA 的表达。细胞活性测定表明，化合物 9i 可以在 1 ～ 5 μM 的浓度下抑制缺氧诱导的 HeLa 细胞迁移、侵袭和增殖。在小鼠乳腺癌异种移植模型中，化合物 9i 在 15 mg/kg 的剂量下表现出明显的肿瘤生长抑制作用和极低的毒性。结果表明，化合物 9i 可能通过抑制 HIF-1 通路成为一种有潜力的抗肿瘤药物。
