Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis
Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis
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DOI：
10.1016/j.bmc.2011.07.060
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发表时间：
2011-09-15
影响因子：
3.5
通讯作者：
Nagasawa, Hideko
中科院分区：
文献类型：
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作者：
Hattori, Hisanori;Okuda, Kensuke;Nagasawa, Hideko
肿瘤微环境以缺氧、低营养水平和酸中毒为特征。基于天然产物化学的方法被用来发现通过缺氧诱导因子(HIF)-1信号通路调节对缺氧微环境适应性反应的小分子。通过报告性实验，从巴西绿蜂胶中鉴定出了调节hif -1依赖性荧光素酶活性的五种化合物，如baccharin(3)、beturetol(4)、山奈素(5)、异樱素(6)和核糖苷(9)。化合物3、9和5降低了hif -1依赖性荧光素酶的活性。肉桂酸衍生物3和9显著抑制HIF-1 α蛋白和HIF-1下游靶基因如葡萄糖转运蛋白1、己糖激酶2和血管内皮生长因子a的表达，在300 ng/CAM剂量的鸡绒毛膜尿囊膜（CAM）实验中也显示出显著的抗血管生成作用。另一方面，在缺氧条件下，黄酮4和6诱导HIF-1依赖性荧光素酶活性和HIF-1靶基因的表达。采用液相色谱-电喷雾电离质谱法测定全蜂胶乙醇提取物中hif -1调节化合物的含量（g/ 100g提取物）分别为1.6(3)、14.2(4)、4.0(5)、0.7(6)和0.7(9)。这些从巴西绿色蜂胶中筛选的小分子可能作为先导化合物用于开发针对缺血性心血管疾病和癌症的新疗法，基于它们分别诱导或抑制HIF-1活性的能力。(C) 2011 Elsevier Ltd.版权所有。
The tumor microenvironment is characterized by hypoxia, low-nutrient levels, and acidosis. A natural product chemistry-based approach was used to discover small molecules that modulate adaptive responses to a hypoxic microenvironment through the hypoxia-inducible factor (HIF)-1 signaling pathways. Five compounds, such as baccharin (3), beturetol (4), kaempferide (5), isosakuranetin (6), and drupanin (9), that modulate HIF-1-dependent luciferase activity were identified from Brazilian green propolis using reporter assay. Compounds 3, 9 and 5 reduced HIF-1-dependent luciferase activity. The cinnamic acid derivatives 3 and 9 significantly inhibited expression of the HIF-1 alpha protein and HIF-1 downstream target genes such as glucose transporter 1, hexokinase 2, and vascular endothelial growth factor A. They also exhibited significant anti-angiogenic effects in the chick chorioallantoic membrane (CAM) assay at doses of 300 ng/CAM. On the other hand, flavonoids 4 and 6 induced HIF-1-dependent luciferase activity and expression of HIF-1 target genes under hypoxia. The contents (g/100 g extract) of the HIF-1-modulating compounds in whole propolis ethanol extracts were also determined based on liquid chromatography-electrospray ionization mass spectrometry as 1.6 (3), 14.2 (4), 4.0 (5), 0.7 (6), and 0.7 (9), respectively. These small molecules screened from Brazilian green propolis may be useful as lead compounds for the development of novel therapies against ischemic cardiovascular disease and cancer based on their ability to induce or inhibit HIF-1 activity, respectively. (C) 2011 Elsevier Ltd. All rights reserved.