Zebrafish bioassay-guided natural product discovery: isolation of angiogenesis inhibitors from East African medicinal plants.
Zebrafish bioassay-guided natural product discovery: isolation of angiogenesis inhibitors from East African medicinal plants.
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DOI：
10.1371/journal.pone.0014694
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发表时间：
2011-02-17
期刊：
影响因子：
3.7
通讯作者：
de Witte PA
中科院分区：
文献类型：
--
作者：
Crawford AD;Liekens S;Kamuhabwa AR;Maes J;Munck S;Busson R;Rozenski J;Esguerra CV;de Witte PA
天然产物代表了早期药物发现中未开发的化学多样性的重要储备。天然来源先导化合物的鉴定将受益于能够促进从多成分提取物中分离生物活性分子的治疗相关生物测定。为此，我们开发了一种体内生物测定引导的天然产物发现分离方法，该方法将斑马鱼胚胎的生物活性筛选与分析薄层色谱（TLC）的快速分级和高分辨率电喷雾质谱（HRESIMS）的初步结构阐明相结合。使用 fli-1:EGFP 转基因斑马鱼胚胎对东非药用植物提取物进行生物活性筛选，发现 Oxygonum sinuatum 和 Plectranthus barbatus 具有抑制血管发育的作用。斑马鱼生物测定引导的分馏鉴定出这些植物的活性成分为大黄素（蛋白激酶 CK2 的抑制剂）和 Coleon A 内酯（一种罕见的松香二萜类化合物，之前没有描述过生物活性）。大黄素和结肠 A 内酯均可抑制哺乳动物内皮细胞的体外增殖、迁移和管形成，以及鸡绒毛尿囊膜 (CAM) 测定中的血管生成。这些结果表明，斑马鱼生物测定与分析色谱方法的结合是快速鉴定生物活性天然产物的有效策略。
Natural products represent a significant reservoir of unexplored chemical diversity for early-stage drug discovery. The identification of lead compounds of natural origin would benefit from therapeutically relevant bioassays capable of facilitating the isolation of bioactive molecules from multi-constituent extracts. Towards this end, we developed an in vivo bioassay-guided isolation approach for natural product discovery that combines bioactivity screening in zebrafish embryos with rapid fractionation by analytical thin-layer chromatography (TLC) and initial structural elucidation by high-resolution electrospray mass spectrometry (HRESIMS). Bioactivity screening of East African medicinal plant extracts using fli-1:EGFP transgenic zebrafish embryos identified Oxygonum sinuatum and Plectranthus barbatus as inhibiting vascular development. Zebrafish bioassay-guided fractionation identified the active components of these plants as emodin, an inhibitor of the protein kinase CK2, and coleon A lactone, a rare abietane diterpenoid with no previously described bioactivity. Both emodin and coleon A lactone inhibited mammalian endothelial cell proliferation, migration, and tube formation in vitro, as well as angiogenesis in the chick chorioallantoic membrane (CAM) assay. These results suggest that the combination of zebrafish bioassays with analytical chromatography methods is an effective strategy for the rapid identification of bioactive natural products.
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