利用斑马鱼模型研究靛玉红及其衍生物抑制血管生成作用的构效关系

韩利文; 何秋霞; 赵亮; 袁延强; 陈锡强; 王雪; 刘可春<sup>*</sup>; 刘昌孝

引用本文:	韩利文,何秋霞,赵亮,袁延强,陈锡强,王雪,刘可春,刘昌孝.利用斑马鱼模型研究靛玉红及其衍生物抑制血管生成作用的构效关系[J].中国现代应用药学,2013,30(5):457-460.
	HAN Liwen,HE Qiuxia,ZHAO Liang,YUAN Yanqiang,CHEN Xiqiang,WANG Xue,LIU Kechun,LIU Changxiao.Study of Structure-angiogenic Activity Relationship of Indirubin and Its Derivatives Using Zebrafish Model[J].Chin J Mod Appl Pharm(中国现代应用药学),2013,30(5):457-460.

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利用斑马鱼模型研究靛玉红及其衍生物抑制血管生成作用的构效关系
韩利文¹, 何秋霞¹, 赵亮², 袁延强¹, 陈锡强¹, 王雪¹, 刘可春¹, 刘昌孝³
1.山东省科学院生物研究所，生物传感器重点实验室，济南 250014;2.山东大学齐鲁医院，济南 250012;3.天津药物研究院释药技术与药代动力学国家重点实验室，天津 300193

摘要:

目的利用斑马鱼模型考察中药单体靛玉红(Ind)及其衍生物的抑制血管生成活性及其量效关系，并为斑马鱼模型在新药构效关系研究中的应用提供实验依据。方法选用TG(VEGFR2：GFP)系血管荧光转基因斑马鱼作为筛选模型，分别用Ind及其衍生物靛玉红-3’-单肟(IMO)、6-溴-靛玉红-3’-单肟(BIO)处理斑马鱼胚胎，以节间血管数作为指标，考察药物对斑马鱼胚胎抑制血管生成的影响。结果在相同的剂量下，Ind、IMO与BIO抑制斑马鱼节间血管(ISV)生成的作用依次增强，三者都显示明显的量效关系。Ind、IMO 与BIO的半数有效剂量(EC₅₀)，分别为89.10，5.188和2.686 μmol·L^-1。结论在靛玉红母体结构改造中，随着C-3’位肟化以及C-6位溴原子的引入，溶解性明显改善，其抑制血管生成活性也逐渐增强。

关键词: 斑马鱼血管生成靛玉红靛玉红-3’ -单肟 6-溴-靛玉红-3’ -单肟

DOI：

分类号:

基金项目:国家自然科学基金青年基金项目(81202584)；山东省医药卫生科技发展计划项目(2011QW015)

Study of Structure-angiogenic Activity Relationship of Indirubin and Its Derivatives Using Zebrafish Model

HAN Liwen¹, HE Qiuxia¹, ZHAO Liang², YUAN Yanqiang¹, CHEN Xiqiang¹, WANG Xue¹, LIU Kechun¹, LIU Changxiao³

1.Key Laboratory for Biosensors of Shandong Province, Biology Institute of Shandong Academy of Sciences, Ji’nan 250014, China;2.Department of Pharmacy, Qilu Hospital, Shandong University, Ji’nan 250012, China;3.State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin 300193, China

Abstract:

OBJECTIVE To investigate the antiangiogenesis effect and dose-effect relationship of indirubin(Ind) and its derivatives using zebrafish model which will contribute to the structure-activity relationship of new drugs. METHODS Intersegmental vessel number(ISV) in transgenic line VEGFR2: GFP zebrafish was used to evaluate angiogenesis inhibition effect after indirubin(Ind), its derivatives indirubin-3'-monoxime(IMO) and (2'Z,3'E)-6-Bromoindirubin-3'-oxime(BIO) treated zebrafish embryos. RESULTS At the same dose, BIO showed the strongest effect of antiangiogenesis, followed by IMO and Ind. The inhibition effects of three compounds were obviously dose-dependent. Furthermore, the median effective concentration(EC₅₀) of Ind, IMO and BIO were 89.10, 5.188 and 2.686 μmol·L^-1, respectively. CONCLUSION After addition of oximido at the C-3' and bromine at the C-6 in the structure of Ind, the solubility of IMO and BIO obviously increased and their antiangiogenesis effect enhanced simultaneously.

Key words: zebrafish angiogenesis indirubin indirubin-3'-monoxime (2'Z,3'E)-6-Bromoindirubin-3'-oxime