CN104434896A - 二咖啡酰基奎尼酸衍生物制备趋化因子受体2b拮抗剂 - Google Patents

二咖啡酰基奎尼酸衍生物制备趋化因子受体2b拮抗剂 Download PDF

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CN104434896A
CN104434896A CN201310421328.6A CN201310421328A CN104434896A CN 104434896 A CN104434896 A CN 104434896A CN 201310421328 A CN201310421328 A CN 201310421328A CN 104434896 A CN104434896 A CN 104434896A
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antagonist
compound
chemokine receptors
chemokine receptor
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严明
苗靖姗
汪豪
胡洁
张陆勇
王蓓
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China Pharmaceutical University
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Abstract

本发明涉及式I和式II的化合物或其药学上可接受的盐用于制备趋化因子受体2b拮抗剂的用途。此化合物为一类二咖啡酰奎尼酸类天然产物提取物，可以拮抗趋化因子受体2b的活性，成为潜在的抗炎、治疗动脉粥样硬化等疾病的候选药物。

Description

二咖啡酰基奎尼酸衍生物制备趋化因子受体2b拮抗剂
技术领域
本发明涉及医药技术领域，具体涉及二咖啡酰基奎尼酸类衍生物用于制备趋化因子受体2b拮抗剂的用途。
背景技术
趋化因子(chemokines)是指具有趋化作用的细胞因子，属于小分子的分泌蛋白超家族(约8-10KDa，含70-90个氨基酸)。它在很多种疾病的病理生理过程中起着重要作用，如多发性硬化、类风湿性关节炎、器官移植排斥、心脑血管疾病、肿瘤以及HIV等。趋化因子通过与受体结合，在某种程度上促进了各种炎症性疾病以及各种自身免疫性疾病的发生和发展。因而通过抑制趋化因子与其受体结合可在一定程度上抑制相关疾病的发生。趋化因子受体拮抗剂的研究已经成为当前新药研究的热点课题之一。
趋化因子受体2b(CCR2b)是单核细胞趋化蛋白-1(Monocyte ChemoattractantProtein-1,MCP-1)的受体，MCP-1是重要的趋化类炎症因子，在炎症、风湿性关节炎、多发性硬化、动脉粥样硬化、肺纤维化等多种疾病的发生和发展过程中起着关键作用。因此筛选趋化因子受体2b拮抗剂在一定程度上对研究以上疾病的发病机制及治疗有一定的意义。
二咖啡酰奎尼酸在菊科、豆科、伞形科、忍冬科及旋花科植物中广泛存在，本发明人在中药药效物质基础研究过程中，出人意料地发现一类二咖啡酰奎尼酸类化合物具有较好的趋化因子受体2b拮抗作用，从而具有潜在的抗炎、治疗动脉粥样硬化等作用。
发明内容
本发明的目的在于二咖啡酰基奎尼酸类衍生物用于制备趋化因子受体2b拮抗剂的用途。本发明筛选的化合物为一批提取自天然植物的单体化合物，利用荧光检测方法建立的高通量筛选模型对该批化合物进行体外筛选，通过功能性验证寻找先导化合物和候选药物，同时对筛选所得活性化合物进行初步药效学和机制研究，找到一类二咖啡酰基奎尼酸类结构的趋化因子受体2b拮抗剂。该类化合物由中国药科大学天然药物化学实验室提取，提取方法可从专利汪豪，严明，江振洲，张陆勇，叶文才，赵守训.二咖啡酰奎尼酸衍生物在制备用于治疗支原体感染疾病药物中的用途.CN101829077中获得。
本发明的技术方案为：建立趋化因子受体2b拮抗剂筛选模型，初筛，复筛，构效关系分析。具体步骤如下：
步骤一：建立趋化因子受体2b拮抗剂高通量筛选模型。
步骤二：通过阳性药验证模型。
步骤三：使用趋化因子受体2b拮抗剂高通量筛选模型对待测化合物进行初筛、复筛，绘制待测化合物拮抗趋化因子受体2b的曲线并测定IC50值。
本发明提供上述化合物或其药学上可接受盐及其药用组合物的医疗用途，尤其是在预防、延缓或治疗趋化因子受体2b参与介导的疾病。以上提及的提取的化合物制备趋化因子受体2b拮抗剂的用途属于本发明的保护范围。
附图说明：
图1：阳性药对趋化因子受体2b的拮抗曲线图。
图2：待测化合物P1对趋化因子受体2b的拮抗曲线图。
图3：待测化合物P2对趋化因子受体2b的拮抗曲线图。
具体实施方式
以下结合附图说明本发明的具体实施方式：
1.待测化合物拮抗趋化因子受体2b活性测试
1)实验材料
CCR2b稳转细胞株，完全培养基(Ham'F12，10％FBS，Ham'sF12，10％FBS，0.4mg／mlGeneticin，5μg／mL Puromycin)，腔肠素h(5μM)，洋地黄皂苷(20mM)，检测液，ATP(50mM)，384孔板(Corning，USA)，枪头(Axygen，USA)。
2)实验步骤
●待测化合物每种精确称量，加入二甲亚砜溶剂成母液，然后使用缓冲液配制待测化合物溶液至所需浓度，初筛浓度约为2×10-4mol／L。将培养的细胞消化重旋，使细胞浓度达到3×105cells／ml，将此细胞悬液加入到T75培养瓶中，让细胞在37℃／5％CO2下过夜培养。
●阳性药验证：在细胞液中加入腔肠素h，室温(24℃)下避光搅拌(300转／min)过夜(12h)。将上述细胞悬液中加入3倍细胞悬液的缓冲液中稀释，在室温(24℃)下避光搅拌(300转／min)反应至少1h。在避光状态下将处理好的细胞加入384孔板中，每孔20ul。在384孔板中每孔加入梯度稀释的阳性药10ul，离心后在室温(24℃)下避光摇晃(300转／min)反应至少2h。配制激动剂最大效应浓度(激动剂的EC80)：用缓冲液稀释激动剂母液，使其浓度为4倍终浓度，同时设加激动剂和缓冲液的孔作为对照孔。将配制好的激动剂利用检测仪泵入反应完全的384孔板中，每孔10ul，即时检测20s内钙离子变化情况，仪器得出的最终结果表示为20s内引起钙离子变化峰的峰面积。对实验数据作图，可得出阳性药的IC50。
●进行趋化因子受体2b拮抗剂筛选实验：步骤与上一步相同，将阳性药替换成待筛选的化合物即可。
2.数据处理
1)根据公式计算阳性药和待测化合物对趋化因子受体2b的IC50。
2)绘制阳性药拮抗趋化因子受体2b的曲线并测定IC50值，见图1。
3)绘制待测化合物拮抗趋化因子受体2b的曲线并测定IC50值，见图2-3。
复筛实验结果
体外拮抗趋化因子受体2b拮抗剂筛选模型测得阳性药BMS CCR222对拮抗趋化因子受体2b的IC50为1.5×10-9M。筛选得到的化合物P1(3,5-二-O-咖啡酰奎尼酸)和P2(4,5-二-O-咖啡酰奎尼酸)分别如下图式I和式II所示：
化合物P1和P2的IC50如下：

Claims (1)

1.要求保护的式I和式II的化合物或其药学上可以接受的盐用于制备趋化因子受体2b拮抗剂的用途。
CN201310421328.6A 2013-09-12 2013-09-12 二咖啡酰基奎尼酸衍生物制备趋化因子受体2b拮抗剂 Pending CN104434896A (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101343225A (zh) * 2008-08-26 2009-01-14 施树云 高纯度二咖啡酰奎宁酸类化合物的制备方法
CN101642450A (zh) * 2008-08-06 2010-02-10 成都中医药大学 二咖啡酰奎宁酸的新用途
CN101829077A (zh) * 2010-05-26 2010-09-15 中国药科大学 二咖啡酰奎尼酸衍生物在制备用于治疗支原体感染疾病药物中的用途
EP2324840A1 (en) * 2009-11-18 2011-05-25 I.R.B. Istituto Di Ricerche Biotecnologiche S.r.l. Production of caffeoylquinic acids from plant cell cultures of echinacea angustifolia

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101642450A (zh) * 2008-08-06 2010-02-10 成都中医药大学 二咖啡酰奎宁酸的新用途
CN101343225A (zh) * 2008-08-26 2009-01-14 施树云 高纯度二咖啡酰奎宁酸类化合物的制备方法
EP2324840A1 (en) * 2009-11-18 2011-05-25 I.R.B. Istituto Di Ricerche Biotecnologiche S.r.l. Production of caffeoylquinic acids from plant cell cultures of echinacea angustifolia
CN101829077A (zh) * 2010-05-26 2010-09-15 中国药科大学 二咖啡酰奎尼酸衍生物在制备用于治疗支原体感染疾病药物中的用途

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Application publication date: 20150325