CN105985347B - 一种苯并大环内酰胺吲哚生物碱及其在制备抗补体药物中的用途 - Google Patents
一种苯并大环内酰胺吲哚生物碱及其在制备抗补体药物中的用途 Download PDFInfo
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Abstract
本发明属中药制药领域，涉及一种苯并大环内酰胺吲哚生物碱青黛碱C及其在制备抗补体药物中的用途。本发明从青黛粉末中分离得到一个结构新颖独特的苯并大环内酰胺吲哚生物碱青黛碱C，其由两个完全相同的3‑羰基吲哚螺合在苯并内酰胺大环上；本发明采用现代药理实验证实其对补体系统经典途径和旁路途径激活均有较强的抑制作用，其CH50和AP50值分别为0.018±0.004mg/ml、0.042±0.014mg/ml。所述化合物可用于制备补体抑制剂。
Description
技术领域
本发明属中药制药领域，涉及青黛中一种苯并大环内酰胺吲哚生物碱及其在制备抗补体药物中的用途。
背景技术
研究公开了补体系统的过度激活会引发系统性红斑狼疮(SLE)、类风湿性关节炎(RA)、急性呼吸窘迫综合征(ARDS)等多种重大疾病。抗补体药物研究多年来一直是世界药学研究的热点和重点。然而目前对此类疾病尚缺乏较为理想的治疗药物，因此临床上急需高效、低毒、专一的新型补体抑制剂。从天然产物中研究开发补体抑制剂是近年来一个受到越来越多关注的重要研究领域，其具有成本低、毒性低等特点。国内外学者已从包括海洋生物在内的多种天然产物中分离得到多种具有补体系统抑制作用的单体化合物，为抗补体药物的研究与开发提供了广阔的前景。
青黛(Indigo Naturalis)为爵床科植物马蓝Baphicacanthus cusia(Nees)Bremek.、蓼科植物蓼蓝Polygonum tinctorium Ait.或十字花科植物菘蓝Isatisindigotica Fort.的叶或茎叶经加工制得的干燥粉末或团块。其性咸味寒，归肝经。可清热解毒、凉血消斑、泻火定惊。用于温毒发斑、血热吐衄、胸痛咳血、口疮、痄腮、喉痹、小儿惊痫。现代药理研究表明，青黛具有抗菌、抗炎、抗肿瘤、抗氧化、治疗银屑病等作用，其活性成分主要是生物碱类成分，以吲哚生物碱二聚体靛玉红、靛蓝等为主。
本发明拟提供一种苯并大环内酰胺吲哚生物碱的新化合物及其在制备抗补体药物中的用途。
发明内容
本发明的目的是提供一种苯并大环内酰胺吲哚生物碱青黛碱C及其在制备抗补体药物中的用途。
本发明提供的新结构化合物苯并大环内酰胺吲哚生物碱，命名为青黛碱C，由两个完全相同的3-羰基吲哚螺合在苯并内酰胺大环上，具有以下化学结构：
本发明应用现代药理筛选方法，对中药青黛中抗补体活性物质进行研究，从青黛的乙醇提取物分离得到一个苯并大环内酰胺吲哚生物碱类化合物青黛碱C，经活性测试，证实其对补体系统的经典途径和旁路途径激活均有较强的抑制作用。
本发明所述的化合物通过下述方法制备：
取青黛粉末，乙醇回流提取，合并提取液并浓缩得浸膏，加水混悬，分别以石油醚、乙酸乙酯和正丁醇萃取，合并萃取液并浓缩至干。将乙酸乙酯萃取部位经硅胶柱色谱分离、Sephadex LH-20柱色谱、反相HPLC等手段纯化，分离得到化合物青黛碱C。
所述化合物青黛碱C：黄色粉末,分子式C24H17N3O4,。ESI-MS m/z:434[M+Na]+。1H-NMR(400MHz,CDCl3)δH:7.59(1H,d,J＝7.7Hz),7.46(1H,dd,J＝8.3Hz,7.2Hz),7.44(1H,d,J＝7.8Hz),7.26(1H,dd,J＝8.3Hz,7.2Hz),7.14(1H,dd,
J＝8.1Hz,7.1Hz),6.87(1H,d,J＝8.2Hz),6.84(1H,d,J＝8.2Hz),6.83(1H,dd,J＝7.8Hz,7.2Hz),6.69(1H,d,J＝8.1Hz),6.67(1H,dd,J＝8.3Hz,7.2Hz),6.53(1H,d,J＝8.3Hz),3.31(1H,d,J＝16.4Hz),2.71(1H,d,J＝16.4Hz).13C-NMR(100MHz,CDCl3)δC:70.3(C-2),202.9(C-3),118.6(C-3a),124.6(C-4),119.1(C-5),138.5(C-6),112.7(C-7),163.7(C-7a),36.3(C-8),172.8(C-9),128.8(C-11),154.6(C-12),116.1(C-13),130.1(C-14),119.4(C-15),120.5(C-16),83.6(C-2'),199.8(C-3'),118.2(C-3a'),123.9(C-4'),118.7(C-5'),138.2(C-6'),111.3(C-7'),162.0(C-7a').。
上述青黛碱C经过体外抗补体活性试验测定，结果表明其对补体系统的经典途径和旁路途径激活均有较强的补体抑制作用，其CH50和AP50值分别为其CH50和AP50值分别为0.018±0.004、0.042±0.014mg/ml。阳性对照肝素CH50和AP50值分别为0.026±0.005mg/ml、0.054±0.016mg/ml。
所述的苯并大环内酰胺吲哚生物碱类化合物青黛碱C可用于制备抗补体药物。
附图说明
图1是青黛中青黛碱C的提取分离流程图。
具体实施方式
实施例1制备青黛碱C
取青黛粉末5kg，95％乙醇回流提取3次(50L×3)，每次2h，合并提取液并浓缩得浸膏0.25kg，加水(4L)混悬，分别以等体积石油醚、乙酸乙酯和正丁醇萃取5次，合并萃取液并浓缩至干，得乙酸乙酯萃取物50g。将乙酸乙酯萃取部位经硅胶(200-300目)柱色谱分离，依次以二氯甲烷-甲醇(50:1-0:1)梯度洗脱，得到8个流份(Fr.1-8)，其中流份Fr.5(4g)再经硅胶柱色谱(二氯甲烷-甲醇，30:1,20:1，10:1，5:1，3:1，1:1)、Sephadex LH-20柱色谱(氯仿-甲醇，1:1)和反相HPLC(甲醇-水，20:80-80:20梯度洗脱)等手段纯化，分离得到化合物青黛碱C。
所述化合物青黛碱C：黄色粉末,分子式C24H17N3O4,。ESI-MS m/z:434[M+Na]+。1H-NMR(400MHz,CDCl3)δH:7.59(1H,d,J＝7.7Hz),7.46(1H,dd,J＝8.3Hz,7.2Hz),7.44(1H,d,J＝7.8Hz),7.26(1H,dd,J＝8.3Hz,7.2Hz),7.14(1H,dd,J＝8.1Hz,7.1Hz),6.87(1H,d,J＝8.2Hz),6.84(1H,d,J＝8.2Hz),6.83(1H,dd,J＝7.8Hz,7.2Hz),6.69(1H,d,J＝8.1Hz),6.67(1H,dd,J＝8.3Hz,7.2Hz),6.53(1H,d,J＝8.3Hz),3.31(1H,d,J＝16.4Hz),2.71(1H,d,J＝16.4Hz).13C-NMR(100MHz,CDCl3)δC:70.3(C-2),202.9(C-3),118.6(C-3a),124.6(C-4),119.1(C-5),138.5(C-6),112.7(C-7),163.7(C-7a),36.3(C-8),172.8(C-9),128.8(C-11),154.6(C-12),116.1(C-13),130.1(C-14),119.4(C-15),120.5(C-16),83.6(C-2'),199.8(C-3'),118.2(C-3a'),123.9(C-4'),118.7(C-5'),138.2(C-6'),111.3(C-7'),162.0(C-7a').。
实施例2体外抗补体经典途径试验
取补体(豚鼠血清)0.04ml，加入巴比妥缓冲液(BBS)配制成1:10的溶液，用BBS对倍稀释成1:20、1:40、1:80、1:160、1:320、1:640和1:1280的溶液，取1:1000溶血素、2％羊红细胞(SRBC)各0.1ml及各浓度补体0.2ml溶于0.2ml BBS中，混匀，37℃水浴30min后放入低温高速离心机，在4000rpm、4℃条件下离心5min。分别取每管上清0.2ml于96孔板，在405nm测定其吸光度。实验同时设置全溶血组(0.1ml 2％SRBC、0.1ml溶血素溶于0.4ml三蒸水)。以三蒸水溶血管的吸光度作为全溶血标准，计算溶血率。以补体稀释度为X轴，溶血百分率为Y轴作图。选择达到相似高溶血率的最低补体浓度作为确保体系能正常溶血所需的临界补体浓度。取临界浓度的补体与供试品混匀，按上述方法于405nm下测定吸光度。实验同时设置供试品对照组、补体组和全溶血组。将供试品吸光度值扣除相应供试品对照组吸光度值后计算溶血率。以供试品浓度作为X轴，溶血抑制率作为Y轴作图，计算50％抑制溶血所需供试品的浓度(CH50)，结果为0.018±0.004mg/ml；阳性对照肝素CH50值为0.026±0.005mg/ml。
实施例3体外抗补体旁路途径试验
取补体(人血清)0.2ml，加入AP稀释液(巴比妥缓冲液，pH＝7.4,含5mMMg2+,8mMEGTA)配制成1:5的溶液，并对倍稀释成1:10、1:20、1:40、1:80、1:160、1:320和1:640的溶液。取各浓度补体0.15ml、AP稀释液0.15ml及0.5％兔红细胞(RE)0.20ml，混匀，37℃水浴30min后置于低温高速离心机，在4000rpm、4℃条件下离心5min。分别取每管上清0.2ml于96孔板，在405nm测定吸光度。实验同时设置全溶血组(0.20ml 0.5％RE溶于0.3ml三蒸水)。以三蒸水溶血管的吸光度作为全溶血标准，计算溶血率。以补体稀释度为X轴，溶血百分率为Y轴作图。选择达到相似高溶血率的最低补体浓度作为确保体系能正常溶血所需的临界补体浓度。取确定的临界浓度的补体与供试品混匀，按上述方法于405nm下测定其吸光度。实验同时设置供试品对照组、补体组和全溶血组。将供试品吸光度值扣除相应供试品对照组吸光度值后计算溶血率。以供试品浓度作为X轴，溶血抑制率作为Y轴作图，计算50％抑制溶血所需供试品的浓度(AP50)，结果为0.042±0.014mg/ml；阳性对照肝素AP50值为0.054±0.016mg/ml。
本发明中，实验采用的试剂均为本领域公知技术，可市购。
Claims (4)
1.具有如下化学结构的苯并大环内酰胺吲哚生物碱类化合物，
所述化合物命名为青黛碱C，由两个完全相同的3-羰基吲哚螺合在苯并内酰胺大环上。
2.权利要求1所述的苯并大环内酰胺吲哚生物碱类化合物在制备抗补体药物中的用途。
3.按权利要求2所述的用途，其特征在于，所述的苯并大环内酰胺吲哚生物碱类化合物对补体系统的经典途径有补体抑制作用。
4.按权利要求2所述的用途，其特征在于，所述的苯并大环内酰胺吲哚生物碱类化合物对补体系统的旁路途径激活有补体抑制作用。
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