CN107550899A - 环烯醚萜类化合物在制备抗补体药物中的用途 - Google Patents
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Abstract
本发明属于中药制药领域,涉及环烯醚萜类化合物及其在制备抗补体药物中的用途。本发明从玄参科植物轮叶马先蒿(Pedicularis verticilata L.)干燥全草乙醇提取物的乙酸乙酯萃取部位提取得到环烯醚萜类化合物,并通过体外抗补体活性评价实验证实其对补体系统的经典途径和旁路途径均有较强的抑制作用。本发明所述的环烯醚萜类化合物可制备抗补体药物并进一步制备治疗与补体相关疾病的药物。
Description
技术领域
本发明属中药制药领域,涉及轮叶马先蒿中环烯醚萜类化合物及其在制备抗补体药物中的新用途。
背景技术
现有技术公开了补体系统的过度激活会引发系统性红斑狼疮、类风湿性关节炎、急性呼吸窘迫综合征等多种重大疾病。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等在内的多种天然产物中分离得到大量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。
轮叶马先蒿(Pedicularis verticilata L.)为玄参科马先蒿属植物。本属植物药用种类繁多,历史悠久,早在《神农本草经》和《本草纲目》等中药典籍中,就有关于该属植物的药用价值的记载。轮叶马先蒿以根人药,性温味甘,微苦,大补元气,生津安神,强心。多用于治疗气血虚损、疲劳多汗、虚脱衰竭、血压降低等症。近年来对马先蒿属植物的化学成分和生物活性研究中发现,该属植物含有环烯醚萜苷、苯丙素苷、木脂素苷、生物碱、黄酮等多类化合物,其中环烯醚萜苷、苯丙素苷类化合物是该属的特征性化合物,表现出抗肿瘤、抗氧化、DNA修复、提高机体免疫力、保肝、降压利尿等各种生理活性。苏保宁(1995,兰州大学,中国学位论文全文数据库),在其硕士论文中报道了从轮叶马先蒿中分离鉴定了16个单体化合物,这些化合物大多属于新木脂素苷、苯丙素苷和单萜环烯醚苷。
迄今为止尚未见从中发现具有补体抑制作用的环烯醚萜类化合物的报道。
发明内容
本发明的目的是提供新的具有抗补体活性的物质,具体涉及从轮叶马先蒿中分离得到的环烯醚萜类化合物,Euphrasin (1) 、轮叶马先蒿素A (2)和轮叶马先蒿素B (3)。
本发明的进一步目的是提供上述轮叶马先蒿中环烯醚萜类化合物在制备抗补体药物中的用途。
本发明应用现代药理筛选方法,对分离得到的单体化合物进行抗补体活性评价研究,从轮叶马先蒿(Pedicularis verticilata L.)干燥全草乙醇提取物的正丁醇萃取部位分离得到3个环烯醚萜类化合物,并证实其对补体系统经典途径有活性。
本发明的抗补体活性环烯醚萜类化合物具有下述结构通式:
其中,R1 = CH2CH3、CH3;R2 = CHO;R3 = O。
当R1 = CH3和R2 = CHO时,化合物为Euphrasin (1)。
当R1 = CH2CH3和R2 = CHO时,化合物为轮叶马先蒿 A (2),为一新结构化合物。
当R1 = CH2CH3和R3 = O时,化合物为轮叶马先蒿 B (3),为一新结构化合物。
本发明所述的环烯醚萜类化合物通过下述方法制备:
干燥的轮叶马先蒿全草,粉碎,用95%乙醇室温冷浸3次,合并提取液并浓缩至无醇味,浸膏加水稀释,依次以等体积(60~90℃)、乙酸乙脂、正丁醇萃取3次,得到石油醚、乙酸乙脂和正丁醇部位。对三个部位进行活性检测,显示乙酸乙酯部位活性最强。取乙酸乙酯部位,依次以石油醚-丙酮 (50:1,30:1,15:1,9:1,7:1,5:1,4:1,3:1,2:1,1:1)梯度洗脱,得9个流份,所得流份近反复硅胶柱色谱、Sephadex LH-20和制备色谱,分离得到3个环烯醚萜类化合物Euphrasin (1) 、轮叶马先蒿素A (2)和轮叶马先蒿素B (3)。
本发明中,
化合物1(Euphrasin):无色油状液体; 1H-NMR(CDCl3, 400MHz) 数据: δ 9.25 (1H,s, H-11), 7.15 (1H, s, H-3), 4.88 (1H, d, J = 4.3, H-1), 3.52 (3H, s, H-OMe),3.19 (1H, dd, J = 15.0, 8.9 Hz, H-5), 2.37 (1H, m, H-6), 2.22 (1H, dd, J =9.1, 4.3 Hz, H-8), 2.21 (1H, m, H-7α), 1.71 (1H, m, H-7β), 1.47(1H, m, H-6),1.25 (3H, s, H-10); 13C-NMR(CDCl3, 100MHz) 数据: δ 101.3 (C-1), 160.7 (C-3),124.4 (C-4), 29.6 (C-5), 29.0 (C-6), 40.8 (C-7), 80.0 (C-8), 51.3 (C-9), 24.8(C-10), 190.6 (C-11), 56.7 (C- OMe).
化合物2(轮叶马先蒿 A):无色油状液体;[α] 25 D = 0.126° (c 0.15 mg/ml,CHCl3);IR (KBr): 3265、2951、2919、1724、1654 cm1; 1H-NMR (CDCl3, 400MHz) 数据:δ5.22 (1H, d, J = 3.6 Hz, H-1), 7.13 (1H, d, J = 1.1 Hz, H-3), 3.19 (1H, d, J = 9.0 Hz, H-5), 1.52 (1H, dddd, J = 12.9, 10.9, 7.6, 4.2 Hz, H-6), 2.41 (1H,dd, J = 13.1, 4.7 Hz, H-6), 1.94 (1H, ddd, J = 13.4, 11.2, 4.6 Hz, H-7), 1.71(1H, dddd, J = 13.4, 9.4, 6.4, 1.0 Hz, H-7), 2.15 (1H, dd, J = 8.4, 3.6 Hz,H-9), 1.41 (3H, s, 8-CH3), 9.30 (1H, s, H-11), 3.88 (1H, dd, J = 9.5, 7.1 Hz,-CH2CH3), 3.55 (1H, dd, J = 9.5, 7.1 Hz, -CH2CH3), 1.21 (3H, t, J = 7.1 Hz, -CH2CH3) ;13C-NMR (CDCl3) 数据:δ 99.77 (C-1), 159.93 (C-3), 124.92 (C-4), 30.10(C-5), 29.90 (C-6), 40.88 (C-7), 81.25 (C-8), 50.53 (C-9), 23.71 (C-10),190.77 (C-11), 65.24 (C-1’), 14.92 (C-2’); HR-ESI-MS: m/z 227.1283[M+Na]+(caled for C15H20O4Na: 227.1259)。
化合物3(轮叶马先蒿 B):无色油状液体;[α] 25 D = -0.001°(c 0.15 mg/ml,CHCl3);IR (KBr): 3245、2911、2929、1724、1644 cm1;1H-NMR (CDCl3, 400MHz) 数据:δ5.42 (1H , s, H-1), 4.38 (1H, d, J = 16.8 Hz, H-3a), 4.05 (1H, d, J = 16.8Hz, H-3b), 3.91 (1H, dq, J = 9.7, 7.1 Hz, H-1’a), 3.62~3.77 (1H, m, H-1’ b),2.59 (1H, dddd, J = 16.8, 8.9, 3.8, 1.6 Hz, H-6a), 2.47 (1H, dddd, J = 16.8,7.9, 6.4, 0.7 Hz, H-6b), 2.15 (1H, dtd, J = 13.2, 8.5, 4.4 Hz, H-7a), 2.00(1H, ddd, J = 13.6, 8.9, 6.4 Hz, H-7b), 1.46 (3H, s, 10-CH3), 1.28 (3H, s,2’-CH3); 13C-NMR (CDCl3)数据:δ 195.11 (C-4), 160.21 (C-9), 135.51 (C-5), 92.86(C-1), 83.52 (C-8), 65.73 (C-3), 64.90 (C-1’), 40.19 (C-7), 25.78 (C-10),25.14 (C-6), 15.19 (C-2’); HR-ESI-MS: m/z 211.0970 [M+Na]+(caled forC15H20O4Na: 211.0946)。
本发明上述的环烯醚萜类化合物通过经典途径和旁路途径体外抗补体活性试验测定,结果表明上述环烯醚萜化合物对补体系统的经典途径和旁路途径均有抑制作用(如表1所示)。
表1. 化合物1-3对补体系统经典和旁路途径的抑制作用(Mean±SD,n=3)
化合物 | 化合物名称 | CH50(mg/ml) | AP50(mg/ml) |
1 | Euphrasin | 0.36±0.06 | 0.53±0.04 |
2 | 轮叶马先蒿素A | 0.27±0.04 | 0.61±0.03 |
3 | 轮叶马先蒿素B | 0.09±0.02 | 0.16±0.03 |
阳性对照 | 肝素钠 | 0.08±0.02 | 0.11±0.04 |
其中,CH50是对经典途径50%抑制溶血所需供试品的浓度;AP50是对旁路途径50%抑制溶血所需供试品的浓度。
本发明的环烯醚萜类化合物可制备抗补体药物。
本发明的环烯醚萜类化合物可进一步制备治疗与补体相关疾病的药物;所述的与补体相关疾病包括系统性红斑狼疮、类风湿性关节炎、急性呼吸窘迫综合征等疾病。
附图说明: 图1.轮叶马先蒿醇提物乙酸乙酯萃取部位环烯醚萜类化合物1-3的提取分离流程图。
具体实施方式
实施例1 制备环烯醚萜类化合物
取干燥的轮叶马先蒿全草18 kg,粉碎,用95%乙醇(60 L)室温冷浸3次,合并提取液并浓缩至无醇味得总浸膏2.2 kg,浸膏加水(3500 mL)混悬,依次以等体积石油醚(60~90℃)、乙酸乙脂和正丁醇萃取3次,得到石油醚部位(52 g)、乙酸乙脂部位(172 g)和正丁醇部位(520 g)。对三个部位进行活性检测,发现乙酸乙酯部位活性最强。取乙酸乙酯部位,依次以石油醚-丙酮 (50:1,30:1,15:1,9:1,7:1,5:1,4:1,3:1,2:1,1:1)梯度洗脱,得9个流份(Fr.1-9)。流份Fr. 9(5.2 g)经石油醚-丙酮 (6:1)反复柱层析,后经石油醚-乙酸乙酯(1:1)薄层制备,得到化合物1 (3.5 mg)。Fr. 7(9.4 g)经石油醚-丙酮 (4:1)反复柱层析,得到化合物2 (8 mg)。Fr.4(7.3 g)经石油醚-乙酸乙酯 (4:1)反复柱层析,后经SephadexLH-20 (甲醇-水= 70:30)柱层析得到化合物3 (12 mg)。
实施例2 体外抗补体经典途径试验
取补体(豚鼠血清)0.1ml,加入巴比妥缓冲液(BBS)配制成1:5的溶液,用BBS对倍稀释成1:10、1:20、1:40、1:80、1:160、1:320和1:640的溶液;取1:1000溶血素、各浓度补体及2%羊红细胞(SRBC)各0.1ml溶于0.3mlBBS中,混匀,37℃水浴30min后放入低温高速离心机,在5000rpm、4℃条件下离心10min,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(0.1m l2%SRBC溶于0.5ml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,各稀释浓度补体造成的溶血百分率为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,于37℃预水浴10min后,加入适量BBS、溶血素和2%SRBC。将每管37℃水浴30min后放入低温高速离心机,5000rpm、4℃条件下离心10min后分别取每管上清0.2ml于96孔板,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;体外抗补体经典途径试验结果如表1所示。
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5 m Mg2+,8 mMEGTA)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)0.20 ml,混匀,37℃水浴30 min后置于低温高速离心机,在5000 rpm、4℃条件下离心10 min,分别取每管上清0.2 ml于96孔板,在405nm测定吸光度,实验同时设置全溶血组(0.20 ml 0.5%RE溶于0.3 ml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,各稀释浓度补体造成的溶血百分率为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,于37℃预水浴10min后,加入0.,2 ml 0.5%RE,将每管37℃水浴30 min后置于低温高速离心机,5000 rpm、4℃条件下离心10 min后,分别取每管上清0.2 ml于96孔板,405 nm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);体外抗补体旁路途径试验结果如表1所示。
表1显示了本发明的化合物1-3对补体系统经典途径和旁路途径的抑制作用
(Mean士SD,n=3)。
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.具有下述结构通式的环烯醚萜类化合物在制备抗补体药物中的用途,
其中,R1 = CH2CH3、CH3;R2 = CHO;R3 = O。
2.按权利要求1所述的用途,其特征在于,当R1 = CH3和R2 = CHO时,化合物为Euphrasin(1)。
3.按权利要求1所述的用途,其特征在于,当R1 = CH2CH3和R2 = CHO时,化合物为Pediverticilatasin A (2),为一新结构化合物。
4.按权利要求1所述的用途,其特征在于,当R1 = CH2CH3和R3 = O时,化合物为Pediverticilatasin B (3),为一新结构化合物。
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