CN101074259B - 一种新皂苷化合物及其制备方法和用途 - Google Patents
一种新皂苷化合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种新皂苷化合物及其制备方法和用途,属于天然药物化学领域,其特征是通过水或有剂溶剂的化学方法,从灰毡毛忍冬花蕾中提取分离、纯化,得到了一种常藤皂苷类新化合物的化学结构,被命名为灰毡毛忍冬皂苷丙。该化合物通过体外抑制PLA2的试验以及对小鼠耳廊二甲苯炎症试验,对角叉菜胶制备大鼠气囊滑膜炎炎症模的影响试验,证明灰毡毛忍冬皂苷丙在医药领域中具有PLA2抑制剂和抗炎药物的新用途。
Description
技术领域:
本发明涉及天然药物领域,具体涉及从中药灰毡毛忍冬中提取分离得到的一种新皂苷,其制备方法,以及该新皂苷抑制磷脂酶A2(PLA2)活性和在制备抗炎药物中的用途。
技术背景:
灰毡毛忍冬(Lonicera macranthoides Hand.-Mazz.)为忍冬科Caprifoliaceae忍冬属植物,具有清热解毒、抗菌消炎的功效,在中医临床及民间广泛应用于痈肿疔疮,喉痹,丹毒,热毒血痢,风热感冒,温热发病等疾病的治疗。2005年新版中国药典收载,将其与红腺忍冬、华南忍冬一同列入山银花项下。忍冬属植物中富含皂苷类成分,其苷元主要为齐墩果酸和常春藤苷元,这些皂苷报道有抑制磷脂酶A2(PLA2)活性,抗炎Inoue,H.et al.J Pharm pharmacol,1988,40:272,抗真菌Favel,A.et al.Planta Medica,1994,60:50等作用。江苏省中国科学院植物研究所在灰毡毛忍冬花及花蕾中,分离得到一个新皂苷化合物,明确了该化合物的结构,药理活性和用途。
磷脂酶A2(PLA2)存在于各种生物体中.其生理功能是专一性水解磷脂sn-2脂键,使之分解为脂肪酸和溶血磷脂。若脂肪酸为花生四烯酸arachidonic acid,则被环氧合酶cyclooxygenase和5-脂氧合酶lipoxygenase分别分解为前列腺素prostaglandins和白三烯leukotrienes,前列腺素是炎症的前体,而白三烯在引发哮喘的发病机理中起着重要的作用;溶血磷脂代谢成的血小板活化因子platelet-activating factor也是导致炎症的重要介质。PLA2处于炎症调节因子生物合成的关键位置.如果能够有效地抑制PLA2的活性,与炎症过程密切相关的三个调节因子的生物合成都将被抑制。高效专一的PLA2抑制剂有可能发展成为新型的非甾体抗炎药。
发明内容:
本发明的目的之一是提供一种新皂苷化合物--灰毡毛忍冬皂苷丙及其制备方法以及该新化合物在制备PLA2抑制剂和抗炎药物的新用途。按照本发明的新化合物制备成药物,用于制备PLA2抑制剂和炎症等相关疾病的治疗。
本发明的化合物为自中提取、分离、纯化得到的这种新皂苷化合物,命名为灰毡毛忍冬皂苷丙。
灰毡毛忍冬皂苷丙,化学名称为:3-O-β-D-吡喃葡萄糖基-(1-3)-α-L-吡喃鼠李糖基(1-2)-α-L-吡喃阿拉伯糖基-23-乙酰基-常春藤皂甙元-28-O-β-D-吡喃葡萄糖基(1-6)-β-D-吡喃葡萄糖苷。
化学结构式为:
上述灰毡毛忍冬皂苷化合物的制备方法,其特征在于:以灰毡毛忍冬干燥花蕾为原料,经水或有机溶剂或混合溶剂提取,水提取液直接过大孔树脂吸附,有机溶剂或混合溶剂提取液浓缩后加水溶解再经大孔树脂吸附或正丁醇萃取,大孔树脂吸附物或正丁醇萃取物经柱层析分离而得。其中,大孔树脂包括D101、AB-5、或HP-20;柱层析用单体选自硅胶、氧化铝、凝胶Sephadex LH-20、聚酰胺和填充料ODS中的一种或几种;有机溶剂包括甲醇、乙醇、氯仿或正丁醇;提取温度低于100℃。
本发明提供了灰毡毛忍冬皂苷丙与医学上可接受的药用辅料组成药物组合物及其制剂。如,片剂、丸剂、膏剂、胶囊剂、口服液、颗粒剂以及注射液粉针剂或水针液。
本发明提供了灰毡毛忍冬皂苷化合物制备PLA2抑制剂和抗炎药物的应用。在体外,灰毡毛忍冬皂苷丙的IC50值与吲哚PLA2抑制剂的IC50相近,体内实验表明灰毡毛忍冬皂苷丙20mg·kg-1和40mg·kg-1两剂量组可通过对PLA2活性的显著抑制作用,从而减少炎症介质PGE的含量,提示灰毡毛忍冬皂苷丙有类似于PLA2抑制剂的作用;此外,40mg·kg-1和80mg·kg-1两剂量组对二甲苯所致小鼠耳肿胀有明显的抑制作用。
本发明公开了从灰毡毛忍冬中提取分离的一种常春藤皂苷类新化合物的化学结构,以及该化合物制备方法及在医药领域中的用途,尤其在制备磷脂酶A2(PLA2)抑制剂和抗炎药物的用途。试验证明,在体外,灰毡毛忍冬皂苷丙的IC50值与吲哚PLA2抑制剂的IC50相近,体内实验表明灰毡毛忍冬皂苷丙20mg·kg-1和40mg·kg-1两剂量组可通过对PLA2活性的显著抑制作用,从而减少炎症介质PGE的含量,提示灰毡毛忍冬皂苷丙有类似于PLA2抑制剂的作用;此外,40mg·kg-1和80mg·kg-1两剂量组对二甲苯所致小鼠耳肿胀有明显的抑制作用,说明灰毡毛忍冬皂苷丙可用于PLA2抑制剂和抗炎药物的开发。
四、附图说明:
图1为新化合物的ESI(+)-MS谱图。
图2为新化合物的ESI(-)-MS谱图。
图3为新化合物的1H-NMR谱图。
图4为新化合物的13C-NMR谱图。
图5为新化合物的COSY谱图。
图6为新化合物的HMQC谱图。
图7为新化合物的HMBC谱图。
图8为新化合物的ROESY谱图。
图9为新化合物的提取分离流程图。
五、具体实施方式:
结合具体实施方式对本发明作进一步说明,但本发明的内容并不仅仅限于所列举的实施方式。本发明从灰毡毛忍冬干燥花蕾中提取、分离、纯化得到的这种皂苷类新化合物,命名为灰毡毛忍冬皂苷丙。
1.提取分离
本发明者将灰毡毛忍冬干燥花蕾在本所中试工厂用90%乙醇回流提取浓缩得浸膏,取浸膏依次用石油醚、乙酸乙酯萃取。得石油醚部、乙酸乙酯部和正丁醇部。
正丁醇部用大孔树脂进行吸附,再以水-乙醇系统分段洗脱,合并含有皂苷的组分,得灰毡毛忍冬总皂苷。所得灰毡毛忍冬总皂苷进行硅胶柱层析,流动相依次为氯仿-甲醇(10∶1、4∶1、1∶1)、甲醇。其中氯仿-甲醇(2∶1)部分经反复反相柱分离及凝胶柱纯化得到单体化合物灰毡毛忍冬皂苷丙。
2.结构鉴定
白色粉末(甲醇-水),[α]D25.9=-3.7°,mp224~227℃,TLC香草醛-浓硫酸试液加热显紫红色,放置后变蓝。Molish反应和Liebermann-Burchard反应阳性。难溶于氯仿、水,微溶于甲醇,易溶于水-甲醇混合溶液。以上信息提示该化合物为皂苷类化合物。ESI(+)-MS显示分子离子峰为1301[M+Na]+,ESI(-)-MS显示分子离子峰为1277[M-H]+结合氢谱和碳谱推测,分子式C61H98O28,分子量1278。1H-NMR(C5D5N,500MHz)δ:0.84,0.85,0.90,1.06,1.06,1.23(3H,s,×6CH3),1.56(3H,d,J=6.1Hz,Rha-Me)。分别为常春藤皂苷母核上的6个甲基的信号和鼠李糖上甲基的信号。13C-NMR(C5D5N,500MHz)δ:176.5(C-28),82.3(C-3),及95-107之间有五个糖端基碳,显示化合物在C-28与C-3位上共有五个糖取代。1H-NMRδ:2.0(3H s)以及13C-NMR δ:170.6,20.8说明该皂苷结构存在乙酰基。比较该化合物和灰毡毛忍冬皂苷甲的碳谱数据,发现该皂苷的C-23,-4,-3,-5和-24δ值分别+2.0,-1.1,+1.0,+1.0和-0.7ppm,说明乙酰基接在C-23位。HMBC谱中H-23和C(COCH3)相关信号进一步证明乙酰基接在C-23位。该皂苷的酸水解实验给出吡喃葡萄糖、吡喃鼠李糖和吡喃阿拉伯糖。他们的连接位置和顺序通过HMBC和ROESY谱确定见图-1。综合各数据及与文献对比[2]鉴定化合物为3-O-β-D-吡喃葡萄糖基-(1-3)-α-L-吡喃鼠李糖基(1-2)-α-L-吡喃阿拉伯糖基-23-乙酰基-常春藤皂甙元-28-O-β-D-吡喃葡萄糖基(1-6)-β-D-吡喃葡萄糖苷。
表1新皂苷的核磁共振数据(δ,ppm,0=TMS,C5D5N)
本发明的新化合物作为药物活性成分可以制成常规的药用剂型,如,片剂、丸剂、膏剂、胶囊剂、口服液、颗粒剂以及注射液粉针剂或水针液。
3.体外抑制PLA2作用
以SIBLINKS类似物为底物,以naja najaPLA2眼镜蛇蛇毒中提取的PLA2作为水解酶,吲哚PLA2抑制剂5-甲氧基-1-苄基-1H-吲哚-3-乙酰胺为对照,通过酶标仪比色系统测定水解的最大反应速率,进行抑制活性的定性定量比较,结果见表2。
表2 对Naja Naja PLA2抑制作用和SCORE的预测值
从表2的结果表明,灰毡毛忍冬皂苷丙的IC50值与吲哚PLA2抑制剂的IC50相近,实验测定值与SCORE预测值呈对应关系,提示灰毡毛忍冬皂苷丙有类似于PLA2抑制剂的作用。
4.抗炎作用
(1)对小鼠耳廓二甲苯炎症的影响
对雄性小鼠60只随机分5组,①对照组②灰毡毛忍冬皂苷丙I(20mg·kg-1)、II(40mg·kg-1)、III(80mg·kg-1)三个剂量组③吲哚美辛组(8mg·kg-1),各组灌胃给药或给予等量的生理盐水,每天1次,连续3d,末次给药后30min,每鼠右耳廓内外侧滴涂20μl二甲苯致炎,左耳作为对照,致炎后30min脱颈椎处死小鼠,用直径7mm打孔器分别于左、右耳相同部位打下耳片,称重,以左、右耳片重量差值表示肿胀度,结果见表3。
表3 灰毡毛忍冬皂苷丙对二甲苯所致小鼠耳廓炎症耳肿胀度的影响(X±S,n=15)
与模型组比较*P<0.05,**P<0.01
实验结果表明,灰毡毛忍冬皂苷丙40mg·kg-1和80mg·kg-1两剂量组对二甲苯所致小鼠耳肿胀有明显的抑制作用,提示灰毡毛忍冬皂苷丙有一定抗炎作用。
(2)对角叉菜胶制备大鼠气囊滑膜炎炎症模型的影响
取健康SD雄性大白鼠,随机分为6组:①正常组;②模型组;③灰毡毛忍冬皂苷丙I(10mg·kg-1)、II(20mg·kg-1)、III(40mg·kg-1)三个剂量;④地塞米松组(0.15mg·kg-1)。各组动物乙醚轻度麻醉,背部正中s.c无菌空气20ml,3d补充注射空气10ml维持气囊肿胀,6d气囊内注射角叉菜胶50mr·kg-1致炎,正常对照组同法注射生理盐水等容积。各组动物于第3d开始灌胃给药①②组给予等容积生理盐水,6d致炎前30min再给药给药一次。致炎6h后动物i.p戊巴比妥钠25mg·kg-1麻醉,气囊内注射无菌无钙镁Hank′s平衡盐液(HBSS)4ml灌洗,收集灌洗液,进行灌洗液中白细胞数和蛋白质含量的测定;采用微量酸滴定法测定PLA2活性;采用放免法测定PGE的含量,结果见表4。
表4 灰毡毛忍冬皂苷丙对大鼠气囊滑膜炎灌洗液中白细胞数、
蛋白质和PGE含量及PLA2活性的影响(X±S,n=8)
组别 | 剂量(mg·kg<sup>1</sup>) | 白细胞数(×10<sup>6</sup>·L<sup>-1</sup>) | 蛋白质含量(g·L<sup>-1</sup>) | PLA<sub>2</sub>活性(μmolHCL·L<sup>-1</sup>·S<sup>-1</sup>) | PGE含量(μg·ml<sup>-1</sup>) |
正常组 | - | 0.23±0.09<sup>**</sup> | 7.44±2.62<sup>**</sup> | 1.15±0.34<sup>**</sup> | 2.31±0.86<sup>**</sup> |
模型组 | - | 0.46±0.19 | 20.60±7.53 | 7.15±2.76 | 9.49±2.88 |
地塞米松组 | 0.15 | 0.24±0.08<sup>**</sup> | 14.25±4.09<sup>*</sup> | 3.20±1.23<sup>**</sup> | 4.15±1.58<sup>**</sup> |
灰毡毛忍冬丙I组 | 10 | 0.41±0.08 | 20.13±5.49 | 6.88±1.79 | 7.37±1.92 |
灰毡毛忍冬丙II组 | 20 | 0.31±0.10<sup>*</sup> | 19.61±4.15 | 4.38±1.78<sup>*</sup> | 6.44±2.02<sup>*</sup> |
灰毡毛忍冬丙III组 | 40 | 0.24±0.08<sup>*</sup> | 14.40±5.33<sup>*</sup> | 3.91±1.05<sup>**</sup> | 5.16±1.98<sup>**</sup> |
与模型组比较*P<0.05,**P<0.01
在小鼠耳廓炎症实验的基础上,又进行了大鼠气囊滑膜炎症试验,结果与上次实验基本一致,灰毡毛忍冬皂苷丙可减少灌流液中白细胞的渗出和蛋白质的含量;与此同时,灰毡毛忍冬皂苷丙20mg·kg-1和40mg·kg-1两剂量组可通过对PLA2活性的显著抑制作用,从而减少炎症介质PGE的含量,此实验结果与其体外抑制PLA2作用一致,说明灰毡毛忍冬皂苷丙可用于PLA2抑制剂和抗眼药物的开发。
结合具体实施方式对本发明作进一步说明,但本发明的内容并不仅仅限于所列举的实施方式。
实施例1
灰毡毛忍冬干燥花蕾40Kg,用90%乙醇回流提取三次,用量200升,每次3天,浓缩合并成无醇味的浓缩液,得总浸膏。再依次用石油醚、乙酸乙酯、正丁醇萃取。正丁醇萃取物经柱层析分离后分别得到灰毡毛忍冬皂苷丙4克。(见附图9)
实施例2
灰毡毛忍冬干燥花蕾10Kg,用水加热提取三次,水用量为20升,提取时间为1小时,提取温度为70℃,提取液经大孔树脂(D101、AB-5、HP-20等)吸附,用水,30%乙醇冲洗后用70%乙醇洗脱,70%乙醇洗脱液减压回收溶剂得皂苷混合物。混合物再经柱层析(硅胶柱层析:氯仿-甲醇系统,RP-C18柱层析;水-甲醇系统)分离后,分别得到灰毡毛忍冬皂苷丙0.8克。
实施例3
灰毡毛忍冬干燥花蕾10Kg,用甲醇冷浸提取三次,甲醇用量为20升,提取时间为1天,提取液经大孔树脂(D101、AB-5、HP-20等)吸附。用水,30%乙醇冲洗后用70%乙醇洗脱,70%乙醇洗脱液减压回收溶剂得皂苷混合物。混合物再经柱层析(硅胶柱层析:氯仿-甲醇系统,RP-C18柱层析:水-甲醇系统)分离后,分别得到灰毡毛忍冬皂苷丙0.9克。
实施例4含本发明新皂苷单体的片剂
取实施例1制得的新皂苷化合物100mg与淀粉50mg,糊精50mg混合,用适量30%乙醇做湿润剂,制成软材,常规方法制粒,加入适量硬脂酸镁混合,制成片剂。
实施例5含本发明新皂苷的胶囊剂
取新皂苷化合物50mg与淀粉70mg,糊精10mg,糖粉10mg混合,用适量30%乙醇做湿润剂,制成软材,常规方法制粒,装入硬胶囊中。
实施例6含本发明新皂苷的缓释胶囊剂
取新皂苷化合物80mg与羟丙基甲基纤维素K15M 120mg,乙基纤维素45cps 40mg,乳糖40mg混合,用10%乙烯吡咯烷酮k30乙醇溶液适量,制成软材,常规方法制粒,装入硬胶囊中制成缓释胶囊。
Claims (6)
2.根据权利要求1所述的化合物的制备方法,其特征在于以灰毡毛忍冬花蕾为原料,经水,甲醇或乙醇提取;水提取液直接过大孔树脂吸附,甲醇或乙醇提取液浓缩后加水溶解再经大孔树脂吸附或正丁醇萃取,大孔树脂吸附物或正丁醇萃取物经柱层析分离而得。
3.根据权利要求2所述的制备方法,其特征在于大孔树脂型号是D101、AB-5或HP-20;柱层析用担体选自硅胶、ODS或凝胶Sephadex LH-20的一种或一种以上。
4.权利要求1所述的化合物与医学上可接受的药用辅料组成的药物制剂。
5.权利要求4所述的药物制剂,其特征在于所述的制剂剂型是片剂、胶囊剂、颗粒剂、口服液和注射剂。
6.权利要求1所述的化合物在制备磷脂酶A2抑制剂或抗炎药物的用途。
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CN102391349B (zh) * | 2011-09-23 | 2014-07-02 | 江苏省中国科学院植物研究所 | 一种忍冬硫酸酯皂苷及其制备方法和用途 |
CN102424699B (zh) * | 2011-09-23 | 2016-02-17 | 江苏省中国科学院植物研究所 | 一种新灰毡毛忍冬皂苷及其制备方法和用途 |
CN102408466B (zh) * | 2011-12-22 | 2014-05-14 | 江苏省中国科学院植物研究所 | 一种新盐角草皂苷及其制备方法和用途 |
CN102603856B (zh) * | 2011-12-31 | 2015-03-25 | 沈阳药科大学 | 银莲花属植物中一种抗肿瘤皂苷及其制备方法和用途 |
CN102659905B (zh) * | 2012-05-21 | 2014-07-30 | 广州博济医药生物技术股份有限公司 | 一种常春藤皂苷元衍生物及其制备方法和应用 |
CN102727556A (zh) * | 2012-07-16 | 2012-10-17 | 西南大学 | 一种清利咽喉的中药复方口含片及制备方法 |
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