CN103664568B - 环草石斛二聚芪类化合物及其制备方法和应用 - Google Patents
环草石斛二聚芪类化合物及其制备方法和应用 Download PDFInfo
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- CN103664568B CN103664568B CN201310692091.5A CN201310692091A CN103664568B CN 103664568 B CN103664568 B CN 103664568B CN 201310692091 A CN201310692091 A CN 201310692091A CN 103664568 B CN103664568 B CN 103664568B
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及环草石斛二聚芪类化合物及其制备方法和在制备降血糖药物中的应用。所述二聚芪类化合物为Loddigesiinols G~K,经如下步骤制得:(1)环草石斛经甲醇提取后的提取液减压浓缩,得到提取物;(2)将提取物用石油醚、乙酸乙酯、正丁醇依次萃取;(3)将乙酸乙酯萃取物经多次Sephadex LH-20凝胶柱层析技术纯化,再经HPLC技术分离,得到五种活性二聚芪类化合物。经实验表明,本发明的环草石斛二聚芪类化合物可用作降血糖药物、降血糖保健品、防治心血管疾病的药物及防治心血管疾病的保健品。
Description
技术领域
本发明属于药物领域,具体涉及环草石斛二聚芪类化合物及其制备方法和应用,尤其是环草石斛二聚芪类化合物及其制备方法和在制备降血糖药物中的应用。
背景技术
糖尿病(diabetes mellitus)是由遗传和环境因素相互作用而引起的一组以慢性高血糖为共同特征的代谢性疾病群,其主要特点是血糖过高、糖尿、多尿、多饮、多食、消瘦、疲乏等。糖尿病与高血压、高血脂一同称为“三高”,是最常见的慢性病之一。糖尿病人体内胰岛素相对或绝对不足,或靶细胞对胰岛素敏感性降低,或胰岛素本身存在结构上的缺陷等而引起碳水化合物、脂肪和蛋白质代谢紊乱,使一些组织或器官发生形态结构改变和功能障碍。糖尿病患者生活质量下降,寿命缩短,还可能发生遍及全身的并发症,严重的糖尿病患者会引发心血管病变、神经病变,肾功能衰竭、肢体坏疽、失明等,致死致残。
随着人们生活水平的提高,人口老龄化以及肥胖发生率的增加,糖尿病的发病率逐年上升,且有呈年轻化的趋势。糖尿病已成为全世界许多国家的常见病和多发病,其死亡率已居肿瘤、心血管疾病之后的第三位,根据WHO预测全球有糖尿病人3.47亿。中国糖尿病发病率6.7%,已高过世界平均水平6.4%,据2011年我国最新一轮糖尿病患者统计报告显示,中国糖尿病患者已达9200万,糖尿病前期患者人数更多达1.48亿,已超过印度成为世界上糖尿病患者人数最多的国家。糖尿病已经成为直接影响中国乃至全世界人类身体健康及寿命长短的一大危害因素。
糖尿病分为四型。II型糖尿病也叫成人发病型糖尿病,占糖尿病患者90%以上。II型糖尿病病人体内或因胰岛素分泌不足,或因靶细胞对胰岛素的作用不敏感,表现为胰岛素相对缺乏,致使糖代谢紊乱。α-葡萄糖苷酶抑制剂通过竞争性抑α-葡萄糖苷酶活性,阻滞双糖水解成单糖,延缓糖的吸收,降低餐后血糖,使血糖平稳且缓慢地维持在一定水平,达到预防、治疗II型糖尿病的效果,是减少糖尿病并发症和降低死亡率的重要措施之一。目前用于临床的抑制a-葡萄糖苷酶药物有阿卡波糖,伏格列波糖,米格列醇等。α-葡萄糖苷酶抑制剂能降低餐后血糖,但不抑制蛋白质和脂肪的吸收,不会造成营养物质的吸收障碍,还可减少脂肪组织的重量和体积,降低甘油三脂水平,有防止动脉粥样硬化防治心血管疾病的疗效。因此α-葡萄糖苷酶抑制剂的研究开发具有广阔的应用前景。
中药治疗糖尿病在我国具有几千年的悠久历史,有较西医毒性较小的优点,因此,从中药中分离提取有效单体,正成为抗糖尿病药物研发的一个重要方向。
兰科石斛属Dendrobium SW.植物全世界约有1100种,我国境内有76种,其中有近40种被作为药用,药用历史悠久。石斛在中医临床上常用于治疗热病津伤,口干烦渴,胃阴不足,食少干呕,病后虚热不退,阴虚火旺,骨蒸劳热,目暗不明,筋骨痿软等症。有报道石斛与多味中药共煎煮,对降低II型糖尿病患者的血糖、血脂、减轻胰岛素抵抗有确切的疗效。但是关于石斛的化学成分研究较少。迄今为止尚未有关于石斛抗糖尿病确切活性物质的报道。
环草石斛也叫小环钗石斛、美花石斛、粉花石斛,主要分布于贵州、广西、云南和广东等省,自2000年起被中国药典收载,是中医临床上广泛应用的石斛药材的代表,但是环草石斛药效物质基础不明确,由于中药起效成分多样,现有技术研究没有明确环草石斛提取物的降血糖有效成分,未能充分发挥环草石斛的良好应用。
发明内容
本发明的目的在于克服现有环草石斛植物资源利用技术的不足,提供五种新的环草石斛二聚芪类化合物。
本发明的另一个目的是提供所述环草石斛二聚芪类化合物的制备方法。
本发明还有一个目的是提供所述环草石斛二聚芪类化合物的应用。
本发明的上述目的通过如下技术方案予以实现:
环草石斛二聚芪类化合物,所述二聚芪类化合物为Loddigesiinols G~J,分别具有如下结构:
所述环草石斛二聚芪类化合物Loddigesiinols G~J分别对应化合物1~4。
所述环草石斛二聚芪类化合物Loddigesiinols G~J的制备方法包括以下步骤:
S1.环草石斛用甲醇冷浸,减压浓缩得提取液浸膏;
S2.将浸膏悬浮于水中,依次用石油醚、乙酸乙酯、正丁醇萃取;
S3.将乙酸乙酯萃取物经Sephadex LH-20凝胶柱层析分离,收集红色馏分;
S4.合并浓缩红色馏分,浓缩物经高效液相色谱及Sephadex LH-20凝胶柱层析分离纯化,得到五种化合物产品。
所述减压浓缩所采用的水浴温度为50~60℃,目的是防止活性成分破坏。
步骤S3或S4所述Sephadex LH-20凝胶柱层析分离采用的洗脱剂为甲醇。
所述高效液相色谱采用的洗脱剂为水-甲醇混合溶剂,所述混合溶剂中甲醇与水的体积比为1:0.8~1.2。
上述制备方法的步骤均采用本领域常规操作进行。
作为一种优选方案,步骤S1所述冷浸时环草石斛与甲醇的质量体积比为4kg:30~50L,冷浸2~4次,每次冷浸的时间为60~90h,目的在于将环草石斛中的有效成分充分提取出来。
步骤S2中将浸膏悬浮于水的目的是充分分散浸膏,便于后续萃取步骤的进行,作为一种优选方案,所述水的用量为每100g浸膏加水2~4L。
步骤S2采用石油醚、乙酸乙酯或正丁醇萃取的目的是通过不同极性的萃取液,将本发明目的化合物分离提取出来,作为一种优选方案,所述石油醚、乙酸乙酯或正丁醇的用量与水的用量相同。
本发明同时提供环草石斛二聚芪类化合物在制备治疗或预防糖尿病药物或保健品中的应用。
本发明公开的5个二聚芪类化合物均为植物多酚类化合物,分子结构中有多个酚羟基存在,具有很好的抗氧化活性,对氧化应激损伤引发的心血管疾病也有预防和治疗作用。因此,本发明也提供环草石斛二聚芪类化合物在制备或预防心血管疾病药物或保健品中的应用。
本发明所述药物或保健品可添加赋形剂,采用本领域的常规方法制备成各种剂型,如片剂、丸剂、胶囊剂、颗粒剂、粉剂或口服液等。
与现有技术相比,本发明具有如下有益效果:
虽然已有文献公开了环草石斛具有一定的降低血糖、血脂、减轻胰岛素的作用,但是由于中药的疗效为多途径和多靶点的特性,因此对有效部位的研究更能体现中药的特色,具有更为重要和迫切的意义。本发明通过提取和纯化方法工艺的优化,成功获得了环草石斛提取物的乙酸乙酯部分,分离得到5种活性化合物,这5种化合物均为首次从自然界中分离得到,并首次报道了环草石斛抑制α-葡萄糖苷酶活性物质的结构。
具体实施方式
下面结合具体实施例对本发明作进一步的解释说明,但具体实施例并不对本发明作任何限定。除非特别说明,实施例中所涉及的试剂、方法均为本领域常用的试剂和方法。
实施例1环草石斛二聚芪类化合物Loddigesiinols G~J(新化合物1~4)的制备
将环草石斛(茎)4kg,甲醇冷浸2次(每次冷浸甲醇用量35L,每次冷浸72h),提取液在55℃下减压浓缩,得浸膏110g。
取浸膏110g悬浮于3L水中,依次用石油醚、乙酸乙酯及正丁醇各3L萃取2次,减压浓缩萃取液,选择乙酸乙酯萃取液在55℃下减压浓缩得浸膏35g。
乙酸乙酯萃取浸膏经Sephadex LH-20凝胶柱层析,甲醇洗脱,收集红色馏分。合并浓缩红色馏分。红色馏分浓缩物经高效液相色谱技术分离,色谱柱采用Ultimate XB-C18柱(250×10mm,5μ;Welch),流动相采用甲醇:水=50:50,流速为3mL/min(室温),紫外(254nm)检测,分别在保留时间为11分,13.5分,15分,17分时,取出显示最高点的分离液4~6ml,分别浓缩,再经SephadexLH-20凝胶柱层析分离纯化,甲醇洗脱,分别得到二聚芪类化合物5(8mg),化合物2(7mg),化合物4(2mg),化合物3(5mg)。这4个化合物经波谱技术结构鉴定,均为文献没有记载的化合物。
实施例2新化合物1~4的理化参数及化合物分子结构确定
化合物(1)~(4)的性状、分子质量等理化参数见表1,化合物(1)~(2)的1HNMR及13CNMR的数据见表2,化合物(3)~(4)的1H NMR及13C NMR的数据见表3。
表1化合物的性状、分子质量、IR、UV数据
表2 loddigesiinols G(1)(500 MHz,C2D6CO)、loddigesiinols H(2).(600MHz,C2D6CO)核磁数据
表3 loddigesiinols I(3)、loddigesiinols J(4)核磁数据(600 MHz,C2D6CO)
通过上述核磁、红外、紫外测试结果可以确定5种新化合物的结构式如下:
实施例3环草石斛二聚芪类化合物Loddigesiinols G~J的α-葡萄糖苷酶抑制活性测定
α-葡萄糖苷酶抑制活性测定参考Lin Ma等的方法(Zhi-yun Du,Lin Ma et al.α-Glucosidase inhibition of natural curcuminoids and curcumin analogs.EuropeanJournal of Medicinal Chemistry.2006,41:213–218.):以对硝基苯酚-α-葡萄糖苷(PNPG)为底物,在λ=400nm处测量在不同浓度的二聚芪类化合物存下吸光度A随时间的变化来计算抑酶的相对活性。再用二聚芪类化合物浓度对抑酶的相对活性作图,得到上述4个二聚芪类化合物对α-葡萄糖苷酶的半抑制浓度IC50值。
所用仪器:岛津uv-2501紫外可见分光光度计。
所用试剂:
1、缓冲溶液:KH2PO4及K2HPO4为分析纯试剂,配制成KH2PO4-K2HPO4缓冲溶液(50mM,PH=7)。
2、底物:对硝基苯酚-α-葡萄糖苷(PNPG),购自Sigma公司,使用时用KH2PO4-K2HPO4缓冲溶液(PH=7)配制成浓度为1mM的溶液。
3、酶:α-葡萄糖苷酶,购自Sigma公司,使用时用KH2PO4-K2HPO4缓冲溶液(PH=7)稀释至所需的浓度。
4、阳性对照物:白藜芦醇,用二甲基亚砜配制成10μmol/mL溶液,使用时按需要稀释后加入不同的量。
5、化合物1~4原液:用二甲基亚砜配制成10μmol/mL溶液,使用时按需要稀释加入不同的量。
6、二甲基亚砜为本领域直接商业购买的分析纯试剂。
绘图使用软件为:origin 7.0,后续活性检测中的IC50值结果使用绘图法做出。
(一)测试方法:
空白对照:取20μL二甲基亚砜,加入10μL酶溶液,950μL KH2PO4-K2HPO4缓冲溶液混合,振摇均匀,在37℃水浴中保温20min,加入20μL底物,振摇匀后立即倒入比色池中,在λ=400nm处测1min吸光度(OD)变化。平行测试3次,取平均值。
化合物1~4抑制α--葡萄糖苷酶活性测试:每一化合物取5分不同体积的样品溶液,使构成终浓度在合适范围的反应体系(通过稀释原液,或加入不同体积等方法),用二甲基亚砜补足反应体系中二甲基亚砜的总量为20μL,加入10μL酶溶液,950μL KH2PO4-K2HPO4缓冲溶液混合,振摇均匀,在37℃水浴中保温20min,加入20μL底物,振摇匀后立即倒入比色池中,在λ=400nm处测1min吸光度变化。
阳性对照测试:取5分不同体积的阳性对照溶液,使构成终浓度在合适范围的反应体系(通过稀释原液,或加入不同体积等方法),用二甲基亚砜补足反应体系中二甲基亚砜的总量为20μL,加入10μL酶溶液,950μL KH2PO4-K2HPO4缓冲溶液混合,振摇均匀,在37℃水浴中保温20min,加入20μL底物,振摇匀后立即倒入比色池中,在λ=400nm处测1min吸光度变化。
(二)抑酶相对活性计算:
抑制百分数(%)=(A0-A)/A0*100%。
A0:无抑制剂体系酶催化活性(单位:OD/min)。
A:含抑制剂体系酶催化活性(单位:OD/min)。
(三)测试结果
二聚芪类化合物α-葡萄糖苷酶抑制活性测试结果见表4。
表4二聚芪类化合物α-葡萄糖苷酶抑制活性
样品号 | 1 | 2 | 3 | 4 | 白藜芦醇 |
IC50(μM) | 10.9 | 16.7 | 2.7 | 3.2 | 27.9 |
有多位国外学者研究证实,白藜芦醇体外抑制α-葡萄糖苷酶的活性很强,IC50(mΜ)比临床降糖药阿卡波糖要小10倍左右(1、ZOHAR KEREM,ITZHAKBILKIS,MOSHE A.et al.Antioxidant Activity and Inhibition ofα-Glucosidase bytrans-Resveratrol,Piceid,and a Novel trans-Stilbene from the Roots of Israeli Rumexbucephalophorus L.J.Agric.Food Chem.2006,54:1243-1247;2、Chun Whan Choi,Yeon Hee Choi.et al.α-Glucosidase Inhibitiors from Seed Extract of Paeonialactiflora.J.Korean Soc.Appl.Biol.Chem.2009,52:638-642.)。
从表4的实验结果可以看出,在4个来自环草石斛的二聚芪类化合物中,化合物3,4抑制α-葡萄糖苷酶要比白藜芦醇强很多,化合物1比白藜芦醇强,化合物2比白藜芦醇较好。因此本发明分离得到的4种二聚芪类化合物具有较强的α-葡萄糖苷酶抑制活性,在制备治疗糖尿病的药物或保健食品领域,有广泛的应用前景。
Claims (10)
1.环草石斛二聚芪类化合物,其特征在于,所述二聚芪类化合物为LoddigesiinolsG~J,分别具有如下结构:
2.权利要求1所述Loddigesiinols G~J的制备方法,其特征在于,包括以下步骤:
S1.环草石斛用甲醇冷浸,减压浓缩得提取液浸膏;
S2.将浸膏悬浮于水中,依次用石油醚、乙酸乙酯、正丁醇萃取;
S3.将乙酸乙酯萃取物经Sephadex LH-20凝胶柱层析分离,收集红色馏分;
S4.合并浓缩红色馏分,浓缩物经高效液相色谱及Sephadex LH-20凝胶柱层析分离纯化,得到五种化合物产品。
3.根据权利要求2所述制备方法,其特征在于,步骤S3或S4所述Sephadex LH-20凝胶柱层析分离采用的洗脱剂为甲醇。
4.根据权利要求2所述制备方法,其特征在于,所述高效液相色谱采用的洗脱剂为水-甲醇混合溶剂,所述混合溶剂中甲醇与水的体积比为1:0.8~1.2。
5.根据权利要求2所述制备方法,其特征在于,所述减压浓缩所采用的水浴温度为50~60℃。
6.根据权利要求2所述制备方法,其特征在于,步骤S1所述冷浸时环草石斛与甲醇的质量体积比为4kg:30~50L,冷浸2~4次,每次冷浸的时间为60~90h。
7.根据权利要求2所述制备方法,其特征在于,步骤S2中所述水的用量为每100g浸膏加水2~4L。
8.根据权利要求2所述制备方法,其特征在于,步骤S2所述石油醚、乙酸乙酯或正丁醇的用量与水的用量相同。
9.权利要求1所述环草石斛二聚芪类化合物在制备治疗或预防糖尿病药物或保健品中的应用。
10.权利要求1所述环草石斛二聚芪类化合物在制备治疗或预防心血管疾病药物或保健品中的应用。
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FLAVAN-3-OLS AND DIHYDROPHENANTHROPYRANS FROM PLEIONE BULBOCODIOIDES;LI BAI et al.,;《Phytochemistry》;19981231;第47卷(第6期);第1126页Scheme 1 * |
Phochinenins A-F, Dimeric 9,10-Dihydrophenanthrene Derivatives, from Pholidota chinensis;Sheng Yao et al.,;《Helvetica Chimica Acta》;20081231;第91卷;第2123页结构式 * |
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