CN108530500B - 一种合欢皮木脂素苷单体的制备方法及其应用 - Google Patents
一种合欢皮木脂素苷单体的制备方法及其应用 Download PDFInfo
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Abstract
本发明属于中药技术领域，尤其涉及一种合欢皮木脂素苷单体的制备方法及其应用，本发明从中药材合欢皮中提取分离对脂肪酸合酶有抑制作用的刺五加甙E1单体，其制备工艺为合欢皮打碎成粉，乙醇回流提取；乙酸乙酯、水饱和正丁醇依次萃取；大孔树脂洗脱；硅胶柱层析分离；半制备高效液相分离，减压浓缩，干燥即得，采用红外光谱、核磁共振技术、质谱确定其化学结构，本发明方法简单快速，所需溶剂少，得率较高，具有较高的经济价值和学术价值。
Description
技术领域
本发明属于中药技术领域，尤其涉及一种合欢皮木脂素苷单体的制备方法及其应用。
背景技术
动物脂肪酸合酶(Fatty acid synthase,FAS)是动物体内催化合成长链脂肪酸途径中的关键酶，是能量代谢的一个多功能复合酶。研究表明，近年来发现FAS成为新的减肥和抗癌的双重潜在靶点。开发具有高活性、低毒性的脂肪酸合酶抑制剂，对于癌症的防治具有重大的意义。到目前为止已报道的FAS抑制剂单体还很少，只有最早发现的天然产物浅蓝菌素(cerulenin) 和以浅蓝菌素结构为模版化学方法合成的C75，以及绿茶中的酯型儿茶素EGCG和ECG。从天然中草药中寻找抑制活性更高的FAS抑制剂是有重大意义的。
合欢皮为豆科植物合欢Albizia julibrissin Durazz.的干燥树皮，药典记载其具有解郁安神、活血消肿的作用，可用于治疗心神不安、忧郁失眠、肺痈疮肿、跌扑伤痛，研究表明，合欢皮中含有三萜、黄酮、木脂素、生物碱、鞣质及多糖等多种化学成分。目前还没有文献记载从合欢皮中提取抑制FAS活性的单体的研究。
发明内容
为解决上述技术问题，本发明的目的是提供一种合欢皮木脂素苷单体的制备方法，本发明采用脂肪酸合酶抑制活性方法对合欢皮进行活性导向分离，最终从75％乙醇提取物的正丁醇相中分离到对脂肪酸合酶起抑制作用的单体：木脂素化合物EleutherosideE1，中文名刺五加甙E1，又名无梗五加苷B，该方法简单快速，所需溶剂少，得率较高，得到的木脂素苷单体对脂肪酸合酶活性具有显著的抑制作用。
一种合欢皮木脂素苷单体的制备方法，包括以下步骤：
步骤1：将合欢皮打碎成粉，使用75％乙醇回流提取，减压浓缩至干，用蒸馏水复溶，然后分别用乙酸乙酯、水饱和正丁醇分级萃取，萃取液减压浓缩，得到乙酸乙酯相、正丁醇相、母液水相；
步骤2：将合欢皮正丁醇相干粉用去离子水溶解，使用D101大孔树脂洗脱，洗脱液为乙醇；
步骤3：将洗脱组分分离、提纯得到木脂素苷单体。
进一步的，步骤1中，回流提取的料液比为1g：10mL，回流温度为75℃，回流时间为2～3h。
进一步的，步骤2中，乙醇的浓度为30％～95％。
进一步的，步骤2中，乙醇的浓度为30％。
进一步的，步骤3中，采用硅胶柱层析分离，洗脱剂为二氯甲烷：甲醇＝18：1，硅胶粒径为200-300目。
进一步的，步骤3中，采用半制备液相色谱进行提纯，采用C18色谱柱，流动相为0.3％磷酸水溶液和甲醇，检测波长为254nm。
本发明提出了一种脂肪酸合酶抑制剂，包括上述的制备方法得到的合欢皮木脂素苷单体。
本发明提出了上述的制备方法得到的合欢皮木脂素苷单体在制备预防和/或***的药物中的应用。
本发明提出了上述的制备方法得到的合欢皮木脂素苷单体在制备减肥药物和保健食品中的应用。
本发明提出了上述的制备方法得到的合欢皮木脂素苷单体在制备功能化妆品中的应用。
借由上述方案，本发明至少具有以下优点：传统的木脂素苷单体的提取纯化手段，如溶剂萃取、分级沉淀、重结晶等，总是难以得到纯品，与传统方法相比，本发明的提取效率高，粗体物得率较高(250g，得率10.0％)，这就为后面分离纯化提供较多的样品；大孔树脂可以将合欢皮中木脂素和皂苷类分离开来，起到富集木脂素类的作用；层析法结合半制备液相分离纯化木脂素可以获得较好的分离效果；本发明的提取方法简单快速，所需溶剂少，产物得率较高，为0.01368‰，得到的木脂素苷单体对脂肪酸合酶活性具有显著的抑制作用。
附图说明
图1是实施例1中组分Fr4的半制备液相色谱图。
图2是实施例1中活性组分的H2分析型液相色谱图。
图3是实施例1中活性组分H2的红外光谱图。
图4是实施例1中活性组分H2的质谱图。
图5是实施例1中活性组分H2的氢谱图。
图6是实施例1中活性组分H2的碳谱图。
图7是组分AJ-B-1、AJ-B-2、AJ-B-3、AJ-B-4、Fr1、Fr2、Fr3、Fr4、Fr5、Fr6抑制脂肪酸合酶活性的分析图。
图8是活性组分H1、H2、H3、H4抑制脂肪酸合酶活性的分析图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。
实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
合欢皮中木脂素苷单体(刺五加甙E1)的分离纯化
合欢皮药材2.5kg打碎成粉，在75％乙醇、75℃下回流提取两次，料液比为1:10(g/mL)，回流提取时间为2h。合并两次提取液，减压浓缩，真空干燥，得到合欢皮总提取物250g(AJ-T)，粗产物得率为10％。总提取物用蒸馏水溶解，然后分别用乙酸乙酯、水饱和正丁醇分级萃取。萃取液减压浓缩，分别得到乙酸乙酯相(124.7g)、正丁醇相AJ-B(52.4g)、母液水相(23.5g)。
取合欢皮正丁醇相干粉20g，用去离子水溶解，水溶液经过D101大孔树脂柱洗脱，依次用3倍柱体积的水、30％乙醇、50％乙醇、70％乙醇、95％乙醇梯度洗脱，得到四个组分：30％乙醇洗脱组分(AJ-B-1)，50％乙醇洗脱组分(AJ-B-2)，70％乙醇洗脱组分(AJ-B-3)，95％乙醇洗脱组分(AJ-B-4)。四个组分通过脂肪酸合酶活测定(测定方法见实施例3)，筛选出活性最高的组分AJ-B-1。
通过薄层色谱法，确定洗脱剂为二氯甲烷：甲醇＝18：1。选取粒径为200-300目硅胶分离，硅胶干法上样组分AJ-B-1，薄层色谱法实时检测并收集合并组分。用旋转蒸发仪浓缩，共得到6个组分：Fr1、Fr2、Fr3、Fr4、Fr5、Fr6。6组分通过脂肪酸合酶活测定(测定方法见实施例3)，筛选出活性最高的组分Fr4。
采用半制备液相色谱对Fr4进行分离纯化，采用C18色谱柱，流速为5mL/min，温度为 23℃。流动相为0.3％磷酸水溶液(A)-甲醇(B)，检测波长为254nm，流动相梯度洗脱程序： 0～15min，10％-20％B 15～30min，20％-38％B 30～65min，38％-80％B 65～66min，80-100％B 66～76min，100％B 76～80min 100-20％B 80～85min，20％B。共富集到4个化合物，分别记为H1(32.4min)、H2(34.0)、H3(38.9min)、H4(45.72min)。共收集H2的质量为13mg，得率为0.01368‰(得率计算相对于合欢皮药材质量)，其半制备液相色谱图谱如图1所示，活性组分H2的分析型液相色谱如图2所示，根据峰面积比例计算，其纯度高达97.4％。
实施例2
合欢皮中木脂素苷单体(刺五加甙E1)的结构鉴定
样品H2经干燥，研磨后用溴化碘直接压片，采用傅里叶红外光谱仪检测，分析中红外区 (波数4000～400cm-1)的变化，记录红外光谱图(图3，样品的红外光谱)，IR谱结果提示化合物中含有苯环，碳氧键或羟基。
质谱条件：离子方式：ESI+；毛细管电压：3.5kVolts；锥孔电压：20Volts；离子源温度： 100℃；脱溶剂气温度：400℃；脱溶剂气流速：500lit/hr；锥孔气流速50lit/hr；碰撞能量：6Volts；质量范围100-1000m/z；电压：1800Volts。采用MassLynx软件采集并处理数据，知道化合物的相对分子质量为580。同时产生多个碎片离子峰。(图4，样品的质谱图)
将样品H2用氘代甲醇溶解于核磁管中，采用全数字化核磁共振波谱仪测定H-NMR、C-NMR。其结果图为图5、6。
综合以上波普数据，确定样品H2为(+)-syringaresinolβ-D-glucoside，中文名为刺五加甙E1，化学结构式为：
实施例3
紫外可见分光光度法检测脂肪酸合酶活性
脂肪酸合酶上清液从鸡肝中提取纯化得到，NADPH在340nm下有吸收，而其产物NADP 在340nm下没有吸收。所以通过酶标仪来测定NADPH的变化值来测定脂肪酸合酶活性的变化。于含有1mmol/L EDTA、pH为7、浓度为0.1mmol/L的磷酸钾缓冲液中进行，底物浓度为乙酰CoA 6μmol/L，丙二酰CoA 12μmol/L，NADPH 37.5μmol/L，待测样品浓度为50ug/mL，总反应体积为2mL，37℃水浴恒温4～5min后，加入50μL稀释后的高速离心脂肪酸合酶上清液启动酶反应，每次从反应体系中吸取200uL反应体系溶液于340nm波长处连续监测吸光度变化。
动物FAS的活性单位(U)规定为每分钟氧化14nmol NADPH的酶量，因此，每毫升高速离心脂肪酸合酶上清液的酶活力用下式计算：
式中：V为测定酶活的体积数0.0002L；C为稀释倍数；106为mmol转换为nmol系数；△A340nm为340nm波长下的吸光度变化值；ε为NADPH氧化为NADP+时在340nm波长处的毫摩尔消光系数，此处为6.022L/mmol。
被测样品加入反应体系，加入FAS启动反应，测得酶活为A，空白对照酶活为A0，A/A0为剩余活性(R.A)。R.A越小，酶反应抑制程度越高，表明样品的抑制酶活能力强。分离过程中各组分抑制酶活能力如图7、8所示。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (2)
1.刺五加甙E1在制备脂肪酸合酶抑制剂中的应用，其特征在于，所述刺五加甙E1的结构式为：
2.根据权利要求1所述的应用，其特征在于，所述刺五加甙E1在制备减肥药物和保健食品中的应用。
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