CN111467361B - 一种环烯醚萜苷类化合物在制备β-葡萄糖醛酸苷酶抑制剂中的应用 - Google Patents
一种环烯醚萜苷类化合物在制备β-葡萄糖醛酸苷酶抑制剂中的应用 Download PDFInfo
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- CN111467361B CN111467361B CN202010405502.8A CN202010405502A CN111467361B CN 111467361 B CN111467361 B CN 111467361B CN 202010405502 A CN202010405502 A CN 202010405502A CN 111467361 B CN111467361 B CN 111467361B
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Abstract
本发明公开了一种环烯醚萜苷类化合物在制备β‑葡萄糖醛酸苷酶活性抑制剂中的应用,本发明从猴面包树果肉中提取的环烯醚萜苷类化合物对大肠杆菌β‑葡萄糖醛酸苷酶抑制活性显著,IC50值范围为20.7‑34.0μM,在治疗伊立替康或非甾体类抗炎药引起的药源性腹泻的药物的研发方面具有广阔的应用前景。
Description
(一)技术领域
本发明涉及猴面包树果肉提取物的新应用,特别涉及环烯醚萜苷类化合物在制备β-葡萄糖醛酸苷酶抑制剂中的应用,该应用有助于对治疗伊立替康或非甾体类抗炎药引起的药源性腹泻药物的研发,属于生物医药技术领域。
(二)背景技术
伊立替康(CPT-11),是一种常用的治疗结肠癌的药物。当它进入人体之后,会在肝脏中被代谢成无活性的SN-38葡萄糖醛酸苷(SN-38G),随后SN-38G经胆管排泄进入肠道,被肠道菌β-葡萄糖醛酸苷酶水解成SN-38,当SN-38在肠道中积累后会引起严重的迟发性腹泻和肠道损伤,严重影响化疗进程。此外许多服用酮洛芬、双氯芬酸和吲哚美辛等含羧酸的非甾体类抗炎药也会引起类似的肠道毒性,从而引起严重的药源性腹泻。
β-葡萄糖醛酸苷酶属于糖苷酶家族2的成员,能水解β-D-连接的葡萄糖醛酸苷键。人和动物肠道内的许多微生物都可以产生β-葡萄糖醛酸苷酶,2010年有学者首次证实了抑制肠道菌β-葡萄糖苷酶能缓解CPT-11引起的药源性腹泻,随后关于肠道菌β-葡萄糖醛酸苷酶抑制剂的开发和应用受到了广泛关注。虽然肠道中的β-葡萄糖醛酸苷酶的来源不限于大肠杆菌,但大肠杆菌β-葡萄糖醛酸苷酶(EcGUS),在人和动物肠道中普遍存在而且又易制备,因此EcGUS常被作为肠道菌β-葡萄糖醛酸苷酶抑制剂研究的常用靶标。
猴面包树(Adansonia digitata),又被称为小药房树、化学家树,广泛分布于非洲大陆,主要生长在炎热、干燥的热带稀树草原。猴面包树的所有部分(树、水果、种子、花)都可作为药材使用。例如猴面包树果肉具有抗氧化、抗菌、镇痛和抗炎等特性,有相关记录证明该果实能够治疗发烧、腹泻、咳嗽、痢疾等疾病。此外猴面包树果肉也具有丰富的营养价值,它自2008年起在欧洲被批准为一种新型食品,在美国于2009年被批准为一种新型食品配料。
环烯醚萜苷类化合物为白色结晶体或无定形粉末,分子量一般较小,且大多含极性基团,易溶于水、甲醇、乙醇等极性溶剂。目前,环烯醚萜苷类化合物主要来自于中药材的提取,具有护肝、利胆、降血糖、降血脂、抗炎等作用。
(三)发明内容
本发明提供了一种环烯醚萜苷类化合物在制备β-葡萄糖醛酸苷酶抑制剂中的应用,有助于对治疗伊立替康或非甾体类抗炎药引起的药源性腹泻的药物的研发。
本发明采用的技术方案是:
本发明提供一种环烯醚萜苷类化合物在制备β-葡萄糖醛酸苷酶(EcGUS)活性抑制剂中的应用,所述环烯醚萜苷类化合物为下列之一:6-O-对香豆酰基梓醇(specioside,5)、梓醇-6-咖啡酸酯(verminoside,6)、6-O-反式阿魏酰梓醇(6-O-(E)-feruloylcatalpol,7)、6-O-对香豆酰基益母草苷(6-O-p-coumaroylajugol,8)、6-O-(E)-咖啡酰基益母草苷(6-O-(E)-caffeoylajugol,9)、6-O-(E)-阿魏酰基益母草苷(6-O-(E)-feruloylajugol,10);
进一步,本发明所述环烯醚萜苷类化合物为以益母草苷为母核,优选为6-O-(E)-咖啡酰基益母草苷,在终浓度为100μM的时候,它们对EcGUS的抑制率范围在54.0%-84.0%。
进一步,本发明所述环烯醚萜苷类化合物对EcGUS的抑制IC50值范围为20.7-34.0μM。
进一步,本发明所述β-葡萄糖醛酸苷酶源自肠道菌,优选大肠杆菌,EcGUS可以从生物化学制品公司采购,比如西格玛奥德里奇(上海)贸易有限公司,或者从大肠杆菌中提取。
进一步,所述抑制剂为治疗伊立替康或非甾体类抗炎药引起的药源性腹泻的药物。
与现有技术相比,本发明有如下有益效果:
本发明提供了从猴面包树果肉中提取的环烯醚萜苷类化合物对β-葡萄糖醛酸苷酶抑制作用,而且抑制活性显著,IC50值范围为20.7-34.0μM(小于阳性对照——D-葡萄糖二酸-1,4-内酯的IC50值67.3μM),在治疗伊立替康或非甾体类抗炎药引起的药源性腹泻的药物的研发方面具有广阔的应用前景。
(四)附图说明
图1为猴面包树果肉提取物和梓醇、益母草苷、D-葡萄糖二酸-1,4-内酯对EcGUS的抑制活性图。
图2为环烯醚萜苷类化合物和D-葡萄糖二酸-1,4-内酯对EcGUS的浓度依赖抑制曲线。
图3为化合物7(A)、8(B)、9(C)、10(D)对EcGUS的抑制类型图。
(五)具体实施方式
下面结合说明书附图和具体实施例对本发明作出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例1:EcGUS抑制剂的筛选
(1)EcGUS的制备:
将-80℃下保存的大肠杆菌(Escherichia coli BL21(DE3))接种到200mL含30μg/mL卡那霉素的LB液体培养基(胰蛋白酶10g/L,酵母提取物5g/L,氯化钠10g/L,溶剂为水,pH7.0)中,于200rpm、37℃条件下培养至OD600达到0.5,接着加入终浓度100mM的异丙基-β-D-硫代半乳糖苷(IPTG),于200rpm、30℃条件下过夜培养诱导EcGUS的表达(SDS-PAGE电泳可以检测酶的表达情况)。待表达完成后,将培养液在4℃,9000rpm条件下离心5min,收集菌体,再用PBS(pH 7.4)洗涤菌体2-3遍,然后按原菌液(离心前的培养液)体积的1/10加裂解液(20mM 4-羟乙基哌嗪乙磺酸(HEPES),300mM NaCl,5mM咪唑(imidazole),体积浓度10%甘油(glycerol),溶剂为水,pH 7.4)20mL重悬菌体,置于冰上,在300W,超声10s间隔10s条件下超声破碎菌体20min,接着在4℃,8000rpm条件下离心10min,取上清。然后用纯净水和NTA-0缓冲液(20mM Tris-HCl,0.5M氯化钠,体积溶度10%甘油,pH 7.9)各15ml分别清洗15mL的Ni-NTA琼脂糖树脂柱料(购于GE医疗公司)2~3次,再将上清与Ni-NTA琼脂糖树脂柱料在4℃下螯合3h,然后用NTA-0缓冲液,NTA-20缓冲液(20mM Tris-HCl,0.5M氯化钠,体积溶度10%甘油,20mM咪唑,pH 7.9),NTA-250缓冲液(20mM Tris-HCl,0.5M氯化钠,体积溶度10%甘油,250mM咪唑,pH 7.9)各15mL分别梯度洗脱,洗脱液每5mL收集一管,分别收集到9管洗脱液,每管洗脱液均进行SDS-PAGE电泳,结果显示NTA-250缓冲液洗脱收集的4管洗脱液含有EcGUS,且EcGUS的分子量约为71kD,然后将这4管洗脱液合并,最后使用10kD的Millipore蛋白超滤管(截留分子量不应大于目的蛋白分子量的1/3)过滤,收集截留液即为酶液,获得EcGUS酶液约7mL;
(2)对硝基苯酚(PNP)标曲制作:配制1mM的PNP溶液(PBS溶解),在96孔板中进行操作,每组做3个平行,分别加0,10,20,40,60,80μL 1mM的PNP溶液,用PBS补齐至100μL,在37℃下孵育30min,使用酶标仪分别测405nM波长下0min和30min的吸光度,然后利用Excel制作散点图,得到吸光度与PNP浓度的关系式为y=3.2617x+0.0547,其中y为吸光度,x为PNP浓度,经单位转换和去除空白干扰,在μM浓度下吸光度与PNP浓度的关系式为y=0.003262x。
(3)EcGUS抑制剂的筛选(抑制剂终浓度100μM):
抑制剂:将猴面包树果肉提取物(表1中化合物1-化合物12)分别用二甲基亚砜(DMSO)配成10mM的溶液,作为抑制剂,待用。
底物:4-硝基苯基-β-D-吡喃葡萄糖苷(PNPG,购于Sigma-Aldrich),用PBS配成2.5mM的溶液,待用。
酶:步骤(1)中制备的β-葡萄糖醛酸苷酶(EcGUS)酶液,用PBS稀释500倍后用试剂盒测得浓度为1μg/mL,作为反应酶液。
阳性对照(DSL):D-葡萄糖二酸-1,4-内酯(D-Saccharic acid 1,4-lactone,DSL,购于Sigma-Aldrich)二甲基亚砜(DMSO)配成10mM的溶液,作为阳性对照。
反应:在96孔板中进行,反应体系如下,空白组:酶10μL+PBS 79μL+体积浓度10%DMSO水溶液1μL+2.5mM底物10μL;实验组:酶10μL+PBS 79μL+10mM抑制剂1μL+2.5mM底物10μL;阳性对照组:酶10μL+PBS 79μL+10mM阳性对照1μL+2.5mM底物10μL;每组做3个平行,按酶、PBS、抑制剂/阳性对照、底物的顺序加样,然后使用酶标仪在405nm波长下分别测量0min和30min的OD值(期间37℃下孵育),通过计算得到各化合物在终浓度100μM下对EcGUS的相对活性值,并用Graphad Prism 6.0软件画出相对活性柱状图(图1),接着又通过进一步计算得到各化合物在终浓度100μM下对EcGUS的抑制率(具体数值见表1),6个环烯醚萜苷类化合物(即表1中化合物5-化合物10)的抑制活性均大于阳性对照化合物DSL,抑制率在20.7%-34.0%之间。
上述的具体计算过程如下:
ΔOD=OD30min–OD0min;
ΔCPNP=ΔOD/0.003262(0.003262为步骤(2)所得的吸光度与PNP溶度的相关性系数);
相对活性(%)=实验组ΔCPNP/空白组ΔCPNP;
抑制率(%)=1–相对活性(%);
(4)IC50值的测定:测定6个环烯醚萜苷类化合物(即表1中化合物5-化合物10)的IC50值,在终溶度0.001-100μM内设置一系列抑制剂浓度点(如0.001、0.01、0.1、0.5、1、3、10、50、100μM),反应在96孔板中进行,反应体系如下:空白组:酶10μL+PBS 70μL+体积分数1%DMSO 10μL+2.5mM底物10μL;实验组:酶10μL+PBS 70μL+不同浓度抑制剂10μL+2.5mM底物10μL;每组设3个平行,按酶、PBS、抑制剂/阳性对照、底物的顺序加样,然后在酶标仪405nm波长下分别测量0min和30min的OD值(期间37℃下孵育),通过计算得到各抑制剂在不同浓度条件下对EcGUS的相对活性值,最后将抑制剂浓度点μM转化成nM并取10为底的导数得lg值,并以lg值为横坐标,相对活性为纵坐标,利用Graphad Prism 6.0软件画出IC50曲线图并经该软件分析得各抑制剂对EcGUS的IC50值(各化合物IC50值见表1),6个环烯醚萜苷类化合物对EcGUS的IC50都小于阳性对照化合物DSL,达到20.7-34.0μM。
表1十种猴面包树果肉中提取的化合物化合物抑制率和IC50值
其中梓醇(Catalpol)和益母草苷(Ajugol)分别为羟基肉桂酸和环烯醚萜苷类化合物的母核
表1中各个抑制剂名称及结构式,其中化合物(1~4)为羟基肉桂酸类化合物,化合物(5~10)为环烯醚萜苷类化合物,化合物12为梓醇,化合物13为益母草苷:
丹参皂甙A(6'-O-a-D-galactosylverminoside,1)、丹参皂甙B(10-O-a-D-galactosylverminoside,2)、丹参皂甙C(6-O-caffeoylscutelloside,3)、丹参皂甙D(6-O-caffeoylglutinoside,4)、6-O-对香豆酰基梓醇(specioside,5)、梓醇-6-咖啡酸酯(verminoside,6)、6-O-反式阿魏酰梓醇(6-O-(E)-feruloylcatalpol,7)、6-O-对香豆酰基益母草苷(6-O-p-coumaroylajugol,8)、6-O-(E)-咖啡酰基益母草苷(6-O-(E)-caffeoylajugol,9)、6-O-(E)-阿魏酰基益母草苷(6-O-(E)-feruloylajugol,10),其中梓醇(Catalpol,11,购买自上海诗丹德生物技术有限公司)为化合物(1~4)的母核,益母草苷(Ajugol,12,购买自上海诗丹德生物技术有限公司)为化合物(5~10)的母核。
实施例2:化合物7、8、9、10对EcGUS的抑制类型研究
选取复筛抑制活性最好的四个化合物,分别为化合物7、8、9、10,它们的结构都类似,其中化合物9抑制活性最好。抑制剂用PBS配制成一系列浓度梯度的溶液,底物也用PBS配制成浓度为2,3,5,10mM的溶液,即终浓度为200,300,500,1000μM。以化合物7为例制作表2,其配制的溶度梯度为0,100,200,300,400μM,即终浓度为0,10,20,30,40μM(见表2);
表2底物与化合物7不同溶度点的排列组合表
注释:CPNPG表示底物终溶度,CIn表示抑制剂(化合物7)终溶度,□表示一个实验组(相当于96孔板的一个样孔),每个溶度组合做3组平行。
化合物8其配制浓度为0,90,200,300μM,即终浓度为0,9,20,30μM;
化合物9其配制浓度为0,70,100,150,200μM,即终浓度为0,7,10,15,20μM;化合物10其配制浓度为0,100,200,300μM,即终浓度为0,10,20,30μM;
然后按反应体系:酶10μL+PBS 70μL+不同浓度抑制剂10μL+不同浓度底物10μL(不同浓度的抑制剂与底物的组合如表2)在96孔板中进行反应,每个组合设3个平行,按酶、PBS、抑制剂/阳性对照、底物的顺序加样加样,使用酶标仪在405nm波长下分别测量0min和30min的吸光度(期间37℃下孵育),按步骤(3)计算过程计算不同浓度组合对应的PNP浓度差值,最后计算出1/V(μmol/min/mg)和1/PNPG值,V(μmol/min/mg)即酶的催化速度,表示在温度、pH值、底物浓度一定的条件下,每毫克酶每分钟催化产生产物的摩尔量;
计算过程如下:
1/V(μmol/min/mg)=1/(ΔCPNP*100/10/30/1);1/PNPG=1/ΔCPNP;
其中ΔCPNP表示0min和30min体系中PNP的浓度差,100表示反应体系100μL,10表示酶的加入量10μL,30表示反应时间30min,1表示酶的配制溶度为1μg/mL。
最后利用Graphad Prism 6.0软件线性回归画出抑制双倒数曲线图(见图3,化合物7、8、9、10分别对应图3中的A、B、C、D),根据曲线交点判断抑制类型,从图3可以看出四个化合物图像交点在第二象限,表明化合物7、8、9、10对EcGUS的抑制属于混合型抑制,既能与酶的活性位点结合也能与酶的变构位点结合。
Claims (3)
1.一种益母草苷类化合物在制备大肠杆菌β-葡萄糖醛酸苷酶活性抑制剂中的应用,其特征在于所述抑制剂为治疗伊立替康或非甾体类抗炎药引起的药源性腹泻的药物;所述益母草苷类化合物为下列之一:6-O-对香豆酰基益母草苷、 6-O-(E)-咖啡酰基益母草苷、6-O-(E)-阿魏酰基益母草苷。
2.如权利要求1所述的应用,其特征在于所述益母草苷类化合物为6-O-(E)-咖啡酰基益母草苷。
3.如权利要求1所述的应用,其特征在于所述的益母草苷类化合物对β-葡萄糖醛酸苷酶抑制的IC50范围为20.7-34.0 μM。
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