CN117257793A - 一种克罗烷二萜在制备防治非酒精性脂肪肝药物中的用途 - Google Patents
一种克罗烷二萜在制备防治非酒精性脂肪肝药物中的用途 Download PDFInfo
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- CN117257793A CN117257793A CN202210660643.3A CN202210660643A CN117257793A CN 117257793 A CN117257793 A CN 117257793A CN 202210660643 A CN202210660643 A CN 202210660643A CN 117257793 A CN117257793 A CN 117257793A
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Abstract
本发明属于生物医药领域，公开了式I所示的一种克罗烷型二萜化合物montanin B在制备预防或治疗非酒精性脂肪肝药物中的用途。本发明的化合物montanin B可显著促进减少高脂诱导的肝细胞内脂肪堆积，且无细胞毒性，在医药领域具有很好的应用和开发前景。
Description
技术领域
本发明属于生物医药领域，具体涉及一类新的克罗烷型二萜化合物montanin B用于预防和/或治疗非酒精性脂肪肝药物中的应用。
背景技术
非酒精性脂肪性肝病(Non-Alcoholic Fatty Liver Disease,NAFLD)是最常见的慢性肝病之一，全球发病率高达25％，在我国发病率也逐年增加，是最常见的肝脏疾病，高发且难治愈。非酒精性脂肪性肝病通常与肥胖有关，但非肥胖人群中的患病率也很常见。非酒精性脂肪性肝病是肝细胞脂肪变性的肝脏疾病。特征为肝实质细胞脂肪变性和脂肪贮积为特征，肝脂肪含量超过肝重量5％，或在组织学上50％以上肝细胞发生脂肪变性。它不仅是肝脏病变，还会影响体内物质代谢，进而影响血脂及血糖水平。可从单纯性脂肪肝经非酒精性脂肪性肝炎发展为肝纤维化，甚至导致肝硬化、肝细胞癌或肝功能衰竭等终末期肝病。是终末期肝病和肝移植的主要原因之一。目前尚无有效抗NAFLD的药物，唯一被认为有效的疗法仍然是干预生活方式疗法。虽然目前有多个针对不同靶点的新药处于临床研究阶段，但效果仍有待验证。因此开发新型药物治疗NAFLD具有重要的临床应用价值。
本发明所述的化合物montanin B是一种克罗烷二萜类化合物。分子式为C19H24O5，分子量为332。该化合物先后从唇形科香科属的多年生草本植物Teucrium montanum L.和Teucrium polium L.中分离得到(Malakov,P.Y.,Papanov,G.Y.,Mollov,N.M.Montanin Aand B,new furanoid diterpenes of nor-clerodane type from Teucrium montanumL.Phytochemistry Lett.1978,19,2025-2026；Fiorentino,A.,D’Abrosca,B.,Pacifico,S.,et al.Structure elucidation and hepatotoxicity evaluation against HepG2human cells of neo-clerodane diterpenes from Teucrium polium L.Phytochemistry2011,72,2037–2044)。其中山香香科(Teucrium montanum L.)主要分布于欧洲南部和中部，延伸至荷兰和乌克兰西部。该植物作为草药和营养食品食用。它被广泛用作利尿剂，治疗消化问题和呼吸系统疾病，包括肺结核。除伤口愈合外，它还被用作抗糖尿病植物、补品和利胆剂。在塞尔维亚民间医学中，它是最受欢迎的草药之一。它含有许多苦味化合物、精油和不同的酚类化合物，如单宁。作为该植物的化学成分之一的克罗烷二萜montanin B的生物活性研究非常有限(Malakov,P.,Papanov,G.,Boneva,I.,Neo-clerodanediterpenoids from Teucrium montanum.Phytochemistry 1992,31,4029–4030)，也未见该化合物其他药理学研究报告。
本发明所述的化合物montanin B是从山香香科(Teucrium montanum L.)植物地上部分通过各种柱色谱分离技术分离制备获得。发明内容主要涉及该化合物制备药物和药物组合，为临床提供预防和/或治疗脂肪肝药物中的应用。目前有关该化合物对脂肪肝方面直接或间接的治疗作用尚没有报道。
发明内容
本发明要解决的技术问题是，提供一种化合物在制备预防和/或治疗非酒精性脂肪肝的药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
(1)本发明提供了如式I所示的化合物montanin B在制备预防和/或治疗非酒精性脂肪肝的药物中的应用；所述的化合物结构如下：
(2)一种药物组合物在制备治疗和/或预防非酒精性脂肪性肝病药物药物中的应用，其特征在于，所述的药物组合物含有有效剂量的如式I所示的化合物及药用赋形剂；
(3)一种药物组合物在制备治疗和/或预防非酒精性脂肪性肝病药物药物中的应用，其特征在于，所述的药物组合物包括控制释放、持续释放制剂及微粒体给药系统的形式。
该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95％(重量)。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重，优选为0.1-100mg/kg体重，更优选为1-60mg/kg体重，最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
有益技术效果：
1.本发明式I化合物montanin B可预防或治疗预防和/或治疗非酒精性脂肪肝的药物中的应用用途方面的报道为首次公开。
2.以往有报道唇形科香科属植物茶具有抗脂肪肝的功效(J Acupunct MeridianStud.2010,3(2):104-10)，本发明进一步明确了该属植物中抗脂肪肝的活性成分，而避免了混合成分可能带来的不良反应，具有明显的优益。
附图说明
图1山香科科(Teucrium montanum L.)的提取分离流程图。
图2.本发明化合物montanin B(1)对高脂诱导的HepG2肝细胞活力的影响。
图3.本发明化合物montanin B(1)可剂量依赖性减少高脂诱导的HepG2肝细胞内脂质堆积，其半数有效浓度为7.58×10-10M。
图4.本发明化合物montanin B(1)改善高脂诱导的HepG2非酒精性脂肪肝细胞内脂质堆积的Bodipy荧光染色结果。
具体实施方式
下面结合本发明进一步说明本发明化合物montanin B(1)在制备预防和/或治疗非酒精性脂肪肝及并发症等疾病的用途。
下述实施例更详细地举例说明本发明，并不是对本发明的任何限制。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
术语与简称
HPLC 高效液相色谱
ESI-MS 电喷雾质谱
1H NMR 核磁共振氢谱
13C NMR 核磁共振碳谱
HSQC 异核单量子相关(一种测定分子中氢碳直接相连关系的二维核磁共振谱)
HMBC 异核多键相关(一种测定分子中远程氢碳连接关系的二维核磁共振谱)
NOESY 欧沃豪斯增益谱(一种测定分子中氢原子空间位置临近关系的二维核磁共振谱)
实施例1：Montanin B的分离及结构表征
山香科科(Teucrium montanum L.)地上部分10kg，粉碎，用95％乙醇回流提取3次，每次2小时。提取液减压浓缩得到提取物1040g，将提取物溶于适量甲醇中，加入1500g200-300目硅胶，搅拌均匀，挥干溶剂后，依次用石油醚、二氯甲烷、乙酸乙酯和甲醇进行索氏回流提取，分别得到187g石油醚部位、90g二氯甲烷部位、105g乙酸乙酯部位和400g甲醇部位。将乙酸乙酯部位经MCI树脂柱色谱，依次以40％，60％，70％，80％，90％和100％甲醇洗脱，分别得到E1，E2，E3，E，E5和E6六个组份。其中E1组份(29.3g)经MCI凝胶柱纯化后(甲醇洗脱)，得到4个流份E1-1～E1-4。E1-2(22.3g)组份经硅胶柱色谱，CH2Cl2-MeOH(80：1—1：1)梯度洗脱，TLC检测合并得到九个组份E1-2-1～E1-2-9。E1-2-4(6g)经反相硅胶ODS柱色谱，依次以5％，20％，40％，60％，80％和100％甲醇梯度洗脱，每个梯度得到4个组份，其中60％甲醇洗脱得到四个组份E1-2-4d-1～E1-2-4d-4。组份E1-2-4d-1(1.6g)经制备型液相色谱(Shimadzu LC-6AD型色谱仪；YMC-pack ODS-A色谱柱，250×10mm，5μm；28％乙腈作为流动相；流速2ml/min)得到化合物1(80mg)。提取分离流程图如附图1所示。
Montanin B(1)的结构式和鉴定方法
Montanin B(1)的理化性质和核磁共振波谱数据
白色粉末，ESI-MS m/z 333[M+H]+；1H NMR和13C NMR波谱数据见表1。
表1化合物1的1H NMR(500MHz)和13C NMR(125MHz)波谱数据(CD3OD)
药物活性实验
将化合物montanin B(1)粉末溶解于DMSO中，配置成10mM的溶液，分装后，贮存于-80℃备用。使用时用生理盐水稀释至相应的浓度。
实施例2.化合物montanin B(1)对高脂诱导的HepG2肝细胞活力的影响
实验方法：HepG2肝细胞培养于含10％灭活胎牛血清的4.5g/L DMEM高糖培养液中，置于37℃、5％CO2细胞培养箱中。当细胞密度达到90％时，用胰蛋白酶消化，以1:3的比例传代培养。取对数生长期的细胞以100μl/孔(8×104个/ml)接种于96孔板中培养24h，24h后，弃去原培养基，加入含0.25mM油酸含10％血清培养基，90μl/孔；正常对照组加入含10％血清培养基90μl/孔。同时将化合物montanin B(1)储备液用生理盐水进行梯度稀释，使终浓度分别为10-13M、10-12M、10-11M、10-10M、10-9M、10-8M、10-7M、10-6M，加入不同浓度的化合物montanin B(1)10μl/孔，正常对照组和模型组加入生理盐水10μl/孔。继续培养24h后，弃去原培养基，加入CCK-8稀释液100ul/孔，并置于37℃培养箱中孵育约1-2h，于450nm处读取吸光度值。
实验结果：化合物montanin B(1)作用24h后，与模型组相比，在10-13M-10-6M浓度时对HepG2肝细胞活力无显著性影响。结果见表2和图2。
表2化合物montanin B(1)对高脂诱导的HepG2肝细胞活力的影响
实施例3.化合物montanin B(1)对高脂诱导的HepG2肝细胞内脂质堆积的作用
实验方法：细胞培养，种板，给药的操作见实施例2。油红O染色方法如下：培养24h后小心吸走培养液，用PBS缓冲液清洗2-3次，加入4％多聚甲醛溶液固定15min。弃去固定液，加入油红O工作液50μl/孔，室温放置1h。弃去染液，用PBS清洗3-5次，洗去多余的杂质和沉淀。显微镜下观察HepG2细胞形态及脂滴分布情况，并拍照记录实验结果。Bodipy荧光染色方法如下：培养24h后小心吸走培养液，用PBS缓冲液清洗1-2次，4％多聚甲醛固定30min；弃去固定液，加入2μg/m1 BODIPY避光室温染色30min；弃去染色液，用PBS清洗3次；M5酶标仪检测荧光值，设置激发波长为500nm，发射波长为550nm；读值后，加入1.2μM DAPI避光室温染色30min；弃去染色液，用PBS清洗3次。荧光显微镜下观察HepG2细胞形态及脂滴分布情况，其中DAPI染核呈蓝色，BODIPY染脂质呈绿色，同时拍照记录实验结果。
实验结果：油红O染色结果表明：化合物montanin B(1)作用24h后，与模型组相比，在10-13M-10-6M浓度范围内，化合物montanin B(1)对高脂诱导的HepG2肝细胞内脂质堆积的抑制作用呈现良好的浓度依赖关系，即随化合物montanin B(1)的浓度升高，抑制作用越强，经计算得化合物montanin B(1)的半数有效浓度为7.58×10-10M。结果见表3，图3。随后，我们在化合物montanin B(1)10-8M,10-7M和10-6M浓度时，通过Bodipy荧光拍照方法分析药物对高脂诱导的HepG2肝细胞内脂质堆积的作用。结果表明，化合物montanin B(1)在10-8M-10-6M浓度范围内可显著性减少高脂诱导的HepG2肝细胞内脂质堆积。结果见图4。
表3化合物montanin B(1)对高脂诱导的HepG2肝细胞内脂质堆积的抑制作用
Claims (3)
1.如式I所示的化合物或其药学上可接受的盐在制备治疗和/或预防非酒精性脂肪性肝病药物中的应用：
2.一种药物组合物在制备治疗和/或预防非酒精性脂肪性肝病药物药物中的应用，其特征在于，所述的药物组合物含有有效剂量的如式I所示的化合物或其药学上可接受的盐及药用赋形剂；
3.根据权利要求2的应用，其特征在于，所述的药物组合物包括控制释放、持续释放制剂及微粒体给药系统的形式。
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