CN104744447B - 水飞蓟宾迷迭香酸酯及其制备方法和用途 - Google Patents
水飞蓟宾迷迭香酸酯及其制备方法和用途 Download PDFInfo
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- CN104744447B CN104744447B CN201410794771.2A CN201410794771A CN104744447B CN 104744447 B CN104744447 B CN 104744447B CN 201410794771 A CN201410794771 A CN 201410794771A CN 104744447 B CN104744447 B CN 104744447B
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- acid esters
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Abstract
本发明涉及式(I)的水飞蓟宾迷迭香酸酯及其药用盐或溶剂化物。本发明还涉及式(I)化合物的制备方法及其药物组合物和医药用途。本发明的式(I)化合物具有保护肝细胞的作用,可以作为治疗肝脏损伤及肝纤维化类疾病药物。
Description
技术领域
本发明涉及水飞蓟宾迷迭香酸酯及其制备方法和用途。本发明的化合物具有保护肝细胞的作用,可以作为治疗肝脏损伤及肝纤维化类疾病的药物。
背景技术
肝纤维化是大多数慢性肝病所共有的病理特征,也是慢性肝炎、肝硬化等进一步发展、恶化的重要中间环节。在国外、尤其是欧美国家,引起肝纤维化的病因以酒精中毒占多数,约50%~80%;在中国,导致肝纤维化的主要原因是感染肝炎病毒。我国是乙型肝炎病毒(HBV)感染的高流行区,约7.5亿人感染过HBV,慢性HBV携带者约1.2亿人。丙型肝炎病毒感染者更易引起慢性化,而慢性HCV感染者有20%~25%发展为肝纤维化、肝硬化。近年来的研究证实,肝纤维化在未进入肝硬化之前尚有逆转可能,这为肝纤维化的有效治疗带来新的希望。目前临床中肝纤维化患者数量的不断增加及病情的发展迫切需要一批安全有效、质量可控的药物。
天然产物一直是创新药物和先导化合物的重要源泉。本发明利用前药原理,针对临床治疗肝纤维化疗效较好、但存在生物利用度低等问题的天然产物水飞蓟宾进行结构改造,以化学方法将其与同样具有抗氧化、肝脏保护作用的天然产物迷迭香酸缩合形成新化合物水飞蓟宾迷迭香酸酯衍生物(Silb-RosA),以期提高其生物利用度及生物活性。
水飞蓟宾(Silybin)是由菊科植物水飞蓟果实中分离提取的有效成分,在治疗肝脏疾病领域已有多年的研究及临床实验的结果。由于其疗效明确,安全性高,使其各种制剂多用于肝病的治疗。其主要通过减少巨噬细胞释放促纤维化因子,抑制贮脂细胞增殖和胶原合成,抑制了肝星状细胞激活等机制而起到抗纤维化作用。其单用或与其他护肝药物联用治疗各种肝病,在降酶、保肝、防治肝纤维化等方面均取得一定疗效。但由于水飞蓟宾不溶于水和油脂,生物利用度低,吸收不稳定,从而影响临床疗效。
迷迭香酸(Rosmarinic Acid)是一种在自然界广泛分布的多酚羟基化合物,具有抗氧化、抗菌、抗病毒、免疫调节等药理作用。近年的研究发现,迷迭香酸对肝脏的保护作用主要通过以下作用实现:抑制肝星状细胞增殖,降低TNF-α诱导的α-平滑肌肌动蛋白、TGF-β、CTGF表达,抑制肝线粒体肿胀,提高膜流动性,降低丙二醛含量,增强琥珀酸脱氢酶活性等。其对四氯化碳诱导的小鼠急性肝损伤有显著的保护作用,并能减轻肝纤维化模型大鼠的肝纤维化程度和肝组织病理形态学改变。
与水飞蓟宾相比,水飞蓟宾和迷迭香酸经化学合成方法缩合得到的新化合物水飞蓟宾迷迭香酸酯(Silb-RosA)水溶性明显增加,其生物利用度得以提高。初步研究显示,水飞蓟宾迷迭香酸酯在体内迅速分解为水飞蓟宾和迷迭香酸,使其可以从各自不同靶点发挥肝脏保护作用;并且其药效活性明显优于同等摩尔浓度的水飞蓟宾或迷迭香酸。
综上所述,本发明设计的水飞蓟宾迷迭香酸酯衍生物作为一种前药分子,在生物利用度、疗效、多靶点作用机制及安全性等方面有诸多优势,作为保肝及抗肝纤维化1.1类新药具有较好的开发价值和广阔的应用前景。
发明内容
本发明的一个目的是提供式(I)所示的水飞蓟宾迷迭香酸酯或其药用盐或溶剂化物:
其中,式(I)所示的水飞蓟宾迷迭香酸酯在立体化学方面处于以下三种形式之一:10、11位的碳原子同时为R构型或同时为S构型,或是二者的混合物。
本发明的另一目的是提供式(I)所示的水飞蓟宾迷迭香酸酯的制备方法。
其中,酯化缩合剂为HOBt-EDCl;溶剂为四氢呋喃、N,N-二甲基甲酰胺或二甲亚砜;迷迭香酸与水飞蓟宾的摩尔比为1:1至1:2;迷迭香酸、HOBt、EDCl三者的摩尔比为1:(1-1.5):(1-1.5);所用碱为三乙胺,迷迭香酸与三乙胺的摩尔比为1:1.5至1:5;反应温度为室温至回流;反应时间24-48小时。
上述英文缩写所对应的中文名称为:
其中,HOBt:羟基苯并三唑。
其中,EDCl:1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐。
其中,TEA:三乙胺。
优选的,本发明的制备方法,包括以下步骤:
氮气保护下,向干燥的反应瓶中加入迷迭香酸、水飞蓟宾、EDCl和HOBt,用无水N,N-二甲基甲酰胺溶解,缓慢滴加三乙胺,室温搅拌24-48小时,停止反应后,将反应液倾入冰水中,析出大量固体,固体抽滤干燥后经硅胶柱层析纯化得到水飞蓟宾迷迭香酸酯(I)。
其中,迷迭香酸与水飞蓟宾的摩尔比为1:1至1:2;
其中,迷迭香酸、HOBt、EDCl三者的摩尔比为1:(1-1.5):(1-1.5);
其中,迷迭香酸与三乙胺的摩尔比为1:1.5至1:5。
进一步优选的,本发明的制备方法,包括以下步骤:
氮气保护下,向干燥的反应瓶中加入2.77mmol迷迭香酸、3.33mmol水飞蓟宾、3.6mmol EDCl和3.6mmol HOBt,用无水N,N-二甲基甲酰胺溶解,缓慢滴加6.9mmol三乙胺,室温搅拌48小时,停止反应后,将反应液倾入冰水中,析出大量固体,固体抽滤干燥后经硅胶柱层析纯化得到水飞蓟宾迷迭香酸酯(I)。
其中,硅胶柱层析过程中所用的洗脱剂为二氯甲烷和甲醇的混合溶剂,二者的体积比为=50/1~10/1,优选为20/1。
本发明另一个目的是提供式(I)化合物在制备用于治疗和/或预防肝脏损伤及肝纤维化类疾病的药物中的应用。
本发明所述的保肝作用,是通过改善血清ALT、AST水平而实现的。
本发明所述的保肝作用,是通过抑制肝星状细胞HSC-T6而实现的。
本发明所述的保肝作用,是通过抑制TGF-β1引起的细胞活化而实现的。
本发明的式(I)化合物可以与药学上常用的辅料或载体结合,从而制备具有治疗肝脏损伤及肝纤维化类疾病的药物组合物。
上述各类药物组合物可以是片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、口服液或软膏剂,还可以是控释或缓释剂型。
在本文中,所有涉及“式(I)化合物”、“式(I)所示的化合物”和类似表述的技术方案均同时涵盖本发明所述水飞蓟宾迷迭香酸酯的药用盐或溶剂化物。
本发明的式(I)化合物适宜以药物组合物的形式给药。这类组合物可以按照常规方式与一种或多种药学上可接受的载体或赋形剂混合使用。若有可能,在治疗上将本发明的式(I)化合物作为原料药给药,优选活性成分直接作为药物制剂。在与其它成分相容和对服药者无害的意义上,载体必须是药学上可接受的。
因此,本发明进一步提供本发明的式(I)化合物的药物制剂,其包含本发明的式(I)化合物和一种或多种药学上可接受的载体或赋形剂,以及含有或不含其它治疗和/或预防性成分。这些制剂适用于口服、胃肠外(包括皮下例如注射或药库片;真皮内;鞘内;肌内例如药库;静脉内等)、直肠和局部(如舌下)给药,但最适合的给药途径应取决于患者的病症。该制剂可以是单位制剂,并且可以通过用药学领域熟知的任一种方法制备。所有方法包括使本发明的式(I)化合物与载体结合的步骤,该载体构成一种或多种辅助成分。一般来说,该制剂的制备过程如下:使本发明的式(I)化合物与液体载体、或微细粉碎的固体载体、或二者的结合均匀而紧密的结合,然后,如果必要的话,使产物成型为所必须的制剂。
通常可使用标准的制药技术,即可将本发明的式(I)化合物和药学上可接受的载体或赋形剂制得本发明药物组合物,这些方法包括混合、制粒和压制。本领域技术人员所熟知的是,药学上可接受的载体或赋形剂的形式和特性取决于与其混合的活性成分的量、给药途径和其它已知因素。
本文中,所用的药学上可接受的载体或赋形剂是可与药物组合物联用给药的各种有机或无机的载体或赋形剂,例如用于固体制剂的赋形剂、润滑剂、粘合剂、崩解剂和包衣剂;也可使用药用添加剂,例如着色剂和甜味剂。所述药学上可接受的载体或赋形剂选自:糖醇,例如甘露醇、山梨醇、木糖醇;氨基酸,例如盐酸半胱氨酸、蛋氨酸、甘氨酸;维生素C;EDTA二钠、EDTA钙钠;无机盐,例如一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液;氯化钠、氯化钾;焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠;碳酸钙、碳酸氢钙;硬脂酸盐,例如硬脂酸钙、硬脂酸镁;无机酸,例如盐酸、醋酸、硫酸、磷酸;有机酸盐,例如乳酸钠;寡糖、多糖、纤维素及其衍生物,例如麦芽糖、葡萄糖、果糖、右旋糖苷、蔗糖、乳糖、环糊精(例如β-环糊精)、淀粉;硅衍生物;藻酸盐;明胶;聚乙烯吡咯烷酮;甘油;琼脂;表面活性剂,例如吐温80;聚乙二醇;磷脂类材料;高岭土;滑石粉等。
其药物制剂形式可以是任何可药用的剂型,这些剂型包括:片剂,例如糖衣片剂、薄膜衣片剂、肠溶衣片剂;胶囊剂,例如硬胶囊剂、软胶囊剂;口服液;口含剂;颗粒剂;冲剂;丸剂;散剂;膏剂;丹剂;混悬剂;粉剂;溶液剂;注射剂;栓剂;膏剂,例如软膏剂、硬膏剂;霜剂;喷雾剂;滴剂以及贴剂。本发明的制剂优选:口服剂型,如胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等;以及注射剂,如粉针剂、注射液、输液等。本发明的制剂最优选为片剂。
其口服给药的制剂可含有常用的赋形剂、粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂,必要时可对片剂进行包衣。
优选的示例赋形剂包括:乳糖、D-甘露醇、D-山梨醇、淀粉如α-淀粉、糊精、结晶纤维素、低取代的羟丙基纤维素、羧甲基纤维素钠、阿拉伯胶、支链淀粉、轻质无水硅酸、合成硅酸铝、硅酸铝镁等。
优选的示例润滑剂包括:硬脂酸镁、硬脂酸钙、滑石粉、硅胶等。
优选的示例粘合剂包括:α-淀粉、蔗糖、明胶、阿拉伯胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、结晶纤维素、糖、D-甘露醇、海藻糖、糊精、支链淀粉、羟丙基纤维素、羟丙基甲基纤维素、吡咯烷酮等。
优选的示例崩解剂包括:乳糖、糖、淀粉、羧甲基纤维素、羧甲基纤维素钙、氨烷基钠、羧甲基淀粉钠、轻质无水硅酸、低取代的羟丙基纤维素等。
优选的示例包衣剂包括:羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羧甲基纤维素、聚乙烯醇等。
优选的示例着色剂包括:水溶性食用枸橼黄染料(食用染料例如食用红No.2和No.3,食用黄No.4和No.5,食用蓝No.1和No.2);水不溶性色沉染料(例如上述水溶性食用枸橼黄染料的铝盐);天然染料(例如β-胡萝卜素、叶绿素、铁丹)等。
优选的示例甜味剂包括:糖精钠、甘草次酸、阿斯帕坦、甜菊等。
片剂的制备方法一般为:将本发明的式(I)化合物与一种或多种药学上可接受的辅料一起压制或模制。
本发明的式(I)化合物还可以制成口服液体制剂,例如水性或油性悬液、溶液、乳剂、糖浆剂等。本发明的式(I)化合物还可以是干燥产品,使用前用水或其它适合的载体混合。这类液体制剂可以含有常规的添加剂,可以包括悬浮剂,例如山梨醇糖浆、甲基纤维素、葡萄糖/糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪;乳化剂,例如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶;非水性载体(可以包括食用油),如杏仁油、分馏椰子油、油性酯、丙二醇或乙醇;以及防腐剂,如对羟基苯甲酸甲酯或丙酯、山梨酸。
用于胃肠道外给药的制剂包括水性与非水性无菌注射液,其中可以含有抗氧化剂、缓冲剂、制菌剂、等渗剂等;以及水性与非水性无菌混悬液,其中可以包括悬浮剂和增稠剂。制剂可以存放在单剂量或多计量容器内,例如密封的安瓿和小瓶,并且可以贮存在冷冻干燥(冻干)条件下,仅需要在临时用前加入无菌的液体载体,例如注射用水。
用于直肠给药的制剂可以是栓剂,含有常规的栓剂基质,例如可可脂、硬脂肪酸或其它甘油酯,或乙二醇。
用于口腔局部、例如颊部或舌下给药的制剂包括锭剂,其中在加味的基质中包含活性成分,该基质例如蔗糖和阿拉伯胶;还包括软锭剂,其中在基质中含有活性成分,该基质可以是明胶和甘油、或蔗糖和阿拉伯胶。
本发明的式(I)化合物还可以配制成药库制剂。这类长效制剂可以通过植入(如皮下或肌内)或肌内注射给药。所以,本发明式(I)化合物可以与适合的聚合物或疏水性材料(例如在可接受的油中的乳剂)或离子交换树脂进行配制,或者配制成微溶性衍生物,例如微溶性盐。
具体实施方式
下面通过具体的实施例进一步说明本发明。下述实施例给出了式(I)所示的水飞蓟宾迷迭香酸酯的制备方法及相关结构鉴定数据。下述实施例是用于说明本发明而不是对本发明的限制,根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1:水飞蓟宾迷迭香酸酯的制备
氮气保护下,向干燥的反应瓶中加入迷迭香酸(Sigma-Aldrich,96%)(1.0g,2.77mmol)、水飞蓟宾(江苏天士力帝益药业有限公司,98%,批号:20110502)[10S,11S+10R,11R的混合物](1.6g,3.33mmol)、EDCl(0.69g,3.6mmol)和HOBt(0.49g,3.6mmol),用30ml无水N,N-二甲基甲酰胺溶解,缓慢滴加三乙胺(0.8g,6.9mmol),室温搅拌48小时。停止反应后,将反应液倾入200ml冰水中,析出大量固体,固体抽滤干燥后经硅胶柱层析(洗脱剂为二氯甲烷/甲醇=20/1)纯化得到水飞蓟宾迷迭香酸酯(I)(黄色固体,0.45g,产率25%)。
1H NMR(CD3OD,400MHz):δ7.57(1H,d,J=16.0Hz),7.10-6.94(6H,m),6.86-6.84(2H,m),6.81-6.78(2H,m),6.63-6.61(2H,m),6.29(1H,d,J=16.0Hz),5.96-5.94(2H,m),5.28-5.25(1H,m),5.00(1H,dd,J1=7.2Hz,J2=3.2Hz),4.75(1H,t,J=7.6Hz),4.54(1H,dd,J1=7.2Hz,J2=3.2Hz),4.42-4.23(2H,m),4.03-3.92(1H,m),3.87(3H,s),3.10-3.06(2H,m);
13C NMR(CD3OD,100MHz)δ196.81,171.60,169.71,167.31,166.92,163.91,162.99,148.44,147.92,147.12,146.73,145.40,144.83,143.99,143.57,130.29,127.31,127.15,126.19,124.72,121.92,120.96,120.51,120.39,116.56,116.25,116.16,115.14,114.95,113.92,112.72,110.77,100.45,96.01,95.01,83.26,76.10,75.72,73.26,72.29,60.13,55.20,36.45;
ESI-MS:822.6[M-H]-.
实施例2:水飞蓟宾迷迭香酸酯的制备
氮气保护下,向干燥的反应瓶中加入2.77mmol迷迭香酸、2.77mmol水飞蓟宾、2.77mmol EDCl和2.77mmol HOBt,用30ml无水N,N-二甲基甲酰胺溶解,缓慢滴加4.16mmol三乙胺,室温搅拌48小时,停止反应后,将反应液倾入冰水中,析出大量固体,固体抽滤干燥后经硅胶柱层析(洗脱剂为二氯甲烷/甲醇=50/1)纯化得到水飞蓟宾迷迭香酸酯(I)。
实施例3:水飞蓟宾迷迭香酸酯的制备
氮气保护下,向干燥的反应瓶中加入2.77mmol迷迭香酸、5.54mmol水飞蓟宾、4.16mmol EDCl和4.16mmol HOBt,用30ml无水N,N-二甲基甲酰胺溶解,缓慢滴加13.85mmol三乙胺,室温搅拌48小时,停止反应后,将反应液倾入冰水中,析出大量固体,固体抽滤干燥后经硅胶柱层析(洗脱剂为二氯甲烷/甲醇=10/1)纯化得到水飞蓟宾迷迭香酸酯(I)。
实施例4:片剂
工艺:
1.制粒
水飞蓟宾迷迭香酸酯及处方中其它辅料分别过100目筛,称取处方量的水飞蓟宾迷迭香酸酯与微晶纤维素、淀粉和羧甲基淀粉钠,采用等量递加法混合均匀,用适量5%(w/v)PVP的无水乙醇溶液制软材,14目筛制粒,于50-60℃干燥1h,加入处方量的硬脂酸镁,用14目筛进行整粒。
2.压片
取上述颗粒用冲模压片机压片。
实施例5:胶囊剂的制备
工艺:
1.制粒
水飞蓟宾迷迭香酸酯及处方中其它辅料分别过100目筛,称取处方量的丹酚酸T与淀粉、羧甲基淀粉钠采用等量递加法混合均匀,用适量5%(w/v)PVP的无水乙醇溶液制软材,14目筛制粒,50-60℃干燥1h,加入处方量的硬脂酸镁,用14目筛进行整粒。
2.灌装
取上述颗粒装入胶囊壳中。
实施例6:注射液的制备
工艺:
取处方量的水飞蓟宾迷迭香酸酯,加注射用水1000mL使溶解,搅拌均匀;另取处方量的甘露醇,加注射用水500mL使溶解,加入上述溶液中,搅匀,用0.5g活性碳保温搅拌30min,过滤,滤液调节pH为4.5-5.0,加注射用水至2500mL,除菌过滤,分装即得。
实施例7:水飞蓟宾迷迭香酸酯对肝损伤的保护作用
1.实验材料
1.1实验动物:
SPF级雄性SD大鼠80只,体重180-200g。购于北京维通利华公司,动物合格证号:SCXK(京)2007-0001。饲养条件:在有空调的动物室饲养,温度为20℃-25℃,相对湿度60%,每笼5只,照明时间12小时,定时定量添加饲料,食用鼠专用饲料(北京科澳协饲料有限公司生产),自由饮水,每日更换垫料。
1.2主要试剂和药品:
试剂:四氯化碳(CCl4):天津市华东试剂厂,进口分装,分析纯
受试药物:制备实施例1中得到的水飞蓟宾迷迭香酸酯
阳性对照药:易善复(批号:121739,赛诺菲安万特北京制药有限公司)
1.3实验仪器:
(1)全自动生化仪(7020型,日立公司生产)
(2)全自动生化仪套用试剂(和光试剂,和光纯药工业株式会社生产)
2.实验方法
2.1分组:
将动物称重,编号,按体重随机分组。整个实验分为6组,分别为正常组、溶媒对照组(Sol)、阳性药对照组(易善复)、水飞蓟宾迷迭香酸酯低剂量组(Silb-RosA-L)、水飞蓟宾迷迭香酸酯中剂量组(Silb-RosA-M)、水飞蓟宾迷迭香酸酯高剂量组(Silb-RosA-H),每组10只,除正常组外连续给药7天。
2.2.给药:
采用尾静脉注射给药,给药剂量参考水飞蓟宾胶囊人临床用药剂量和药代动力学数据参考换算而成,具体计算方法及数值如下:
表1.药物溶液的配制
组别 | Sol | Silb-RosA-L | Silb-RosA-M | Silb-RosA-H | 易善复 |
人临床剂量 | / | / | / | / | 7.75mg/kg |
大鼠剂量 | / | 3.42mg/kg | 6.84mg/kg | 13.68mg/kg | 60mg/kg |
常用给药量 | 5ml/kg | 5ml/kg | 5ml/kg | 5ml/kg | 5ml/kg |
药物配制浓度 | / | 0.68mg/ml | 1.37mg/ml | 2.74mg/ml | 12mg/ml |
药物依照上述浓度配制,空白溶剂为以PEG400:乙醇:水=25:10:65的比例配制的混合溶剂。
2.3.模型制备
于给药第6天禁食24小时,除正常组以外的各组于第7天末次给药后立即采用25%CCl4花生油溶液按照0.5ml/100g皮下注射。造模后18小时眼内眦取血约1ml,3500r/min离心10min,取血清-20℃冻存。
3.检测指标
采用全自动生化仪测定血清中ALT、AST的含量。
4.数据统计方法
在原始数据整理时,以95%置信区间定义异常数据,即将数值超过范围外的数据予以剔除。
采用SPSS11.5软件进行统计分析。计量资料以表示,溶媒对照组与正常组之间采用独立样本t检验,以观察造模是否成功。随后以各药物组与溶媒对照组相比较,采用单因素方差分析,以评价药物的作用。P<0.05为差异有显著性意义。
5.实验结果
实验结果显示,溶媒对照组与正常组比较,ALT、AST明显增高(P<0.01),说明实验模型成功。与溶媒对照组比较,水飞蓟宾迷迭香酸酯中剂量组、高剂量组以及阳性药对照组大鼠血清ALT、AST数值明显降低(P<0.05,P<0.01)。但是水飞蓟宾迷迭香酸酯低剂量组仅AST数值有所降低(P<0.01)。实验结果表明,水飞蓟宾迷迭香酸酯较好地改善了CCl4肝损伤大鼠的血清ALT、AST水平,起到良好的肝保护作用。
表2:各组对CCl4诱导的急性肝损伤大鼠ALT、AST的影响
组别 | 剂量(mg/kg) | ALT | AST |
正常组 | / | 22.7±6.3** | 88.8±30.4** |
Sol | / | 247.5±132.7 | 617.4±221.2 |
Silb-RosA-L | 3.42 | 149.3±126.6 | 259.2±177.7** |
Silb-RosA-M | 6.84 | 130.8±88.0* | 258.8±149.3** |
Silb-RosA-H | 13.68 | 95.9±42.7** | 220.1±118.3** |
易善复 | 7.75 | 42.6±18.6** | 109.4±78.2** |
注:与溶媒对照组比较,*P<0.05,**P<0.01
实施例8:水飞蓟宾迷迭香酸酯对肝星状细胞HSC-T6活性的影响
研究背景:肝纤维化是各种慢性肝病(在我国主要是病毒性肝炎)共同的病理基础,是慢性肝病发展到肝硬化、肝癌的必经阶段。近年来研究表明肝纤维化的病理机制十分复杂,涉及到多种细胞、细胞因子和细胞外基质(extracellular matrix,ECM)之间的相互作用。而多数报道认为肝纤维化的实质是ECM生成过多和(或)降解减少导致异常增多和过度沉积的病理过程。肝星状细胞(hepatic stellate cell,HSC)是ECM的主要生成细胞,HSC的活化是肝纤维化发生的中心环节和细胞学基础。本实验选用肝星状细胞为研究对象,测定水飞蓟宾迷迭香酸酯对肝星状细胞HSC-T6活性的影响,对其抗肝纤维化作用进行初步评价。
1.实验材料
1.1细胞株:肝星状细胞由上海中医药大学肝病研究所提供,其表现型为活化的HSC,可表达高水平的I型胶原
1.2受试样品:制备实施例1中得到的水飞蓟宾迷迭香酸酯
1.3试剂:DMEM培养基(货号C11875)、胎牛血清(货号071108)、抗生素(货号15140),购于Gibco公司;MTT(四甲基噻唑蓝),批号2317KH,购于Sigma公司;DMSO,分析纯,购于天津市化学试剂一厂;
1.4仪器:多功能酶标仪:TECAN Infinite 200l
2.实验方法
2.1.MTT法:收集生长良好的HSC-T6(P12)肝星状细胞,用含10%小牛血清的DMEM培养基配制成2.5×104cells/ml细胞悬液,于96孔培养板内接种,每孔100μl(含2.5×103cells/孔),置于37℃、5%CO2温箱内培养,24小时后换180ul培养基,随后加入20ul用培养基稀释的受试样品。
实验设空白对照;水飞蓟宾迷迭香酸酯(Silb-RosA)组(终浓度为1000μg/ml,等倍稀释8个浓度);每浓度2个平行孔,置37℃、5%CO2温箱内,培养2天。
换100μl无血清培养基后每孔加入MTT溶液(5mg/ml,无酚红DMEM)10μl,37℃孵育4小时,2000rpm离心10min。弃去上清液,每孔加入DMSO 100μl,溶解Fomazan颗粒,轻度振荡5min后,用酶标仪在检测波长578nm下测定OD值。
3.实验结果
3.1水飞蓟宾迷迭香酸酯对HSC-T6细胞生长抑制作用
根据吸光度值求出抑制率,拟合得出水飞蓟宾迷迭香酸酯的IC50值为17.17μg/ml。该结果表明,水飞蓟宾迷迭香酸酯对肝星状细胞HSC-T6有抑制作用,在体外实验中体现了抗肝纤维化效果。具体数据见表3。
表3药物(Silb-RosA组)对HSC-T6细胞生长抑制作用
实施例9:水飞蓟宾、迷迭香酸、水飞蓟宾迷迭香酸复合物、水飞蓟宾迷迭香酸酯体外对TGF-β引起HSC-T6细胞增殖作用初步研究
研究目的:考察水飞蓟宾、迷迭香酸、水飞蓟宾迷迭香酸复合物(1:1)、水飞蓟宾迷迭香酸酯在体外对TGF-β引起HSC-T6细胞增殖的影响,从抗星状细胞活化的角度初步探讨提取物抗肝纤维化的作用机制。
1.实验药物及细胞株
1.1受试物:水飞蓟宾、迷迭香酸、水飞蓟宾迷迭香酸复合物(1:1)、水飞蓟宾迷迭香酸酯由天士力研究院中药所提供。
1.2细胞株:大鼠肝星状细胞HSC-T6,购买于均购于中国肿瘤医院肿瘤研究所。在含10%进口胎牛血清的DMEM培养液(含青霉素100U/ml,链霉素100μg/ml)中生长,培养条件为37℃、5%CO2,饱和湿度。用含0.25%胰蛋白酶和0.02%EDTA液消化传代。
1.3试剂:胎牛血清,DMEM培养液,青霉素,链霉素均购于Gibco公司。DMSO,胰蛋白酶,MTT(四甲基噻唑蓝)均购于Sigma公司。
EDTA购于上海生工生物工程公司进口分装。
1.4仪器:多功能酶标仪:TECAN Infinite 200l
2.实验方法
HSC-T6细胞接种于96孔细胞培养板,培养24h后,撤原培养基换含0.5%进口胎牛血清的DMEM培养液,继续培养细胞24h,加入不同浓度待测物,同时加入2ng/ml TGF-β1刺激细胞。作用细胞48h后,弃去培养液,每孔加入MTT(0.5mg/ml)液100μl,继续培养4h,弃去MTT液,每孔加入DMSO 150μl,混和振荡器振荡,于酶标仪570nm波长处测定吸光度值。细胞存活率(%)=100%×(给药组OD值/溶剂对照组OD值)。细胞增殖抑制百分率(%)=100%×(TGF-β1组细胞存活率-待测物组细胞存活率)/TGF-β1组细胞存活率。
3.实验结果
TGF-β1(2ng/ml)作用48h,能显著促进HSC-T6细胞的增殖。水飞蓟宾、迷迭香酸、水飞蓟宾迷迭香酸复合物(1:1)、水飞蓟宾迷迭香酸酯在对细胞无毒浓度下,对TGF-β1引起的HSC-T6细胞活化均具有一定的抑制作用。
其中水飞蓟宾组(125μg/ml,250μg/ml)、迷迭香酸(125μg/ml,250μg/ml)、水飞蓟宾迷迭香酸复合物(1:1)(62.5μg/ml,125μg/ml,250μg/ml)、水飞蓟宾迷迭香酸酯(31.25μg/ml,62.5μg/ml,125μg/ml,250μg/ml)与模型组比较,均有统计学差异。见表4-表7。
表4.水飞蓟宾对TGF-β1引起HSC-T6细胞增殖的影响
###P<0.001,与溶剂对照组比较;**P<0.01,与TGF-β1比较。
表5.迷迭香酸对TGF-β1引起HSC-T6细胞增殖的影响
###P<0.001,与溶剂对照组比较;**P<0.01,与TGF-β1比较。
表6.水飞蓟宾迷迭香酸复合物对TGF-β1引起HSC-T6细胞增殖的影响
###P<0.001,与溶剂对照组比较;**P<0.01,与TGF-β1比较。
表7.水飞蓟宾迷迭香酸酯对TGF-β1引起HSC-T6细胞增殖的影响
###P<0.001,与溶剂对照组比较;**P<0.01,与TGF-β1比较。
4.讨论
肝纤维化的中心环节是肝星状细胞HSC的激活,转化生长因子TGF-β是重要的促进肝纤维化的细胞因子。本实验观察水飞蓟宾、迷迭香酸、水飞蓟宾迷迭香酸复合物(1:1)、水飞蓟宾迷迭香酸酯对TGF-β1作用于大鼠肝星状细胞系HSC-T6增殖作用,探索其疗效和可能机制。采用TGF-β1活化HSC-T6细胞模型,分析了水飞蓟宾、迷迭香酸、水飞蓟宾迷迭香酸复合物(1:1)、水飞蓟宾迷迭香酸酯的作用,结果显示水飞蓟宾、迷迭香酸、水飞蓟宾迷迭香酸复合物(1:1)、水飞蓟宾迷迭香酸酯对TGF-β1引起的细胞活化均有一定的抑制作用,其中水飞蓟宾迷迭香酸酯的抑制作用相对较强。
Claims (11)
1.式(I)所示的水飞蓟宾迷迭香酸酯或其药用盐:
其中,式(I)所示的水飞蓟宾迷迭香酸酯在立体化学方面处于以下三种形式之一:10、11位的碳原子同时为R构型或同时为S构型,或是二者的混合物。
2.权利要求1中所述的水飞蓟宾迷迭香酸酯的制备方法,包括将迷迭香酸和水飞蓟宾经过酯化反应得到式(I)化合物:
其中,酯化缩合剂为HOBt-EDCl;溶剂为四氢呋喃、N,N-二甲基甲酰胺或二甲亚砜;迷迭香酸与水飞蓟宾的摩尔比为1:1至1:2;迷迭香酸、HOBt、EDCl三者的摩尔比为1:(1-1.5):(1-1.5);所用碱为三乙胺,迷迭香酸与三乙胺的摩尔比为1:1.5至1:5;反应温度为室温至回流;反应时间24-48小时。
3.权利要求2所述的制备方法,其特征在于,包括以下步骤:
氮气保护下,向干燥的反应瓶中加入迷迭香酸、水飞蓟宾、EDCl和HOBt,用无水N,N-二甲基甲酰胺溶解,缓慢滴加三乙胺,室温搅拌24-48小时,停止反应后,将反应液倾入冰水中,析出大量固体,固体抽滤干燥后经硅胶柱层析纯化得到水飞蓟宾迷迭香酸酯(I),
其中,迷迭香酸与水飞蓟宾的摩尔比为1:1至1:2;
其中,迷迭香酸、HOBt、EDCl三者的摩尔比为1:(1-1.5):(1-1.5);其中,迷迭香酸与三乙胺的摩尔比为1:1.5至1:5。
4.权利要求2所述的制备方法,其特征在于,包括以下步骤:
氮气保护下,向干燥的反应瓶中加入2.77mmol迷迭香酸、3.33mmol水飞蓟宾、3.6mmolEDCl和3.6mmol HOBt,用无水N,N-二甲基甲酰胺溶解,缓慢滴加6.9mmol三乙胺,室温搅拌48小时,停止反应后,将反应液倾入冰水中,析出大量固体,固体抽滤干燥后经硅胶柱层析纯化得到水飞蓟宾迷迭香酸酯(I)。
5.权利要求4所述的制备方法,其特征在于,所述硅胶柱层析过程中所用的洗脱剂为二氯甲烷和甲醇的混合溶剂,二者的体积比为=50/1~10/1。
6.权利要求4所述的制备方法,其特征在于,所述硅胶柱层析过程中所用的洗脱剂为二氯甲烷和甲醇的混合溶剂,二者的体积比为=20/1。
7.权利要求1中所述的水飞蓟宾迷迭香酸酯或其药用盐在制备用于治疗和/或预防肝脏损伤及肝纤维化类疾病的药物中的应用。
8.权利要求7所述的应用,其特征在于,是通过改善血清ALT、AST水平而实现的,或者是通过抑制肝星状细胞HSC-T6而实现的,或者是通过抑制TGF-β1引起的细胞活化而实现的。
9.如权利要求7所述的应用,所述药物处于片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、口服液或软膏剂的形式,并且所述药物是控释剂型或缓释剂型。
10.一种药物制剂,所述药物制剂包含权利要求1中所述的水飞蓟宾迷迭香酸酯或其药用盐作为活性成分,同时含有药学上可接受的载体或赋形剂。
11.如权利要求10所述的药物制剂,所述药物制剂处于片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、口服液或软膏剂的形式,并且所述药物是控释剂型或缓释剂型。
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