CN114159449B - 3β,23-O-异丙叉基羟基白桦酸在制备抗肝纤维化药物中的应用 - Google Patents
3β,23-O-异丙叉基羟基白桦酸在制备抗肝纤维化药物中的应用 Download PDFInfo
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- CN114159449B CN114159449B CN202111579818.XA CN202111579818A CN114159449B CN 114159449 B CN114159449 B CN 114159449B CN 202111579818 A CN202111579818 A CN 202111579818A CN 114159449 B CN114159449 B CN 114159449B
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- isopropylidene
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Abstract
本发明公开了一种3β,23‑O‑异丙叉基羟基白桦酸在制备抗肝纤维化药物中的应用，本发明构建胆总管结扎SD大鼠肝纤维化模型，并对大鼠肝功能、肝组织病理结构、肝组织纤维化程度、胶原纤维含量进行检测。结果显示，3β,23‑O‑异丙叉基羟基白桦酸能够抑制肝纤维化的产生，可用于制备抗肝纤维化药物。
Description
技术领域
本发明属于医药领域，涉及3β,23-O-异丙叉基羟基白桦酸在制备抗肝纤维化药物中的应用。
背景技术
肝纤维化(hepatic fibrosis)是肝脏受到各种损伤后细胞外基质(即胶原、糖蛋白和蛋白多糖等)弥漫性过度沉积与异常分布的修复反应，是各种慢性肝病向肝硬化发展过程中的关键步骤，如何对其进行有效控制是困扰医学界的重大难题。虽然近年来对肝纤维化基础和临床研究及其认识方面有不少进展，但肝纤维化治疗方面，尚未有公认特异有效的化学药物和生物制剂(中华医学会肝病学分会，中华医学会消化病学分会，中华医学会感染病学分会. 肝纤维化诊断及治疗共识2019年[J].实用肝脏病杂志，2019，22(6):793-803)。而中药干预肝纤维化的进程有着独特疗效,中药可通过抑制肝星状细胞活化、调控脂肪细胞因子、减轻肝脏炎性反应、改善氧化应激、抑制肝窦内皮细胞毛细血管化等方式拮抗肝纤维化，是抗肝纤维化药物研发的天然宝库(谢爱泽,吕超,石清兰等.中医药防治肝纤维化机制的研究进展[J]. 中国医药导报，2020，17(17):34-37.)。
赤芍(Paeonia lactiflora Pall)为毛茛科芍药属植物，其干燥根是一味常用的中药，具有清热凉血、散瘀止痛的功效。现在临床上用于治疗心脑血管疾病的活血中成药如蒲参胶囊、脑栓通胶囊、通心络胶囊及大活络丸等都含有赤芍成分。研究表明赤芍水提物入血后可通过影响乙醛造模后的肝星状细胞(HSC-T6)中Bcl-2、Bax、Caspase-3等基因蛋白异常表达，来实现对HSC-T6的增殖抑制及促凋亡作用，具有一定的抗肝纤维化作用(韩海啸.酒精性肝硬化中医证候学特点和赤芍对HSC增殖和凋亡的影响[D].北京中医药大学，2007)。此外，赤芍总苷具有明显的抗肝纤维化作用，其机制可能与其阻断TGF-β1/Smad信号传导通路有关(高世乐，胡宗涛，董六一.赤芍总苷对大鼠放射性肝纤维化的保护作用及机制[J].中药药理与临床，2012(2):65-68)。但针对其抗纤维化的药效物质研究尚未见报道。
3β,23-O-异丙叉基羟基白桦酸(7C)是从赤芍中分离得到的具有抗肝纤维化活性的羽扇豆烷型五环三萜类化合物。其结构首次公开是在1982年，具体参阅文献Chen,WenKan；Wang, Bi Yu；Lu,De Yu；et al.The saponin of Chinese drug bai-tou-wengPulsatilla chinensis Regal (Anemone chinensis Bunge).III.The structure ofanemosapogenin[J].Chem.Nat.Prod.,Proc. Sino-Am.Symp.1982,240-3。但在后续的公开发表中未见关于7C的结构数据和抗肝纤维化的作用。2017年Sergio R.Peraza-Sanchez团队从墨西哥植物PhoradendronvernicosumGreenm. (Santalaceae)的甲醇提取物中分离得到3α,23-O-异丙叉基-3α,23-二羟基羽扇豆酸，为化合物7C 的同分异构体。研究表明3α,23-O-异丙叉基-3α,23-二羟基羽扇豆酸具有显著的抗癌活性，也未涉及抗肝纤维化的作用，参见文献Valencia-Chan,Lia S.；Garcia-Camara,Isabel；Torres-Tapia,etal.Lupane-Type Triterpenes of Phoradendronvernicosum[J].J.Nat.Prod.2017,80(11):3038-3042。
发明内容
本发明的目的是克服现有技术的不足，提供3β,23-O-异丙叉基羟基白桦酸在制备抗肝纤维化药物中的应用。
本发明的技术方案概述如下：
本发明技术方案提供了一种如下式所示的3β,23-O-异丙叉基羟基白桦酸(7C)在制备抗肝纤维化药物中的应用。
本发明技术方案的第二方面是提供了一种药物组合物，其中包括作为有效成分的技术方案第一方面所提供的3β,23-O-异丙叉基羟基白桦酸(7C)及其药学上可接受的盐，和制药领域中常用的载体。
通常本发明药物组合物含有0.1-99.9％重量的本发明化合物。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时，如果需要，可将本发明的化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合，制成可作为人药或兽药使用的适当的施用形式或剂量形式。
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、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等，优选口服。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射和皮内注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明提取物或化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、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。
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、 Gelucire、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊，将有效成分本发明提取物或化合物与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明化合物制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
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、甜味剂或其它材料。
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。
本发明化合物、药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围本发明的提取物或化合物的用量为0.001-150mg/kg体重，优选为0.01-100mg/kg体重，更优选为0.01-60mg/kg体重，最优选为0.1-10mg/kg体重。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物、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并调整剂量。
本发明的有益效果：
1)本发明首次公开了3β,23-O-异丙叉基羟基白桦酸在制备抗肝纤维化药物中的应用；
2)实验证明3β,23-O-异丙叉基羟基白桦酸在SD大鼠胆总管结扎诱导的肝纤维化模型中，具有抗实验性肝纤维化作用。
本发明构建胆总管结扎SD大鼠肝纤维化模型，并对大鼠肝功能、肝组织病理结构、肝组织纤维化程度、胶原纤维含量进行检测。结果显示，3β,23-O-异丙叉基羟基白桦酸能够抑制肝纤维化的产生。对于肝纤维化的治疗具有重要价值。
附图说明
图1各组大鼠肝脏组织病理评价(A，HE染色结果图；B，各组动物组织胆管增生情况统计图；C，各组动物组织坏死情况统计图；)
图2 Sirius red染色评价各组大鼠肝脏组织胶原沉积情况(A，Sirius red染色结果示意图；B，各组动物组织胶原染色阳性统计图)；
图3 7C对大鼠肝脏组织羟脯氨酸含量的影响。
具体实施方式：
下列所描述的实施例是本发明一部分实施例，而不是全部的实施例，仅用于说明本发明，而不应视为限制本发明的范围。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。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，均为可以通过市售购买获得的常规产品。
实施例1 3β,23-O-异丙叉基羟基白桦酸(7C)的制备
23-羟基白桦酸(130mg，0.28mmol)与2,2-二甲氧基丙烷类似物(258mg，2.48mmol)在酸性丙酮溶液中反应产物。上述参与反应原理均可通过商业购买获得。该反应在室温条件下进行，TLC监测至原料点消失，旋干后加水用DCM萃取，得白色固体140mg(7C)。7C 的相关核磁数据见表1.
表1.1H and 13C NMR Data for 7C in pyridine-d5.(NMR data were measuredat 600MHz for 1H NMR and at 150MHz for 13C NMR.The assignments were based on1H-1H COSY,HSQC,and HMBC experiments.)
实施例2 SD大鼠胆总管结扎诱导的肝纤维化模型制备
选取健康的SD雄性大鼠21只，体重范围180-220g，随机分为假手术组、模型组、7C给药组三组，其中假手术组7只，模型组7只，7C给药组7只。构建模型前禁食12h，用异氟烷麻醉动物进行手术。其中模型组和给药组在无菌条件下做胆总管结扎(BDL)手术。步骤：上腹正中切口，抬高肝缘，拉开十二指肠，分离总胆管2-3cm，在近十二指肠处和近肝门处用000号丝线各结扎两道，从中间剪断胆总管。假手术组仅作上腹正中切口并缝合，不做胆总管结扎。动物麻醉清醒后，正常饲养，自由饮水，肌注青霉素3天，以防感染，实验温度(22±2)℃。造模后第2天开始腹腔给药，分别给予生理盐水(假手术组、模型组)和 7C(50mg/kg，7C给药组)，每天1次，连续给药14天。
实施例3 7C对BDL诱导的大鼠血清ALT/AST水平升高的抑制作用
取样前禁食12h，用10％水合氯醛麻醉大鼠，取腹主动脉血。2000rpm离心10min，取血清进行谷草转氨酶(AST)和谷丙转氨酶(ALT)的活性检测。结果显示，7C能够抑制大鼠血清中ALT和AST的含量(表2)，表明7C能够改善大鼠肝功能。
表2.对BDL诱导的大鼠血清ALT/AST水平的影响
**p<0.01与假手术组相比，#p<0.05与BDL组相比。
实施例4 7C对BDL诱导的大鼠肝脏病理结构改变的抑制作用
取样前禁食12h，处死大鼠，取肝脏组织，切下肝大叶组织块放入10％福尔马林中固定。经过脱水、石蜡包埋、切片、烤片等制作石蜡切片。利用苏木素-伊红(HE)染色液进行染色，观察大鼠肝脏组织病理结构变化情况。结果显示，假手术组大鼠肝脏组织肝细胞规则排列，肝小叶完整，无炎性细胞浸润和胆管增生情况；BDL后大鼠肝脏组织病理结构发生明显改变，胆管增生十分明显，组织坏死明显增多；7C给药组的大鼠肝组织结构得到明显改善，胆管增生情况得到显著抑制，组织坏死程度明显降低(图1)。表明，7C能够明显改善BDL大鼠肝脏组织的病理结构。
实施例5 7C对BDL诱导的大鼠肝脏胶原沉积的抑制作用
将石蜡切片进行Sirius red染色，观察大鼠肝脏组织纤维化情况。结果显示，BDL后大鼠肝脏组织纤维化程度明显增加，胶原沉积明显；7C给药后，纤维化程度得到明显抑制(图2)。结果表明，7C能够明显抑制BDL诱导的大鼠肝纤维化。
实施例6 7C对大鼠肝脏组织中羟脯氨酸含量的影响
取样前禁食12h，处死大鼠，取肝脏组织，精确称取30-100mg，按照羟脯氨酸测试盒(购自南京建成生物工程研究所)说明书进行操作。结果显示，与假手术组大鼠相比，BDL组大鼠肝脏组织中羟脯氨酸含量明显升高；与BDL组相比，给药化合物7C后，大鼠肝脏组织中羟脯氨酸含量显著降低(图3)。结果表明，7C能够明显降低肝脏组织中羟脯氨酸的含量，即7C能够明显抑制BDL大鼠中胶原纤维的产生。
Claims (1)
1.3β,23-O-异丙叉基羟基白桦酸在制备抗肝纤维化药物中的应用，所述3β,23-O-异丙叉基羟基白桦酸的结构如式(I)所示：
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