CN108379245B - N-(2-乙氧基苯基)-n-羟基辛二酰胺在制备抗肝纤维化药物中的应用 - Google Patents
N-(2-乙氧基苯基)-n-羟基辛二酰胺在制备抗肝纤维化药物中的应用 Download PDFInfo
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- CN108379245B CN108379245B CN201810112756.3A CN201810112756A CN108379245B CN 108379245 B CN108379245 B CN 108379245B CN 201810112756 A CN201810112756 A CN 201810112756A CN 108379245 B CN108379245 B CN 108379245B
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
本发明涉及医药的技术领域，公开了N‑(2‑乙氧基苯基)‑N‑羟基辛二酰胺在制备抗肝纤维化药物中的应用。本发明研究显示N2E对HDAC的靶向抑制作用显著，较原药SAHA强5倍以上；动物肝纤维化模型有良好的抗纤维化作用和保护肝功能作用。实验结果发现，N2E对由四氯化碳诱导的肝纤维动物模型的具有较强的抗肝纤维化作用，逆转纤维化进程，恢复肝脏功能。N2E对HDAC靶向性抑制剂的抗肝纤维化作用，对治疗肝纤维化疾病，逆转纤维化损害肝脏功能，具有较为重要的意义。
Description
技术领域
本发明涉及医药的技术领域，更具体的，涉及N-(2-乙氧基苯基)-N-羟基辛二酰胺在制备抗肝纤维化药物中的应用。
背景技术
组肝病是危害人类身体健康的危险因素之一。据统计，全球每年超过100万死于病毒性肝炎,我国每年有许多急性肝炎和肝炎病毒携带者发展为慢性肝炎，且发病率一直居法定传染病报告前列，慢性肝炎可发展为肝硬化，最终演变成肝癌，我国肝癌发病率每年约占世界肝癌死亡人数的40%，是我国目前面临的严峻的公共卫生问题之一。而肝纤维化（hepatic fibrosis）是多种病因导致慢性肝损害的共同结果，是肝脏对一系列慢性刺激的损伤修复的病理性反应，以细胞外基质过度沉积为主要特征。目前为止，仍然未出现获得临床批准使用的抗纤维化的药物。治疗方法主要是靠肝移植。然而这里面临的问题是有限的肝脏捐赠。因此，研制出有效的抗纤维化药物是极其关键和必要的。
人肝星状细胞（hepatic stellate cells，HSCs）的活化与增殖是肝纤维化形成的中心环节。因此，HSCs的激活机制及抑制活化途径的研究已成为防治肝纤维化的关键，目前国际上肝纤维化药物研发的思路是从肝纤维化发生机制中寻找靶点，但由于HSCs活化是多条信号通路相互协调的结果，其复杂性、未知性造成了阻断方式的特异性、多样性，使得该研究仍处于实验室阶段，要想应用于临床还需要大量实验证明，寻找出合适的靶点进行相关药物研究开发。
而近年最新研究进展提出表观遗传学的调控异常可能是肝纤维化发病和发展主要驱动力的观点。主要表现为由组蛋白乙酰化（histone acetylation）所参与的调节HSCs的活化增殖环节。并提出组蛋白去乙酰化酶（histone deacetylase，HDAC）可能是具有较高潜在应用价值的特异性靶标。
文献报道，表观遗传学的调控变化在肝纤维化的发生发展过程中起着重要作用。HDAC（组蛋白去乙酰化酶）是重要的表观遗传学组成酶之一。组蛋白去乙酰化酶作为表观遗传学中组蛋白去乙酰化调控中较为重要的酶类之一，与组蛋白乙酰转移酶（Histoneacetyltransferase，HAT）维持着真核生物细胞内乙酰化水平的动态平衡。乙酰化转移酶(HAT)主要是在组蛋白3和组蛋白4的N—端尾上的赖氨酸部位加上乙酰基团，而去乙酰化酶(HDAC)则与之不同，不同关键部位的修饰均需要特异性的酶来辅助完成。
组蛋白是第一个被发现能被特异性酶作用后产生乙酰化的蛋白，作用后一方面能够影响蛋白质的功能，另一方面使某些基因转录后进行修饰最为突出的作用之一。有研究表明，通过对全基因组的高通量筛选中，一些非组蛋白的蛋白质也同样发生了乙酰化作用和去乙酰化作用，进而调节在细胞中扮演重要角色的关键蛋白复合物。HDAC的各类亚型在机体的分布存在着多样性，且发挥着功能各异的作用。
近年大量研究显示，HDAC在肝纤维化的发生和发展进程中发挥着重要的作用：通过作用于由TGF-β1所引导的Smad通路来发挥抗肝纤维化。SAHA（vorinostat 伏立诺他）为首个被美国FDA批准上市的HDAC抑制剂。最近，研究发现SAHA对博来霉素所诱导的特发性肺纤维化有显著的修复作用。
发明内容
本发明解决的技术问题是克服现有的问题，提供N-(2-乙氧基苯基)-N-羟基辛二酰胺在制备抗肝纤维化药物中的应用。
本发明通过以下技术方案予以实现：
一种N-(2-乙氧基苯基)-N-羟基辛二酰胺及其药学上可接受的盐、水合物、溶剂合物在制备抗肝纤维化药物中的应用。
所述N-(2-乙氧基苯基)-N-羟基辛二酰胺(N -(2-ethoxyphenyl)-N-hydroxyoctanediamide，简称N2E)的结构式如下：
优选地，所述药学上可接受的盐由N-(2-乙氧基苯基)-N-羟基辛二酰胺与无机酸、有机酸、无机碱或有机碱进行化学反应得到。
优选地，所述无机酸或有机酸选自：盐酸、氢溴酸、氢碘酸、硫酸、硝酸、碳酸、磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、苯磺酸、取代的苯磺酸、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸或蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸、山梨酸；所述无机碱或有机碱选自：氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸钾、碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、 碳酸氢钙、碳酸氢钡、碳酸氢镁、碳酸氢化有机季铵盐。
与现有技术相比，本实用新型的有益效果：
本发明研究显示，N2E对HDAC的靶向抑制作用显著，较原药SAHA强5倍以上；动物肝纤维化模型有良好的抗纤维化作用和保护肝功能作用。实验结果发现，N2E对由四氯化碳诱导的肝纤维动物模型的具有较强的抗肝纤维化作用，逆转纤维化进程，恢复肝脏功能。
N2E对HDAC靶向性抑制剂的抗肝纤维化作用，对治疗肝纤维化疾病，逆转纤维化损害肝脏功能，具有较为重要的意义。
附图说明
图1为N2E对肝损伤的保护作用（HE染色×200）；
图2为N2E抗肝脏纤维化作用（天狼星红红染色×200），（*p <0.001，vs.CCl4）；
图3为N2E对肝脏胶原纤维含量的影响，（*p <0.001，***p <0.001，vs.CCl4）；
图4为N2E对肝组织中羟脯氨酸含量的影响，（*p <0.05, **p <0.01, ***p <0.001，vs.CCl4）；
图5为N2E对肝脏功能的影响，（*p <0.001，#p <0.001，vs.CCl4）。
具体实施方式
本发明可以结合以下具体实施例进一步解释和阐明，但具体实施例并不对本发明有任何形式的限定。
一种药学上可接受的盐由N-(2-乙氧基苯基)-N-羟基辛二酰胺与无机酸、有机酸、无机碱或有机碱进行化学反应得到。
无机酸或有机酸选自：盐酸、氢溴酸、氢碘酸、硫酸、硝酸、碳酸、 磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、 苯磺酸、取代的苯磺酸、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、 富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸或蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸、山梨酸；无机碱或有机碱选自：氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸钾、 碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、 碳酸氢钙、碳酸氢钡、碳酸氢镁、碳酸氢化有机季铵盐。
实施例1 N2E抗动物肝纤维化模型实验
C57小鼠70只，雌雄各半，8周龄，体重19~22g，随机均分7组，即阴性对照组、肝纤维化模型组、N2E三个剂量治疗组（10mg/kg、20 mg/kg、 40mg/kg）和两个阳性药物对照组SAHA治疗组、水飞蓟宾治疗组。阴性对照组给予腹腔注射玉米油5mL/kg，进行空白溶剂对照。除阴性对照组外，其它组小鼠腹腔注射20%CCl4（玉米油1：4稀释）5mL/kg，每周2次，持续6周，同时治疗组隔天同体积灌胃给药，直至6周实验结束停止给药。实验结束后24h，将小鼠麻醉，眼眶取血收集血样于EP管中，以备检测ALT和AST，然后处死小鼠，收集肝脏标本。将肝组织分为两部分，一部分用于石蜡包埋，以备病理切片，另一部分液氮速冻，然后-80℃贮存，以备检测羟脯氨酸含量。
（一）HE染色肝组织，观察N2E对CCl4损伤肝脏的保护作用
主要材料：肝组织石蜡切片。
主要试剂：苏木精水溶液，酒精伊红染色液。
主要仪器：普通光学显微镜。
试验方法（HE染色）：剖腹取肝，将小鼠肝脏组织用10%中性缓冲甲醛液固定，脱水，石蜡包埋、切片、脱蜡，使用苏木素和伊红对组织进行染色，脱水，中性树胶封片，观察其肝脏组织形态学变化。
实验结果：光镜下进行组织病理学检查，观察肝小叶结构、细胞形态及排列、炎性细胞浸润及纤维组织增生程度，见图1（小鼠HE染色结果×200）。空白对照组小鼠细胞排列规则,肝小叶结构完好，肝脏无明显炎症浸润，肝细胞无变性此坏死，肝索围绕于中央静脉呈放射状。模型组小鼠可见明显炎症细胞浸润，肝细胞坏死，胶原纤维生成，并交联成网状。N2E组有明显改善，存在少量炎症浸润，且修复程度强于SAHA组以及水飞蓟宾组。
（二）天狼星红染色肝组织，观察N2E对小鼠肝纤维化模型胶原纤维的作用
主要材料：肝组织石蜡切片。
主要试剂：天狼星红-饱和苦味酸液：0.5%天狼星红，苦味酸饱和水溶液、天青石蓝液。
主要仪器：普通光学显微镜。
试验方法（天狼星红染色）：对石蜡切片进行脱蜡至水，入天青石蓝夜5~10min。在用蒸馏水冲洗3次。天狼星红饱和苦味酸浸泡15~30min，再使用无水乙醇分化与脱水，二甲苯使切片透明可见，光学树胶封固。
实验结果：对于研究肝纤维化病变的发生机理和演变过程有一定的意义。利用胶原蛋白聚合及其缠绕螺旋排列不同的特点，使用天狼星红苦味酸染色法，在光学显微镜下，可以根据显示出胶原纤维（显红色）来判断肝纤维化的程度。结果显示，模型组（CCl4）纤维化严重的，N2E组纤维化明显减轻，见图2；Image J软件对其胶原纤维含量进行统计学处理，与正常组比较，N2E组的胶原纤维含量已经接近正常水平，具有良好的抗纤维化作用，见图3。
（三）检测肝组织羟脯氨酸，观察N2E对小鼠肝纤维化进程的下调作用
主要材料：肝组织。
主要试剂：二甲基亚砜（DMSO）、羟脯氨酸试剂盒（购自南京建成生物工程研究所）。
主要仪器：680型酶联检测仪。
实验方法：采用羟脯氨酸试剂盒进行肝脏组织羟脯氨酸的含量检测，精确称取组织湿重 30~100mg 放入试管中，准确加水解液 1ml，混匀。加盖后95°C或者沸水浴水解20分钟，调PH值至6.0~6.8左右。取3~4ml稀释的水解液加适量活性炭(约20~30mg左右，以上清液离心后澄清无色为准)，混匀，3500 转/分离心10分钟，小心取上清1ml作检测。根据试剂盒加入对应试剂到检测样本。混匀，60°C水浴15分钟，冷却后，3500转/分离心10分钟，取上清在550nm处，1cm光径，双蒸水调零，测各管吸光度。根据公式换算出羟脯氨酸含量。
实验结果：羟脯氨酸是胶原所特有的氨基酸，测定肝组织中羟脯氨酸含量可知胶原总体水平，是反映肝纤维化程度的直接指标。与阴性对照组比较，模型组肝组织羟脯氨酸的含量升高具有非常显著性差异，N2E三个剂量组和阳性药物对照组肝组织羟脯氨酸的含量降低均有显著性差异，而N2E的降低作用更加明显，说明N2E具有良好的抗肝纤维化作用，能够抑制肝纤维化的进程。实验结果见表1和图4。
表1 N2E对肝纤维化小鼠作用后肝组织羟脯氨酸含量（`x ±SD）
| 组别 | 动物数 | 羟脯氨酸（μg/g） |
| 低剂量组 | 8 | 302.35±63.76<sup>***</sup> |
| 中剂量组 | 9 | 327.99±49.48<sup>**</sup> |
| 高剂量组 | 7 | 328.23±69.69<sup>**</sup> |
| SAHA组 | 8 | 323.83±95.66<sup>**</sup> |
| 空白组 | 6 | 205.37±27.11 |
| CCl<sub>4</sub>组 | 5 | 458.36±48.03<sup>#</sup> |
注：用药组与模型组比较， ***P＜0.001、**P＜0.01；‚模型组与空白组比较 ，# P＜0.001；ƒ用药组之间无显著性差异。
（四）检测血清ALT、AST的活力，观察N2E对小鼠肝纤维化模型的肝功能
保护作用
主要材料：60只C57BL/6J小鼠血清。
主要试剂：ALT、AST试剂盒购置于南京建成生物工程公司。
主要仪器：680型酶联检测仪。
实验方法：对小鼠采取眼球取血，再置4℃冰箱内3～4小时或过夜；待血液凝固血块收缩后，4000rpm离心10分钟；取上清于干净的离心管中，保存于-20℃，或加入防腐剂(0.01％硫柳汞或0.02％叠氮钠)，置4℃冰箱中保存备用。根据ALT、AST试剂盒说明书方法操作，使用酶标仪进行检测。
实验结果：ALT与AST是检测肝功能的指标，能反映肝细胞是否损伤及损伤程度。与正常组比较，模型组血清ALT、AST的活力升高均有非常显著性差异。与模型组比较，N2E三个剂量组和阳性药物对照组血清ALT、AST的活力降低均具有非常显著性差异，而N2E的降低作用更加明显，说明N2E具有良好的抗肝纤维化作用。实验结果见表2和图5。
表2 N2E对肝纤维化小鼠血清转氨酶(AST，ALT)的影响（`x ±SD）
| 组别 | 动物数 | ALT（U/L） | ALT（U/L） |
| 低剂量组 | 5 | 44.2±5.9*** | 41.2±8.2*** |
| 中剂量组 | 6 | 41.2±5.6*** | 58.9±9.9*** |
| 高剂量组 | 6 | 25.1±6.9*** | 55.1±9.9*** |
| SAHA组 | 6 | 29.5±9.9*** | 37.6±9.0*** |
| 水飞蓟宾组 | 7 | 187.5±50.5** | 103.7±26.8** |
| 空白组 | 5 | 25.1±4.4*** | 37.9±4.4 |
| 四氯化碳组 | 6 | 262.2±58.0 | 145.8±44.5<sup>***</sup> |
注：用药组与模型组比较， ***P＜0.001；‚模型组与空白组比较，# P＜0.001。
本发明中N2E对动物肝纤维化模型（CCl4灌胃，6周）的药效学实验、抗肝脏纤维化作用和保护肝脏功能等的实验结果如下：
一、苏木素-伊红 (hematoxylin-eo-sin，HE)染色肝脏病理切片检测结果
光镜下进行组织病理学检查，观察肝小叶结构、细胞形态及排列、炎性细胞浸润及纤维组织增生程度。模型组小鼠可见明显炎症细胞浸润，肝细胞坏死，交联成网状胶原纤维。N2E组较模型组有明显改善，存在少量炎症浸润，修复程度强于SAHA组以及水飞蓟宾组。实验结果见图1。
二、天狼星红染色肝脏病理切片检测结果
N2E对CCl4引起的慢性肝纤维化小鼠模型具有显著的抗纤维化作用和良好的肝纤维化修复作用，见图2。采用Image J软件对其胶原纤维含量进行统计学处理，与正常组比较，N2E组的胶原纤维含量已经接近正常水平，呈良好的抗纤维化作用，见图3。
三、肝组织羟脯氨酸检测结果
肝纤维化形成过程中随着胶原酶活性增加，胶原降解产物也必然增加，反过来可用其产物反映肝纤维化形成情况。当胶原降解之后，羟脯氨酸不再重复利用，因而肝组织中羟脯氨酸含量最能反映胶原降解情况，即反映N2E的抗纤维化作用。实验结果显示，N2E具有显著的降低肝组织羟脯氨酸含量作用。实验结果见表1和图4。
四、血清肝功能检查
谷丙转氨酶(ALT)是最常用的敏感指标，1%的肝细胞发生坏死时，血清ALT水平即可升高一倍。与CCl4模型组比较，N2E均能明显降低肝纤维化模型小鼠血清谷草转氨酶(AST)和谷丙转氨酶(ALT)水平，比阳性药物SAHA组更接近空白组的正常值。实验结果见表2和图5。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。
Claims (1)
1.一种N-(2-乙氧基苯基)-N-羟基辛二酰胺及其药学上可接受的盐在制备抗肝纤维化药物中的应用；所述药学上可接受的盐由N-(2-乙氧基苯基)-N-羟基辛二酰胺与无机酸、有机酸、无机碱或有机碱进行化学反应得到。
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