CN108484431A - 一种肉桂酰氨基酸类化合物及其用途 - Google Patents
一种肉桂酰氨基酸类化合物及其用途 Download PDFInfo
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- CN108484431A CN108484431A CN201810249960.XA CN201810249960A CN108484431A CN 108484431 A CN108484431 A CN 108484431A CN 201810249960 A CN201810249960 A CN 201810249960A CN 108484431 A CN108484431 A CN 108484431A
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- Prior art keywords
- cinnamoyl
- tyrosine
- amino acids
- hydroxycinnamoyls
- hydroxy
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- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种肉桂酰氨基酸类化合物及其用途，涉及药物化学和药物治疗学领域，具体涉及一种具有诱导型一氧化氮合酶（iNOS）抑制活性的肉桂酰氨基酸类化合物或其药学上可接受的盐或酯，含有这些化合物的药用组合物以及它们的医药用途，特别是在预防和治疗神经细胞损伤相关的神经变性疾病，包括缺血性脑中风、帕金森症等方面的应用。
Description
技术领域
本发明涉及一种肉桂酰氨基酸类化合物，具体涉及一种具有诱导型一氧化氮合酶(iNOS)抑制活性的肉桂酰氨基酸类化合物，及其在治疗和预防缺血性脑中风、帕金森症的药物中的应用，属于药学技术领域。
背景技术
急性缺血性脑中风具有高发生率、高致残率和高死亡率的特点，流行病学调查结果显示，该类病症发病渐趋年轻化，已经引起了广泛了重视。炎症反应在缺血所致的脑损伤病理过程中起着重要的作用。脑缺血后发生炎症反应的重要标志之一是胶质细胞的活化。胶质细胞是中枢神经系统内数量最多的一类免疫细胞，不仅能为神经元提供营养和支持，而且还能调节神经递质的释放，维持脑内稳态的平衡，因此在神经系统疾病中发挥着极其重要的作用。当其被大量激活时也会分泌产生大量的炎症因子和神经毒性物质，引发炎症反应。在局灶性脑缺血损伤的大鼠脑内发现星型胶质细胞活化标志物神经胶质纤维酸性蛋白(GFAP)表达明显提高。此外，在缺血性脑中风患者脑内可见大量活化的小胶质细胞，表明小胶质细胞与脑缺血的发病过程密切相关。因此抑制脑缺血损伤中小胶质细胞的过度活化，阻断小胶质细胞介导的炎症反应将为缺血性脑中风的治疗提供新的思路和途径。
帕金森症是指一种慢性的运动系统退行性疾病，主要引起原因是患者黑质纹状体多巴胺能神经通过发生渐进性或者选择性变性导致。通常认为高龄或者遗传倾向是造成患者PD的主要原因，但现代临床研究证明神经性炎症对PD的病程发展也具有重要影响作用。医学研究者通过相关的医学试验发现，神经性炎症既可以诱导PD的发生，同时又可以加重PD的病情发展，在神经性炎症中的小胶质细胞和外周入侵的T淋巴细胞会导致PD的发生，并加重病情的发展。
诱导性一氧化氮合酶(iNOS)在生物体内一般处于静默状态，由炎症细胞因子或内毒素等诱导激活，生成后即可大量合成NO。过量的NO引起DNA损伤、线粒体呼吸抑制等等，最重要的是与超氧负离子(O2-)形成过氧亚硝酸盐阴离子(ONOO-)等活性氮，对关键蛋白进行氮化修饰，改变信号途径，直接和间接介导NO的细胞毒性效应；此外多重级联信号被活化，这些信号通路之间又相互影响，形成炎症级联瀑布反应，推动炎症发展，导致多种疾病，如上述所说的缺血性脑中风及帕金森症。
阿魏酸(Ferulic Acid)，化学名为4-羟基-3-甲氧基苯丙烯酸，是肉桂酸(Cinnamic acid)化学名为苯丙烯酸的衍生物。研究表明，阿魏酸及其钠盐具有神经保护作用。阿魏酸钠对慢性脑缺血造成的神经氧化损伤具有保护作用；阿魏酸钠可减轻谷氨酸产生的神经细胞的兴奋性毒性，减少大脑梗死面积，对减轻局部脑缺血损伤具有明显的治疗效果。上述神经保护机制均与阿魏酸的抗神经炎症作用密切相关。但是由于阿魏酸及其钠盐亲脂性较差，难以通过血脑屏障，且存在生物利用度低，体内有效药物浓度维持时间段等问题。这些问题严重限制了其作为神经保护药物的临床应用。而其衍生物肉桂酸的亲脂性较强，易于通过血脑屏障，因此，以肉桂酸为先导化合物进行结构改造，对于发现活性抗炎神经保护药物意义重大。
发明内容
目的：本发明提供一种具有诱导型一氧化氮合酶(iNOS)抑制活性的肉桂酰氨基酸类化合物及医药用途。
技术方案：为解决上述技术问题，本发明采用的技术方案为：
一种肉桂酰氨基酸类化合物，为通式I所示的化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐：
其中：R1表示4-羟基苯甲基、苯甲基、乙酸基或丙酸基，
R2表示H或羟基，R3表示H、羟基或甲氧基。
作为优选方案，所述的肉桂酰氨基酸类化合物，选自：4-羟基肉桂酰-L-酪氨酸，肉桂酰-L-酪氨酸，3-羟基肉桂酰-L-酪氨酸，4-羟基-3-甲氧基肉桂酰-L-酪氨酸，4-羟基肉桂酰-L-苯丙氨酸，肉桂酰-L-苯丙氨酸，3-羟基肉桂酰-L-苯丙氨酸，4-羟基-3-甲氧基肉桂酰-L-苯丙氨酸，4-羟基肉桂酰-L-天冬氨酸，3-羟基肉桂酰-L-天冬氨酸，肉桂酰-L-谷氨酸，3-羟基肉桂酰-L-谷氨酸，4-羟基-3-甲氧基肉桂酰-L-谷氨酸，或其药学上可接受的盐。
更为优选的，所述化合物为4-羟基-3-甲氧基肉桂酰-L-酪氨酸。
另一方面，本发明提供上述的肉桂酰氨基酸类化合物在制备预防或治疗神经细胞损伤相关的神经变性疾病的药物中的应用。所述神经变性疾病包括缺血性脑中风、帕金森症。
另一方面，本发明提供一种药物组合物，其中含有治疗有效量的一种或多种上述的肉桂酰氨基酸类化合物或其药学上可接受的盐。
本发明还要求所述的药物组合物在制备预防或治疗神经细胞损伤相关的神经变性疾病的药物中的应用。神经变性疾病包括缺血性脑中风、帕金森症。
本发明通过大量的现代药理科学研究，证实了肉桂酰氨基酸类化合物具较强的抗神经炎症作用，并且可以有效抑制iNOS。同时对治疗及预防缺血性脑中风及帕金森症的作用进行研究。结果表明，该类化合物药理作用清晰，治疗缺血性脑中风及帕金森症效果显著，毒副作用小，安全性高，为缺血性脑中风及帕金森患者提供一种高效低度的药物。
有益效果：本发明设计、合成了肉桂酰氨基酸类化合物，体外活性研究表明其具有双重的Nrf2和AMPK激动活性。在多个体内模型中，杂合物显示比丁苯酞联合替米沙坦更强的抗脑缺血活性，也显示了比Edaravone更强的抗脑缺血活性。含有这些化合物的药用组合物以及它们的医药用途，特别是在预防和治疗与神经炎症相关的疾病，包括缺血性脑中风、阿尔兹海默病、脑外伤、帕金森病、多发性硬化和抑郁症等方面具有良好的应用前景。
附图说明
图1是本发明NO释放量结果图；
图2是本发明化合物帕金森小鼠转棒实验效果图；
图3是化合物4对MCAO后脑梗死面积影响图。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1
1.肉桂酰氨基酸类化合物体外抗炎活性研究
1.1实验材料：BV-2细胞、DMEM细胞培养液、Gibico胎牛血清、96孔细胞培养板、DMSO(Sigma)、LPS(Sigma)、NO检测试剂盒(碧云天)、酶标仪。
1.2实验方法：
将BV-2细胞以1×104个细胞/孔的密度接种于96孔板中，随后进行分组；空白组、LPS模型组、LPS+10μM不同测试药物组，培养24小时。然后将药物及空白培养液分别加入相应组别中继续培养4小时。最后，除空白组外，其余每组均加入终浓度为500ng/mL的LPS刺激24小时。最终，吸取50μL上清液按照NO检测试剂盒要求进行NO含量测定。
1.3实验结果：如图1所示，NO释放量。4-羟基肉桂酰-L-酪氨酸(化合物1)，肉桂酰-L-酪氨酸(化合物2)，3-羟基肉桂酰-L-酪氨酸(化合物3)，4-羟基-3-甲氧基肉桂酰-L-酪氨酸(化合物4)，4-羟基肉桂酰-L-苯丙氨酸(化合物5)，肉桂酰-L-苯丙氨酸(化合物6)，3-羟基肉桂酰-L-苯丙氨酸(化合物7)，4-羟基-3-甲氧基肉桂酰-L-苯丙氨酸(化合物8)，4-羟基肉桂酰-L-天冬氨酸(化合物9)，3-羟基肉桂酰-L-天冬氨酸(化合物10)，肉桂酰-L-谷氨酸(化合物11)，3-羟基肉桂酰-L-谷氨酸(化合物12)，4-羟基-3-甲氧基肉桂酰-L-谷氨酸(化合物13)。**P＜0.05vs.空白组；#P＜0.01和##P＜0.01vs.模型组。
1.4结果讨论：10μM下，肉桂酰氨基酸类化合物可以显著地抑制NO的释放。其中化合物2，4，7抑制作用最为明显。证实，该类化合物具有较强的体外抗炎活性。
实施例2
2.肉桂酰氨基酸类化合物体外抑制iNOS作用
2.1实验材料：BV-2细胞、DMEM细胞培养液、Gibico胎牛血清、96孔细胞培养板、DMSO(Sigma)、LPS(Sigma)、iNOS活力检测试剂盒(碧云天)、酶标仪。
2.2实验方法：将BV-2细胞以1×104个细胞/孔的密度接种于96孔板中，随后进行分组；空白组、LPS模型组、LPS+(0.01-10μM)不同测试药物组，培养24小时。然后将药物及空白培养液分别加入相应组别中继续培养4小时。最后，除空白组外，其余每组均加入终浓度为500ng/mL的LPS刺激24小时。最终，按照iNO检测试剂盒要求进行iNOS活力测定。
2.3实验结果：
表1所示，肉桂酰氨基酸类化合物对iNOS的半数抑制IC50值。4-羟基肉桂酰-L-酪氨酸(1)，肉桂酰-L-酪氨酸(2)，3-羟基肉桂酰-L-酪氨酸(3)，4-羟基-3-甲氧基肉桂酰-L-酪氨酸(4)，4-羟基肉桂酰-L-苯丙氨酸(5)，肉桂酰-L-苯丙氨酸(6)，3-羟基肉桂酰-L-苯丙氨酸(7)，4-羟基-3-甲氧基肉桂酰-L-苯丙氨酸(8)，4-羟基肉桂酰-L-天冬氨酸(9)，3-羟基肉桂酰-L-天冬氨酸(10)，肉桂酰-L-谷氨酸(11)，3-羟基肉桂酰-L-谷氨酸(12)，4-羟基-3-甲氧基肉桂酰-L-谷氨酸(13)
2.4结果讨论：iNOS抑制实验结果可以看出该类化合物具有较强的iNOS抑制作用，其中化合物肉桂酰-L-酪氨酸(2)，4-羟基-3-甲氧基肉桂酰-L-酪氨酸(4)和3-羟基肉桂酰-L-苯丙氨酸(7)抑制作用较强。该结果与NO释放量一致。
实施例3
3.优选化合物4-羟基-3-甲氧基肉桂酰-L-酪氨酸体内抗帕金森活性
3.1实验材料：10周龄C57BL/6、转棒疲劳仪、MPTP(Sigma)
3.2实验分组：小鼠随机分为5组，每组5只：正常对照组、单独给予地骨皮甲素组、模型组、4-羟基-3-甲氧基肉桂酰-L-酪氨酸低剂量组(10mg/kg)，4-羟基-3-甲氧基肉桂酰-L-酪氨酸高剂量组(20mg/kg)。连续预给药12天，空白组和造模组给予等剂量的PBS，第13天进行造模，模型组和给药组给与腹腔注射MPTP(20mg/kg)每2h注射一次，连续注射4次。造模结束后，进行行为学测试。使用YLS-4C小鼠转棒仪测试小鼠的转棒行为表现。MPTP造模结束后4，24，48，72h分别将小鼠置于转棒上，转速为20rpm，测试小鼠从转棒开始旋转到离开转棒的时间作为小鼠转棒潜伏期，测试时间180s，每只小鼠测3次取平均值。测试前连续训练3天，每天两次。
3.3实验结果：如图2所示，帕金森小鼠转棒实验。其中，化合物4为4-羟基-3-甲氧基肉桂酰-L-酪氨酸。4-羟基-3-甲氧基肉桂酰-L-酪氨酸可以有效的改善帕金森小鼠的运动障碍，并且存在明显的剂量依赖性。该实验结果表明，4-羟基-3-甲氧基肉桂酰-L-酪氨酸可以作为制备治疗及预防帕金森症药物的应用。
实施例4
4.优选化合物4-羟基-3-甲氧基肉桂酰-L-酪氨酸体内抗缺血性脑损伤活性
4.1实验材料：SD大鼠，雄性，体重250-300g，由南京大学模式动物中心提供，饲养于中国药科大学实验动物中心；红四氮唑TCC购买于Sigma。
4.2动物分组及给药方法：将大鼠随机分为4组，即空白组、模型组(MCAO组)、MCAO+化合物4(25mg/kg)、MCAO+化合物4(50mg/kg)。造模成功后，每日灌胃给与不同剂量的化合物4，连续给药15天。给药结束后，取脑，进行TCC染色，拍照记录。所述化合物4即为4-羟基-3-甲氧基肉桂酰-L-酪氨酸。
4.3实验结果：如图3所示，采用大鼠缺血再灌注体内模型结合TTC染色法验证4-羟基-3-甲氧基肉桂酰-L-酪氨酸对于大鼠缺血再灌注24h后而导致的大脑梗死面积的影响。实验结果显示：4-羟基-3-甲氧基肉桂酰-L-酪氨酸可以有效地减小由缺血再灌注引起的脑梗死面积增加，并且呈现出明显的剂量依赖性。该结果一方面证实了4-羟基-3-甲氧基肉桂酰-L-酪氨酸体内的有效性，另一方面也可以间接对体外实验结果进行了验证。
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种肉桂酰氨基酸类化合物，为通式I所示的化合物或其旋光异构体、对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐：
其中：R1表示4-羟基苯甲基、苯甲基、乙酸基或丙酸基，
R2表示H或羟基，R3表示H、羟基或甲氧基。
2.根据权利要求1所述的肉桂酰氨基酸类化合物，其特征在于，所述化合物选自：4-羟基肉桂酰-L-酪氨酸，肉桂酰-L-酪氨酸，3-羟基肉桂酰-L-酪氨酸，4-羟基-3-甲氧基肉桂酰-L-酪氨酸，4-羟基肉桂酰-L-苯丙氨酸，肉桂酰-L-苯丙氨酸，3-羟基肉桂酰-L-苯丙氨酸，4-羟基-3-甲氧基肉桂酰-L-苯丙氨酸，4-羟基肉桂酰-L-天冬氨酸，3-羟基肉桂酰-L-天冬氨酸，肉桂酰-L-谷氨酸，3-羟基肉桂酰-L-谷氨酸，4-羟基-3-甲氧基肉桂酰-L-谷氨酸，或其药学上可接受的盐。
3.根据权利要求1所述的肉桂酰氨基酸类化合物，其特征在于：所述化合物为4-羟基-3-甲氧基肉桂酰-L-酪氨酸。
4.权利要求1-3任一项所述的肉桂酰氨基酸类化合物在制备预防或治疗神经细胞损伤相关的神经变性疾病的药物中的应用。
5.根据权利要求4所述的应用，其特征在于：神经变性疾病包括缺血性脑中风、帕金森症。
6.一种药物组合物，其中含有治疗有效量的一种或多种权利要求1-3任一项所述的肉桂酰氨基酸类化合物或其药学上可接受的盐。
7.权利要求6所述的药物组合物在制备预防或治疗神经细胞损伤相关的神经变性疾病的药物中的应用。
8.根据权利要求7所述的应用，其特征在于：神经变性疾病包括缺血性脑中风、帕金森症。
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| CN113444015A (zh) * | 2020-03-24 | 2021-09-28 | 中国药科大学 | 一种肉桂酰氨基酸类化合物及其用途 |
| CN115417789A (zh) * | 2022-09-03 | 2022-12-02 | 郑州大学 | 一种治疗帕金森氏病的新化合物、其制备方法以及复方药物组合物和应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021115412A1 (zh) * | 2019-12-12 | 2021-06-17 | 南方医科大学珠江医院 | 一氧化氮合酶通路抑制剂在制备药物中的用途 |
| CN113164605A (zh) * | 2019-12-12 | 2021-07-23 | 南方医科大学珠江医院 | 一氧化氮合酶通路抑制剂在制备药物中的用途 |
| CN113444015A (zh) * | 2020-03-24 | 2021-09-28 | 中国药科大学 | 一种肉桂酰氨基酸类化合物及其用途 |
| WO2021189750A1 (zh) * | 2020-03-24 | 2021-09-30 | 中国药科大学 | 一种肉桂酰氨基酸类化合物及其用途 |
| CN113444015B (zh) * | 2020-03-24 | 2022-11-08 | 中国药科大学 | 一种肉桂酰氨基酸类化合物及其用途 |
| CN115417789A (zh) * | 2022-09-03 | 2022-12-02 | 郑州大学 | 一种治疗帕金森氏病的新化合物、其制备方法以及复方药物组合物和应用 |
| CN115417789B (zh) * | 2022-09-03 | 2023-08-04 | 郑州大学 | 一种治疗帕金森氏病的化合物、其制备方法以及复方药物组合物和应用 |
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