CN108478568B - 一种香豆素类化合物在制备单胺氧化酶抑制剂中的用途 - Google Patents

一种香豆素类化合物在制备单胺氧化酶抑制剂中的用途 Download PDF

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CN108478568B
CN108478568B CN201810103341.XA CN201810103341A CN108478568B CN 108478568 B CN108478568 B CN 108478568B CN 201810103341 A CN201810103341 A CN 201810103341A CN 108478568 B CN108478568 B CN 108478568B
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monoamine oxidase
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孔德信
王栋
左之利
王雅琪
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Abstract

本发明公开了一种通式(I)所示的香豆素类化合物在制备单胺氧化酶抑制剂中的用途，属于医药技术领域。经过体外酶活性实验测试，该类化合物对单胺氧化酶A和B具有良好的抑制活性，为开发新型MAO抑制剂提供参考和启发新思路。

Description

一种香豆素类化合物在制备单胺氧化酶抑制剂中的用途
技术领域
本发明属于医药技术领域，涉及一种香豆素类化合物的制药新用途，尤其是在制备单胺氧化酶抑制剂中的新用途。
背景技术
单胺类神经递质主要包括去甲肾上腺素、肾上腺素、多巴胺和5-羟色胺。这些神经递质及其代谢产物在人体的神经、心血管、内分泌等组织和系统中起着广泛的调节作用。单胺类神经递质的代谢失调会导致其在体内的表达水平发生变化，影响人的行为、情感，从而引起一系列相关的疾病。单胺氧化酶(MAO)位于多巴胺能神经元的线粒体膜上，主要分布于大脑、肠道、肝脏和其他组织中，是单胺类物质降解的重要调节酶，通过催化单胺氧化脱氨反应调节着单胺类神经递质的浓度。MAO的表达水平过高会引起单胺类神经递质的减少从而导致神经紊乱等疾病。同时，在单胺氧化酶催化单胺类物质代谢时会产生大量活性氧类物质同样对人体的神经系统有着很大程度的伤害，导致神经退行性疾病的发生。
单胺氧化酶存在两种异构形式，即单胺氧化酶A(MAO-A)和单胺氧化酶B(MAO-B)。单胺氧化酶A(MAO-A)存在于胃肠道、肝脏、肾脏、肺脏、大脑等器官的肾上腺素能神经元内，主要与5－羟色胺(5-HT)、去甲肾上腺素、多巴胺和酪胺结合；单胺氧化酶B (MAO-B)主要存在于外周的血小板以及脑内5-HT能神经元和神经胶质细胞中。研究认为抑制单胺氧化酶A对于抗抑郁药物效应是必要的，而抑制单胺氧化酶B对于治疗帕金森病(PD)是有效的。此外，相关研究指出，MAO底物对心肌功能有着重要的调节作用； MAO与前列腺癌的发病机制有着密切的关系；MAO还可能是引起糖尿病中心血管氧化应激的来源之一。由此可见，MAO是研发相关疾病治疗药物的重要靶标。
香豆素是一类广泛存在的天然产物，具有抗氧化、抗癌、抗炎、镇痛等生物活性，近年来，研究者发现香豆素对单胺氧化酶具有很好的抑制活性作用，并不断对其进行结构改造与优化，以获得低毒高效的香豆素类单胺氧化酶抑制衍生物。目前，在现有技术中，未见本发明所涉及的此类香豆素衍生化合物及其对单胺氧化酶A、单胺氧化酶B抑制活性的相关报道。
发明内容
本发明的目的是提供式(I)中香豆素类化合物，以其为活性成分，在制备单胺氧化酶抑制剂中的应用。
为了实现本发明的上述目的，本发明采用了如下的技术方案：
所述香豆素类化合物的结构式如下：
Figure BDA0001566996230000021
式(I)中，R1为H、甲基或如下基团之一：
Figure BDA0001566996230000022
R2为H或C1-3烷基；
R1与R2也可以通过如下方式形成五元不包合环：
Figure BDA0001566996230000023
R3为H或卤素；
R4为H或甲基；
R5为H或如下基团之一：
Figure BDA0001566996230000024
下表列出的是十二种具体化合物。
表1化合物种类及其取代基
Figure BDA0001566996230000031
本发明首次发现并通过活性测试，验证了式(Ⅰ)所示的香豆素类化合物具有单胺氧化酶A、B抑制活性，提供了该类化合物作为单胺氧化酶抑制剂的新用途，有望被开发成抑郁症、社交恐惧症、疼痛、偏头痛、阿尔茨海默症、帕金森综合症等疾病的治疗药物。
具体实施方式
下面用本发明的下述实施例对本发明的实质性内容进行详细叙述，但并不以此来限定本发明。实施例中所使用的化合物均可购自荷兰specs公司(http://www.specs.com)，均为 specs公司化合物库中的化合物。
实施例1：本发明化合物对单胺氧化酶抑制活性的测试
1.实验试剂
本发明化合物、MAO-A(Active Motif,Cat.No.31502)、MAO-B(Active Motif,Cat.No. 31503)、氯吉兰(Clorgyline)(Sigma,Cat.No.M3778)、司来吉兰(R(-)-deprenyl)(Abcam, Cat.No.ab120604)、384孔板(Perkin Elmer,Cat.No.6007299)。
2.实验方法
1)用100％的DMSO将本发明化合物溶解至10mM，在多孔板中加入HEPES为缓冲液，将化合物转移至多孔板中，使DMSO的浓度降低至1％。
2)将酶和底物分别溶解到缓冲溶液中，移入10μL酶溶液到多孔板中，静置15分钟至室温。
3)加入10μL的底物溶液，启动反应，静置60分钟，加入20μL的荧光素，混匀，室温下静置20分钟，测量并记录荧光信号的相对亮度，分别在10个浓度条件下测定化合物对酶的百分抑制率。
试验中，分别以氯吉兰、司来吉兰为对照，实验重复2-3次，分别计算最大荧光值和最小荧光值及其标准差，以最大荧光值和最小荧光值之比计算每一组多孔板数据的可靠性(Z)。
3.数据处理
1)抑制率：Inh％＝(Max-Signal)/(Max-Min)*100 (1)
2)采用GraphPad Prism 5将各个化合物在10个浓度条件下所得的酶的百分抑制率，按照公式2进行拟合，计算化合物的IC50值，式中Y和X分别是百分抑制率和化合物浓度。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope)) (2)
4.实验结果
本发明选自式(I)的12个香豆素类化合物的化学结构及其对单胺氧化酶A、B的抑制率及IC50活性如下表所示。
表2.本发明化合物对MAO-A和MAO-B的抑制率及IC50值
Figure BDA0001566996230000051
从上表结果可以看出，本发明提供的化合物对MAO-A和MAO-B均表现出良好的抑制活性。

Claims (1)

1.下述式(I)所示的香豆素类化合物在制备单胺氧化酶抑制剂中的用途，
Figure FDA0002312837040000011
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CN115490680B (zh) * 2022-09-30 2024-01-23 常州大学 基于苯并噻唑衍生物的香豆素类荧光探针及其制备方法和应用

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CN101043886A (zh) * 2004-10-22 2007-09-26 帝斯曼知识产权资产管理有限公司 用于预防和治疗与受损神经传递相关的失调症的新型试剂
CN102784132A (zh) * 2012-09-04 2012-11-21 光明乳业股份有限公司 琥珀酸或其盐或其酯在制备单胺氧化酶抑制剂中的用途
WO2015200514A2 (en) * 2014-06-24 2015-12-30 The University Of Kansas Biphenyl amides with modified ether groups as hsp90 inhibitors and hsp70 inducers

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101043886A (zh) * 2004-10-22 2007-09-26 帝斯曼知识产权资产管理有限公司 用于预防和治疗与受损神经传递相关的失调症的新型试剂
CN102784132A (zh) * 2012-09-04 2012-11-21 光明乳业股份有限公司 琥珀酸或其盐或其酯在制备单胺氧化酶抑制剂中的用途
WO2015200514A2 (en) * 2014-06-24 2015-12-30 The University Of Kansas Biphenyl amides with modified ether groups as hsp90 inhibitors and hsp70 inducers

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