CN114773277A - 柠檬醛含氮衍生物及其制备方法和应用 - Google Patents

柠檬醛含氮衍生物及其制备方法和应用 Download PDF

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CN114773277A
CN114773277A CN202210584230.1A CN202210584230A CN114773277A CN 114773277 A CN114773277 A CN 114773277A CN 202210584230 A CN202210584230 A CN 202210584230A CN 114773277 A CN114773277 A CN 114773277A
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ethyl acetate
tyrosinase
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黄亚茹
杨杰芳
龚春
杨海宽
廖圣良
刘新亮
李升星
郭捷
华小菊
周诚
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Jiangxi Agricultural University
Jiangxi Academy of Forestry
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Abstract

本发明公开了柠檬醛含氮衍生物及其制备方法和应用。该柠檬醛衍生物具有如式(I)所示的结构，该衍生物由柠檬醛为底物合成得到，其抗酪氨酸酶活性IC50为105±2μM，能够满足制备抗酪氨酸酶组合物的需求。

Description

柠檬醛含氮衍生物及其制备方法和应用
技术领域
本发明属于化药合成领域，具体涉及一种柠檬醛含氮衍生物及其制备方法和应用。
背景技术
酪氨酸酶是一种多功能酶，可从微生物、植物和动物中广泛分离出来。作为一种含有双核铜的酶，它可以催化邻二酚或单酚向合适的醌类物质的转化，从而产生黑素。因此，在黑色素的生物合成中起着重要的作用。黑色素是分布在动物头发、眼睛和皮肤中的一种重要色素。然而，过量的黑色素产生可能导致白化病或皮肤癌，不规则分布可能导致皮肤不规则色素沉着，如黄褐斑、雀斑和老年性黑斑。此外，酪氨酸酶引起的一个严重问题是褐变酶反应，它会导致水果和蔬菜的快速颜色和质量降解。
柠檬醛是从几种植物的精油中提取的，柠檬醛除了是饮料、食品和化妆品中重要的气味成分外，在体外还表现出良好的生物活性，包括抗菌、抗真菌、抗氧化和抗炎作用，还能作为平滑肌局麻药和松弛剂。
发明内容
本发明的目的是解决现有技术的不足，以樟树精油中的柠檬醛为底物合成出一个新型化合物，其抗酪氨酸酶活性IC50为105±2μM，为本领域提供了一种新的解决方案，具体采用以下的技术方案：
一种如式(I)所示的化合物：
Figure BDA0003665222920000011
本发明还提供了上述化合物的制备方法，包括以下步骤：将3-氟-邻氨基苯甲酰胺、柠檬醛和DMSO置于100℃条件下反应过夜，反应完全后冷却至室温，加入水中，然后用乙酸乙酯萃取，有机层干燥，减压除去DMSO，柱层析分离得到所述化合物。
优选地，在上述制备方法中，柱层析分离中的洗脱剂为体积比为5:1的石油醚和乙酸乙酯。有机层用无水硫酸钠干燥。
优选地，在上述制备方法中，3-氟-邻氨基苯甲酰胺和柠檬醛的摩尔比为5:6。
上述化合物能够用于制备抗酪氨酸酶组合物(例如药物)；具体可以是用于制备皮肤美白组合物或果蔬保鲜剂。
本发明的有益效果为：本发明提供了一种以柠檬醛为底物合成的新型化合物，其抗酪氨酸酶活性IC50为105±2μM，能够满足制备抗酪氨酸酶组合物的需求。
附图说明
图1所示为化合物1的1H NMR图谱；
图2所示为化合物1的13C NMR图谱。
具体实施方式
以下将结合实施例和附图对本发明的构思及产生的技术效果进行清楚、完整的描述，以充分地理解本发明的目的、方案和效果。
实施例1：
一种柠檬醛含氮衍生物的制备方法，其合成路线如下所示：
Figure BDA0003665222920000021
具体包括以下步骤：
在50mL圆底烧瓶中加入0.771g 3-氟-邻氨基苯甲酰胺(5.0mmol)、0.913g柠檬醛(6.0mmol)和10mL DMSO，100℃下反应过夜，TLC监测至反应完全(约20小时)。反应完全后，将反应液冷却至室温，加入10mL H2O，用乙酸乙酯萃取，有机层用无水硫酸钠干燥，减压除去溶剂，柱层析分离(洗脱剂：石油醚：乙酸乙酯＝5:1)得到287mg化合物1。
对其进行检测，检测结果如图1-2所示。1H NMR(400MHz,CDCl3)δ11.4(s,1H),7.6(td,J＝8.2,5.5Hz,1H),7.5(d,J＝8.2Hz,1H),7.1–7.0(m,1H),6.2–6.0(m,1H),5.3–5.0(m,1H),2.4–2.3(m,3H),2.3(s,4H),1.7(s,3H),1.6(s,3H).13C NMR(101MHz,CDCl3)δ161.6,161.4(d,J＝265.4Hz),156.0,152.4,151.8,134.7(d,J＝10.4Hz),132.5,123.4(d,J＝4.2Hz),123.1,116.6,112.5(d,J＝20.5Hz),110.1(d,J＝6.6Hz),41.5,26.2,25.7,19.5,17.7.
实施例2：
二酚酶活力分析实验：
具体操作是：将样品溶于双蒸水中，配成不同浓度的样品溶液(柠檬醛类化合物水溶性较差，因此溶于DMSO中)。在该实验中，底物为0.5mmol/L L-DOPA，且所有操作均在30℃下进行。在3mL体系中，在比色皿中依次加入底物溶液0.3mL、0.05mol/L磷酸缓冲液(pH6.8)0.75mL、双蒸水1.8mL、不同浓度样品溶液0.1mL，最后加入0.05mL蘑菇酪氨酸酶水溶液，立即摇匀，使用紫外可见分光光度计测定其吸光值随时间变化的曲线(波长为475nm)。所得直线的斜率即为酶活力，消光系数按照3700L/(mol*cm)-1进行计算。对照组将样品换为蒸馏水。使用紫外可见分光光度计测量在475nm处的吸光值，可得到酶的初始活力。在该体系中酶的终浓度为3.33μm/mL。
以酶的相对剩余活力对样品浓度作图，得到样品的浓度效应曲线，则样品的半抑制浓度为酶相对剩余活力为50％对应的样品浓度，这个浓度就是样品的IC50值。
二酚酶活力测定实验进行三次平行实验。
将实施例1制得的化合物1、其它化合物作为样品，利用上述实验测定其IC50值，具体结果如表1所示。
表1
Figure BDA0003665222920000031
Figure BDA0003665222920000041
由表1可知，本发明的化合物1相比于酪氨酸酶标准抑制剂熊果苷(IC50＝180μM)具有更好的抗酪氨酸酶活性，而相似母核结构的化合物并不都具备这种效果。
以上所述，只是本发明的较佳实施例而已，本发明并不局限于上述实施方式，只要其以相同的手段达到本发明的技术效果，都应属于本发明的保护范围。在本发明的保护范围内其技术方案和/或实施方式可以有各种不同的修改和变化。

Claims (8)

1.一种如式(I)所示的化合物：
Figure FDA0003665222910000011
2.一种权利要求1所述的化合物的制备方法，其特征在于，包括以下步骤：将3-氟-邻氨基苯甲酰胺、柠檬醛和DMSO置于100℃条件下反应过夜，反应完全后冷却至室温，加入水中，然后用乙酸乙酯萃取，有机层干燥，减压除去DMSO，柱层析分离得到所述化合物。
3.根据权利要求2所述的制备方法，其特征在于，采用无水硫酸钠对有机层进行干燥。
4.根据权利要求2所述的制备方法，其特征在于，柱层析分离中的洗脱剂为石油醚和乙酸乙酯。
5.根据权利要求4所述的制备方法，其特征在于，石油醚和乙酸乙酯的体积比为5:1。
6.根据权利要求2所述的制备方法，求特征在于，3-氟-邻氨基苯甲酰胺和柠檬醛的摩尔比为5:6。
7.权利要求1所述的化合物在制备抗酪氨酸酶组合物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述组合物包括药物。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466718A (en) * 1993-04-02 1995-11-14 Takasago Institute For Interdisciplinary Tyrosinase inhibitors
CN108033881A (zh) * 2017-11-30 2018-05-15 五邑大学 一种半天然来源的酪氨酸酶抑制剂及其制备方法与应用
CN109384731A (zh) * 2017-08-04 2019-02-26 南京理工大学 一种由烯醇制备喹唑啉酮的方法
CN112730017A (zh) * 2021-01-07 2021-04-30 中国计量大学 挥发油复配增溶剂及挥发油酪氨酸酶活性抑制的测定方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466718A (en) * 1993-04-02 1995-11-14 Takasago Institute For Interdisciplinary Tyrosinase inhibitors
CN109384731A (zh) * 2017-08-04 2019-02-26 南京理工大学 一种由烯醇制备喹唑啉酮的方法
CN108033881A (zh) * 2017-11-30 2018-05-15 五邑大学 一种半天然来源的酪氨酸酶抑制剂及其制备方法与应用
CN112730017A (zh) * 2021-01-07 2021-04-30 中国计量大学 挥发油复配增溶剂及挥发油酪氨酸酶活性抑制的测定方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RUI WANG等: "2-(4-Fluorophenyl)-quinazolin-4(3H)-one as a novel tyrosinase inhibitor: Synthesis, inhibitory activity, and mechanism" *
叶丽;刘亚青;巨修练;: "酪氨酸酶抑制剂的研究进展" *

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