CN108727321A - 没食子酸曲酸酯类化合物及其作为酪氨酸酶抑制剂的应用 - Google Patents

没食子酸曲酸酯类化合物及其作为酪氨酸酶抑制剂的应用 Download PDF

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CN108727321A
CN108727321A CN201810493780.6A CN201810493780A CN108727321A CN 108727321 A CN108727321 A CN 108727321A CN 201810493780 A CN201810493780 A CN 201810493780A CN 108727321 A CN108727321 A CN 108727321A
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刘进兵
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Abstract

本发明涉及式(Ⅰ)的没食子酸曲酸酯类化合物的合成和这类化合物在抑制酪氨酸酶中的应用。体外抑制酪氨酸酶的筛选结果表明：没食子酸曲酸酯具有较强的抑制酪氨酸酶活性，优于阳性对照曲酸。本发明所涉及的化合物结构新颖、制备简单，在药物、化妆品及食品保鲜领域具有广泛的应用前景。所述没食子酸曲酸酯类化合物的化学结构式如下式所示，其中R为氢、甲基、苄基。

Description

没食子酸曲酸酯类化合物及其作为酪氨酸酶抑制剂的应用
技术领域
本发明涉及到食品、医药、化妆品、生物杀虫剂领域，具体地，涉及没食子酸曲酸酯类化合物及作为酪氨酸酶抑制剂的应用。
背景技术
酪氨酸酶( EC 1. 14. 18. 1 , Tyrosinase) 又称酚氧化酶、多酚氧化酶、儿茶酚氧化酶，化学和光谱学研究表明，该酶的生物活性中心有一个双核铜离子活性部位，这个双铜活性部位能以3种不同的形式存在于酶促反应中，广泛存在于微生物、动植物及人体中。酪氨酸酶具有独特的双重催化功能。酪氨酸酶三种存在形式及相互转化在生物体内黑色素合成过程中起着重要作用，酪氨酸酶催化酪氨酸氧化成多巴，多巴氧化成多巴醌，多巴醌经一系列的酶促和非酶促反应后，形成由5，6-二羟吲哚和5，6-二羟吲哚-2-羧酸单元构成的异聚体——黑色素。
酪氨酸酶是导致果蔬褐变的重要原因，对人的皮肤、眼睛、毛发颜色及昆虫的伤口愈合与发育也起着至关重要的作用。部分色素沉着性皮肤病，如黄褐斑、雀斑、白癜风等与酪氨酸酶有密切关联，黑色素瘤的形成与酪氨酸酶同样密不可分，因此酪氨酸酶抑制剂可用于临床治疗与之相关的皮肤病及恶性黑色素瘤。鉴于酪氨酸酶抑制剂在医学、食品保鲜等领域的广泛应用，国内外很多学者致力于寻找高效、稳定、低毒的酪氨酸酶抑制剂，并探讨其抑制动力学、抑制机理及相关应用。然而到目前为止，并未找到比曲酸和熊果苷等酪氨酸酶抑制剂更安全有效的替代品，而且近期因曲酸致癌性致使日本政府禁止其在本国临床使用。因此，开发新型高效低毒的酪氨酸酶抑制剂仍然是本领域的重要研究课题。
发明内容
本发明的目的是提供一种具有较高抑制酪氨酸酶活性没食子酸曲酸酯类化合物，及其在医药、化妆品、食品保鲜及生物杀虫剂领域中的应用。
本发明的另一目的是提供没食子酸曲酸酯类化合物作为药物组合物的活性成分，以及该组合物作为酪氨酸酶抑制剂的应用。
本发明是通过以下技术方案予以实现的：
式（I）所示的没食子酸曲酸酯类化合物：
（I）
其中
R为氢、甲基、苄基中的一种。
本发明还提供了式（I）所示的没食子酸曲酸酯类化合物的制备方法，其合成路线如下：
首先，在缚酸剂的存在下，曲酸和硫酸二甲酯或氯苄反应得到甲氧基取代曲酸和苄氧基取代曲酸。然后在Novozym 435的作用下，将没食子酸分别和曲酸、甲氧基曲酸、苄氧基曲酸反应，经后处理得目标产物。
本发明所涉及的没食子酸曲酸酯类化合物可用于制备与色素相关皮肤病、黑色素瘤及帕金森病药物，还可用于制备化妆品美白剂、食品保鲜剂、生物杀虫剂。
本发明所涉及的没食子酸曲酸酯类化合物结构新颖、合成方法简单，对酪氨酸酶具有较强的抑制活性，具有很好的应用前景。
具体实施方式
以下是对本发明的进一步说明，但并不是对本发明的限制。
实施例一：甲氧基曲酸的合成
将10mmol曲酸加入到50毫升反应瓶中，加入15毫升10%氢氧化钾溶液，搅拌溶解，冷至10oC以下，滴加11mmol硫酸二甲酯，30min滴完，滴加过程中温度不超过10oC，滴完后保温1小时，升温至室温，搅拌反应，反应过程中产生大量固体，TLC跟踪反应，反应完毕后，抽滤，滤饼以丙酮洗涤，得类白色固体，收率87.6%。
1H NMR (300 MHz, DMSO-d6) δ 3.64 (s, 3H), 4.28-4.30 (m, 2H), 5.69 (t,1H, J = 6.9 Hz), 6.29 (s, 1H), 8.07 (s, 1H).
实施例二：苄氧基曲酸的合成
将10mmol曲酸加入到50毫升反应瓶中，加入20毫升甲醇，搅拌溶解，加入11mmol氢氧化钾，升温至回流，滴加11mmol氯苄，滴完后于回流状态下保温反应。 TLC跟踪反应，反应完毕后，冷至室温，减压蒸除溶剂，加入30毫升二氯甲烷，充分搅拌，过滤，二氯甲烷洗涤固体得类白色固体。二氯甲烷液分别经10%氢氧化钠溶液、水洗，无水硫酸钠干燥，减压浓缩，剩余物以乙醇重结晶等产品收率83.4%。
1H NMR (300 MHz, DMSO-d6) δ 4.31-4.33 (m, 2H), 4.96 (s, 2H), 5.69 (bs,1H), 6.32 (s, 1H), 7.34-7.44 (m, 5H), 8.17 (s, 1H).
实施例三：没食子酸曲酸酯的合成
将2mmol曲酸加入到250毫升锥形瓶中，加入50毫升环己酮和8mmol没食子酸，空气浴升温至55oC，加入0.2克Novozym 435固定化脂肪酶，封闭反应体系，在转速为150-200r/min的振荡摇床中反应12小时，加入0.2克4Å分子筛，在同样条件下继续反应12小时。冷至室温，过滤，滤液经饱和食盐水系4次，减压蒸除溶剂的产品，收率46.3%。1H NMR (300 MHz,DMSO-d6) δ 4.28-4.30 (m, 2H), 5.38 (s, 3H), 6.29 (s, 1H), 6.95 (s, 2H), 8.07(s, 1H), 9.01 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 67.6, 109.7, 112.8, 125.5,128.1, 140.3, 148.5, 163.2, 166.0, 177.4, 181.5; ESI-MS m/z = 293 [M-1]-1。
实施例四：没食子酸甲氧基曲酸酯的合成
方法同没食子酸曲酸酯的合成，收率52.8%。1H NMR (300 MHz, DMSO-d6) δ 3.60 (s,3H), 4.28-4.31 (m, 2H), 5.39 (s, 3H), 6.28 (s, 1H), 6.95 (s, 2H), 8.08 (s,1H); 13C NMR (75 MHz, DMSO-d6) δ 52.8, 67.8, 109.6, 112.6, 124.5, 125.4,139.8, 140.3, 148.5, 166.2, 177.5, 181.5; ESI-MS m/z = 307 [M-1]-1。
实施例五：没食子酸苄氧基曲酸酯的合成
方法同没食子酸曲酸酯的合成，收率42.6%。1H NMR (300 MHz, DMSO-d6) δ 4.28-4.31 (m, 2H), 5.16 (s, 2H), 5.41 (s, 3H), 6.28 (s, 1H), 6.96 (s, 2H), 7.21-7.32 (m, 5H), 8.08 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 67.9, 69.5, 109.8,112.5, 124.6, 125.5, 127.1, 127.8, 129.3, 139.9, 140.2, 141.5, 148.6, 166.1,177.8, 181.3; ESI-MS m/z = 383 [M-1]-1。
实施例六：没食子酸曲酸酯类化合物的体外酪氨酸酶抑制活性测试
在总计1000 μL的测试体系中加入940~950μL 0.1mol/L pH6.8磷酸盐缓冲液，10 μL样品溶液（10 μL样品作对照，以去除样品的颜色对实验的影响），10-20μL酶液，25℃孵化10min，加入30μL DOPA溶液，475nm进行时间扫描，记录一分钟的OD值。改变样品溶液的剂量，分别测试酶催化活性。可以通过稀释的方式改变样品的浓度。以没有加入样品的酶催化活性OD/min值为100%，用抑制百分数（指被抑制而失去活力的百分数）表示不同浓度样品对酶的抑制活性，做图求出抑制50%时样品的浓度，即得到IC50值。
抑制率（%）=[(OD样)/ OD标]×100%
OD样为加入抑制剂的光密度，OD标为未加抑制剂的光密度。
由上述方法测得的目标化合物的酪氨酸酶抑制活性如下表：
编号 化合物结构 抑制活性IC50 (μΜ)
1 0.035
2 0.28
3 0.69
由上表可知，三个目标化合物都具有较强的酪氨酸酶抑制活性，比报道的曲酸酪氨酸酶抑制活性好，其中化合物1的抑制活性强于另外两个，说明曲酸环上的羟基还是必要的。本发明提出的三个化合物结构新颖，活性好，具有较好的应用前景。
上列详细说明是针对本发明可行实施例的具体说明，但并非限制本发明的专利范围，凡未脱离本专利所为的等效实施或变更，均应包含于本案的发明保护范围内。

Claims (5)

1.式（I）所示的没食子酸曲酸酯类化合物
（I）
其中
R为氢、甲基、苄基。
2.权利要求1的化合物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的药物。
3.权利要求1的化合物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的美白化妆品。
4.权利要求1的化合物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的食品保鲜剂。
5.权利要求1的化合物具有较强的抑制酪氨酸酶活性的作用，可用于制备具有抑制酪氨酸酶作用的生物杀虫剂。
CN201810493780.6A 2018-05-22 2018-05-22 没食子酸曲酸酯类化合物及其作为酪氨酸酶抑制剂的应用 Withdrawn CN108727321A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114983845A (zh) * 2022-04-22 2022-09-02 昆明理工大学 一种没食子酸多聚体化合物在制备美白产品中的应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114983845A (zh) * 2022-04-22 2022-09-02 昆明理工大学 一种没食子酸多聚体化合物在制备美白产品中的应用
CN114983845B (zh) * 2022-04-22 2023-06-23 昆明理工大学 一种没食子酸多聚体化合物在制备美白产品中的应用

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