CN108586400A - 大黄酸及衍生物Vc酯作为酪氨酸酶抑制剂的应用 - Google Patents

大黄酸及衍生物Vc酯作为酪氨酸酶抑制剂的应用 Download PDF

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CN108586400A
CN108586400A CN201810493569.4A CN201810493569A CN108586400A CN 108586400 A CN108586400 A CN 108586400A CN 201810493569 A CN201810493569 A CN 201810493569A CN 108586400 A CN108586400 A CN 108586400A
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刘进兵
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Abstract

本发明涉及式(Ⅰ)的大黄酸及衍生物Vc酯的合成及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：大黄酸及衍生物Vc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、食品保鲜及生物杀虫剂领域具有广泛的应用前景。所述大黄酸及衍生物Vc酯的化学结构式如下式所示，其中R为氢或乙酰基。

Description

大黄酸及衍生物Vc酯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，涉及大黄酸及衍生物Vc酯，大黄酸及衍生物Vc酯作为酪氨酸酶抑制剂的应用。
背景技术
蒽醌类化合物具有广泛的药理作用（中国药理学通报, 2003 , 19 (8) : 851-854）,能抑制肿瘤细胞增殖和转移（Life Sci , 1997 , 61 (23) : 2335-2344），具有抗菌、抗炎、抑制肝脏和肾脏纤维化、扩张血管及利尿等作用（Eur J Pharmacol , 1991 ,205 (3) : 289-294），具有很好的临床应用价值。大黄酸及其衍生物是一类重要的蒽醌类化合物，在医药、农业、化工领域具有广泛的应用，其中大黄酸衍生物双醋瑞因作为关节炎的治疗药物已经上市。Vc是一种重要的具有抗氧化性的水溶性维生素，可用于食品保鲜、护色，但由于水溶性太强而限制了其应用，Vc成酯，可以很好的解决这一问题。Vc成酯后不仅保持原有的抗氧化性和其他 活性，而且在非水体系中的溶解性和稳定性明显增强，清除自由基的能力得到了提高，已经成为了一种高效无毒的抗氧化剂（食品与发酵工业，2013,39（12）：123-127），但未经关于大黄酸及衍生物Vc酯的报道，也未见其Vc酯具有抑制酪氨酸酶活性的相关报道。
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。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的大黄酸及衍生物Vc酯，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大黄酸及衍生物Vc酯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）所示的大黄酸及衍生物Vc酯：
（I）
其中
R为氢或乙酰基中的一种。
本发明涉及式（I）所示的大黄酸及衍生物Vc酯的制备方法参照文献（Phytochem,2007, 68( 8 ) : 1147 - 1155）采用DCC脱水直接合成，其合成路线如下：
在DMAP存在下，采用DCC作为脱水剂，将大黄酸及衍生物和Vc直接酯化，经后处理得目标产物。
本发明所涉及的大黄酸及衍生物Vc酯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。
本发明所涉及的大黄酸及衍生物Vc酯结构新颖，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：大黄酸Vc酯的合成
将1.25mmol大黄酸加入到反应瓶中，加入1.25mmol DCC，1.25mmol DMAP和1.25mmol维生素C，加入20毫升干燥的二氧六环做溶剂，搅拌，升温至80℃，保温反应，反应过程以TLC跟踪（展开剂：乙酸乙酯/石油醚=1:2），反应完毕后，减压蒸除溶剂，向剩余物中加入20毫升无水甲醇，搅拌30分钟，滤除不溶物，蒸除大部分溶剂，冷却得固体，经乙醇重结晶，得黄色产品。
1H NMR (300 MHz, DMSO-d6) δ 3.55 (s, 1H, OH), 4.28-4.51 (m, 3H, OCH2,OCH), 5.02 (d, 1H, COOCH), 7.45(d, 1H, J = 8.4 Hz, Ar-H), 7.87-7.76(m, 2H,Ar-H), 8.07 (s, 1H, Ar-H), 8.13(s, 1H, Ar-H), 11.07 (s, 2H, COH), 11.91(s,1H, Ar-OH), 11.92(s, 1H, Ar-OH); 13C NMR (75 MHz, DMSO-d6) δ 182.4, 167.8,166.9, 161.6, 161.2, 156.3, 135.8, 135.5, 135.1, 133.8, 126.5, 122.9, 122.4,122.1, 119.8, 119.2, 118.6, 77.8, 65.9, 65.3; m/z = 443 [M+1]+1.
实施例二：双醋瑞因Vc酯的合成
将1.25mmol双醋瑞因加入到反应瓶中，加入1.25mmol DCC，1.25mmol DMAP和1.25mmol维生素C，加入20毫升干燥的二氧六环做溶剂，搅拌，升温至80℃，保温反应，反应过程以TLC跟踪（展开剂：乙酸乙酯/石油醚=1:2），反应完毕后，减压蒸除溶剂，向剩余物中加入20毫升无水甲醇，搅拌30分钟，滤除不溶物，蒸除大部分溶剂，冷却得固体，经乙醇重结晶，得黄色产品。
1H NMR (300 MHz, DMSO-d6) δ 2.39(s, 3H, CH3), 2.42(s, 3H, CH3), 3.55(s, 1H, OH), 4.28-4.51 (m, 3H, OCH2, OCH), 5.02 (d, 1H, COOCH), 7.68 (d, 1H,J = 8.4 Hz, Ar-H), 7.99(t, 1H, J =8.0Hz, Ar-H), 8.07 (s, 1H, Ar-H), 8.17(d,1H, J =7.6Hz, Ar-H), 8.55(s, 1H, Ar-H), 11.07 (s, 2H, COH); 13C NMR (75 MHz,DMSO-d6) δ 182.6, 169.2, 167.5, 166.9, 156.4, 153.9, 153.6, 134.8, 134.3,134.0, 132.8, 132.2, 127.9, 126.8, 126.5, 125.3, 124.6, 118.5, 77.6, 65.8,65.2, 20.8; m/z = 527 [M+1]+1.
实施例三：大黄酸及衍生物Vc酯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 0.016
2 0.78
3 曲酸 23.6
由上表可知，两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，其中大黄酸Vc酯的抑制酪氨酸酶活性强于双醋瑞因Vc酯，说明芳环上的羟基还是必要的，对提高酪氨酸酶抑制活性有利。本发明提出的两个化合物结构新颖，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）所示的大黄酸及衍生物Vc酯类化合物
（I）
其中
R为氢或乙酰基。
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。
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