CN117510560A - 阿魏酸葡萄糖苷及其制备方法与用途 - Google Patents
阿魏酸葡萄糖苷及其制备方法与用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
- A61K8/602—Glycosides, e.g. rutin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Animal Behavior & Ethology (AREA)
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Abstract
本发明属于化妆品领域,具体涉及阿魏酸葡萄糖苷及其制备方法与用途,阿魏酸葡萄糖苷的结构式为:本发明的阿魏酸葡萄糖苷的溶解性更好,透皮吸收率更高,对弹性蛋白酶和酪氨酸酶的抑制率更高,具有优异的抗衰老和美白效果。
Description
技术领域
本发明属于化妆品领域,具体涉及阿魏酸葡萄糖苷及其制备方法与用途。
背景技术
阿魏酸(Ferulic acid,FA),化学名称为4-羟基-3-甲氧基肉桂酸,其分子式为C10H10O4,熔点169~173℃,溶于热水、乙醇乙酸乙酯,微溶于苯和石油醚。具有顺式、反式两种异构体,顺式异构体为黄色油状物质,反式异构体为斜方针状结构。阿魏酸是一种广泛存在于植物中的酚酸,在细胞壁中与多糖和蛋白质结合成为细胞壁的骨架,为当归、大三叶升麻、川芎等中药材的重要有效成分。
现代医学研究表明,阿魏酸作为药品具有抗菌消炎,止痛,保护心血管系统,抗紫外线辐射,清除自由基以及调节人体免疫功能的作用;在临床上用于动脉粥样硬化、心脏病、白细胞和血小板减少等疾病的治疗;在食品中则主要作为抗氧化剂使用,随着研究的深入,阿魏酸的医药用途越加显现,因此具有广泛的应用价值和发展前景。
阿魏酸的生物活性研发已经较为成熟,在此基础上,对阿魏酸进行衍生化,开发出效果更优异的阿魏酸衍生物,是有必要的。
发明内容
本发明的目的是提供一种阿魏酸的衍生物,即阿魏酸葡萄糖苷。
本发明的另一目的是提供阿魏酸葡萄糖苷的制备方法。
本发明的另一目的是提供阿魏酸葡萄糖苷的新用途。
阿魏酸葡萄糖苷,其结构式为:
阿魏酸葡萄糖苷的制备方法,包括以下步骤:
S1、溴代五乙酰葡萄糖与阿魏酸甲酯、无机碱反应得到化合物A;
S2、化合物A在碱性条件下酯基水解,得到阿魏酸葡萄糖苷。
进一步地,所述无机碱为碳酸钾,所述溴代五乙酰葡萄糖、阿魏酸甲酯、无机碱的摩尔比为(1~2):1:(2~3),所述S1的溶剂为二氯甲烷。
进一步地,S2具体为:化合物A溶于水中,加入氢氧化钠,进行水解,所述化合物A和氢氧化钠的摩尔比为1:(3~8)。
阿魏酸葡萄糖苷由于其透皮吸收率更高、细胞毒性更低、抗衰老和美白功效更好,可以用于化妆品。
具体而言,阿魏酸葡萄糖苷的透皮吸收率在40%以上。
具体而言,阿魏酸葡萄糖苷在0.2mol/L的浓度时对弹性蛋白酶的抑制率在40%以上。
具体而言,阿魏酸葡萄糖苷在0.2mol/L的浓度时对体外酪氨酸酶的抑制率在80%以上。
具体而言,阿魏酸葡萄糖苷在250μM的浓度时对细胞内酪氨酸酶的抑制率在60%以上。
本发明具有以下有益效果
1、阿魏酸葡萄糖苷的溶解性更好,有助于形成更加均匀稳定的化妆品体系。
2、阿魏酸葡萄糖苷的透皮吸收率更高。有效成分只有透过皮肤屏障到达到相应的皮层,才能够发挥功效,透皮吸收率的提高有助于阿魏酸葡萄糖苷的高效吸收。
3、阿魏酸葡萄糖苷对弹性蛋白酶的抑制率更高,可减少弹性蛋白降解,促使皮肤更紧致和具有弹性,具有更优异的抗衰老功效。
4、阿魏酸葡萄糖苷对酪氨酸酶的抑制率更好,可降低黑色素生成,防止黑色素沉着,具有更好的美白活性。
说明书附图
图1为实施例2溶解度柱形图;
图2为实施例3透皮吸收率柱形图;
图3为实施例4弹性蛋白酶抑制率柱形图;
图4为实施例5酪氨酸酶抑制率柱形图;
图5为实施例6阿魏酸细胞毒性柱形图;
图6为实施例6阿魏酸葡萄糖苷细胞毒性柱形图;
图7为实施例7酪氨酸酶抑制率柱形图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
实施例1
阿魏酸葡萄糖苷的合成
1、阿魏酸甲酯乙酰葡萄糖的制备
物料名称 | 分子量 | 质量(g) | 摩尔量 | 当量 |
溴代葡萄糖 | 410.2 | 100 | 0.244 | 1.1 |
阿魏酸甲酯 | 207.7 | 46.0 | 0.222 | 1 |
碳酸钾 | 138.02 | 61.2 | 0.444 | 2 |
二氯甲烷 | 500 |
具体操作:将100g溴代五乙酰葡萄糖加入到500g二氯甲烷中,加入46.0g阿魏酸甲酯,61.2g碳酸钾,加毕,20~30℃保温反应12h,TLC跟踪反应完全,分别用300mL水洗涤3次,无水硫酸钠干燥,得黄色油状物(化合物A)128g。
2、阿魏酸葡萄糖苷的制备
物料名称 | 分子量 | 质量(g) | 摩尔量 | 当量 |
对接物A | 538.17 | 128 | 0.237 | 1 |
氢氧化钠 | 40 | 56.8 | 1.422 | 6 |
水 | 200 | |||
盐酸30% | 80 |
具体操作:将化合物A加入到200g水中,加入氢氧化钠56.8g,在55~65℃反应5h,TLC跟踪反应完全,降温至0~5℃,用20wt%盐酸调pH=3~4,体系白色成粥状,过滤,滤饼用200mL水室温打浆1h,过滤,45℃以下减压干燥得白色粉末46g。总摩尔收率58.2%,HPLC:99.889%。
1H NMR(400MHz,D2O)δ7.51(d,J=16.0Hz,1H),7.15(d,J=1.9Hz,1H),7.12–7.00(m,2H),6.34(d,J=16.0Hz,1H),5.11–4.99(m,1H),3.84–3.74(m,4H),3.71–3.60(m,1H),3.56–3.46(m,3H),3.45–3.36(m,1H)。
实施例2
用HPLC-标准曲线法比较阿魏酸和阿魏酸葡萄糖苷的水溶性
采用称量法,用乙醇配制不同浓度的阿魏酸和阿魏酸葡萄糖苷溶液,过22μm滤膜,12000rpm离心10min,Agilent公司1260型HPLC仪测试含量。采用Phenomenex Luna C18色谱柱(250mm×4.6mm,5μm),以甲醇-0.1%磷酸水溶液为流动相,322nm,进样量为20μL,柱温为30℃。根据HPLC峰面积和样品浓度,绘制标准曲线。
配制阿魏酸和阿魏酸葡萄糖苷的双蒸水饱和溶液,按照上述HPLC条件进行检测,根据标准曲线计算样品含量。
结果如图1所示,阿魏酸饱和水溶液的浓度为401μg/mL,溶解度有限,限制了其使用;阿魏酸葡萄糖苷饱和水溶液的浓度为1191μg/mL,这说明阿魏酸葡萄糖苷在水中的水溶性优于阿魏酸,在生产使用中可以进一步提升有效物含量,更容易形成均匀稳定的水溶性体系。
实施例3
比较阿魏酸和阿魏酸葡萄糖苷的透皮吸收能力
体外透皮实验参照SCCS(2012),OECD(2004a,b)指南进行。整个扩散池安装完毕后,排出气泡,放置在带有磁力搅拌及温控的水浴箱中,在实验过程中,以300r/min的速度持续搅拌受体室,恒温进行,以确保皮肤表面温度为(32±1)℃。
皮肤准备:以猪耳皮肤作为模型,屠宰3h内的新鲜猪耳,用自来水和蒸馏水清洗干净,软布擦干,用手术刀小心取下猪耳无物理损伤,无异常的外侧皮肤为全厚猪耳皮肤(Fullthickness porcine ear skin,FPES)用手术刀切成边长3mm的正方形。所有皮肤在实验前需要进行:
i.完整性检查,电导率≤0.9mS/cm的皮肤用于实验;
ii.厚度测定,使用厚度在0.95~1.05mm之间的皮肤;
iii.称重,使用皮肤质量在0.2~0.4g之间的皮肤。
操作方法:用弹簧夹将处理好的猪耳皮肤固定在透皮吸收仪的接收池与供给池之间,角质层面向供给池朝上放置,接收池中加入生理盐水,注意排尽皮肤下面气泡。将组装好的扩散池放入磁力搅拌在器中,分别取阿魏酸和阿魏酸糖苷饱和溶液溶于基质溶液(含有双蒸水86%,甘油5%,丙二醇5%,PEG400 2%,吐温80 2%),置于供给池中,接收液选用300rpm搅拌48h。透皮实验结束后,用剪刀剪碎皮肤组织,放入10mL离心管进行提取。提取过程为:涡流30s;加入5mL乙醇超声;离心10min,转速3 000r/min。上清液与接受液合并后浓缩,经0.45μm滤膜过滤,12000rpm离心10min,取上清液按照水溶性测试所采用的HPLC条件,做HPLC分析。接收液和皮肤组织内的阿魏酸和阿魏酸糖苷所占供给池中物质的比例,即为透皮吸收率。
结果如图2所示,阿魏酸的透皮吸收率为35.1%,阿魏酸葡萄糖苷的透皮吸收率为46.3%,阿魏酸经糖苷修饰后对透皮吸收率有所提升。透过皮肤屏障,达到相应的皮层,是化妆品有效成分发挥作用的首要条件。阿魏酸糖苷透皮吸收率的提高,有助于其顺利克服皮肤屏障导致的有效浓度降低等问题,促进其在体内高效发挥作用。
实施例4
弹性蛋白酶抑制实验比较阿魏酸和阿魏酸葡萄糖苷的抗衰老作用
弹性蛋白酶抑制方法:取2mg/mL弹性蛋白酶溶液2mL,加入不同浓度样品,充分涡旋混匀,在37℃、400r/min摇床振荡20min,立即加入pH6.0的0.5mol/L磷酸盐缓冲液5mL,涡旋混匀,取混匀液适量至2mL离心管内,在9 391×g下离心10min,精密吸取上清液200μL至96孔板内,在波长495nm处酶标仪测定吸光度,同时进行400~800nm光谱扫描。
以底物加酶溶液为空白对照组,底物加酶和样品溶液为酶抑制组,底物加样品不加酶溶液作扣背景用。每组均设3复孔。抑制率(%)=[1–(An–An′)/(A0–A0′)]×100%,式中,A0为加酶不加样品的吸光度,A0′为仅加底物不加样品和酶的吸光度,An为仅加样品溶液的吸光度,An′为加样品不加酶的吸光度。若An′>An,则表现为促进作用,促进率(%)=[1–(An′–An)/(A0–A0′)]×100%。
结果如图3所示,在各个浓度下,阿魏酸葡萄糖苷都比阿魏酸表现出更好的对弹性蛋白酶的抑制率,在0.1mol/L的浓度时阿魏酸葡萄糖苷对弹性蛋白酶的抑制率为32.8%,相比之下阿魏酸的抑制率为15.6%;在0.2mol/L的浓度时阿魏酸葡萄糖苷对弹性蛋白酶的抑制率为40.5%,相比之下阿魏酸的抑制率为21.8%。弹性蛋白是结缔组织中弹性纤维的组成部分,可以使得组织富有弹性,并且还与胶原等其他细胞外基质共同维持组织结构稳定性。弹性蛋白酶在炎症或长期紫外辐照等条件下可以降解弹性蛋白,因此引发皮肤组织的衰老。阿魏酸葡萄糖苷抑制弹性蛋白酶的活性提升,证实其比阿魏酸具有更好的抗衰潜力。
实施例5
酪氨酸酶抑制实验比较阿魏酸和阿魏酸葡萄糖苷的美白作用
体外酪氨酸酶法检测美白功效:取对应浓度样品1mL(以pH 6.8磷酸缓冲溶液PBS为空白替代),加入625μL酪氨酸酶(200U/mL),37℃恒温水浴10min。加入0.05%L-酪氨酸溶液1mL,继续37℃水浴反应40min,测试475nm波长处吸光度。计算酪氨酸酶活性抑制率=1-(C-D)/(A-B)(A为无样品含酶体系;B为无样品无酶体系;C为含样品含酶体系;D为含样品无酶体系)。维生素C作为阳性对照,同法进行测试。
结果如图4所示,在各个浓度下,阿魏酸葡萄糖苷都比阿魏酸表现出更好的对酪氨酸酶的抑制率,在0.05mol/L的浓度时阿魏酸葡萄糖苷对酪氨酸酶的抑制率为23.7%,相比之下阿魏酸的抑制率为14.4%;在0.1mol/L的浓度时阿魏酸葡萄糖苷对酪氨酸酶的抑制率为47.2%,相比之下阿魏酸的抑制率为39.1%;在0.15mol/L的浓度时阿魏酸葡萄糖苷对酪氨酸酶的抑制率为69.6%,相比之下阿魏酸的抑制率为62.5%;在0.2mol/L的浓度时阿魏酸葡萄糖苷对酪氨酸酶的抑制率为82.3%,相比之下阿魏酸的抑制率为71.2%。酪氨酸酶为黑色素合成过程中的主要限速酶,因此其活性强弱与否将直接决定黑色素的产量。抑制酪氨酸酶活性表达是美白的重要手段。阿魏酸葡萄糖苷相比阿魏酸表现出的更好的酪氨酸酶抑制率,表明其具有更优异的美白活性。
实施例6
MTT法比较阿魏酸和阿魏酸葡萄糖苷的细胞毒性
将HaCaT细胞以1×104个/孔的密度种于96孔板,培养箱内过夜。24h后弃去上清液,加入含不同浓度样品的培养基100μL,继续孵育24h后除去培养基,每孔中加入100μL噻唑蓝(MTT),测定450nm处吸光度,计算细胞存活率=A给药孔/A空白孔×100%。
结果如图5、6所示,在浓度0.24mg/mL时,阿魏酸的细胞毒性显著上升,细胞存活率降至60.2%,在浓度0.32mg/mL时,细胞存活率为39.8%,IC50为0.2735mg/mL。
相比之下,阿魏酸葡萄糖苷的细胞毒性更低,在浓度低于0.714mg/mL时,细胞存活率基本不受影响,到0.952mg/mL时,细胞存活率显著下降,IC50为0.9399mg/mL。
实施例7
通过细胞内酪氨酸酶抑制方法比较阿魏酸和阿魏酸葡萄糖苷的美白功效
细胞内酪氨酸酶法检测美白功效:将B16细胞种于96孔板(密度1×104个/孔),培养箱内孵育24h后,弃去上清液,加入100μL经DMEM培养基稀释的不同浓度样品,不含药的DMEM培养基为阴性对照组,继续孵育24h后弃去含药培养液,用PBS清洗两次后加入100μL1%Triton X-100置于-80℃1h急冻成冰,后置于室温下融化。融化后每孔加入20μL0.5%L-多巴于室温水平振荡4h反应,反应结束后于490nm波长处测定吸光度,并计算细胞酪氨酸酶抑制率=A给药孔/A空白孔×100%。
结果如图7所示,每种浓度柱形图的左边为阿魏酸,右边为阿魏酸葡萄糖苷。在250μM的浓度时,阿魏酸葡萄糖苷对细胞内酪氨酸酶的抑制率为59.8%,相比之下,阿魏酸的抑制率为50.1%,其他浓度时阿魏酸葡萄糖苷也比阿魏酸的酪氨酸酶抑制率高。
以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (10)
1.阿魏酸葡萄糖苷,其结构式为:
2.阿魏酸葡萄糖苷的制备方法,包括以下步骤:
S1、溴代五乙酰葡萄糖与阿魏酸甲酯、无机碱反应得到化合物A;
S2、化合物A在碱性条件下酯基水解,得到阿魏酸葡萄糖苷。
3.根据权利要求2所述的制备方法,其特征在于,所述无机碱为碳酸钾,所述溴代五乙酰葡萄糖、阿魏酸甲酯、无机碱的摩尔比为(1~2):1:(2~3),所述S1的溶剂为二氯甲烷;S2具体为:化合物A溶于水中,加入氢氧化钠,进行水解,所述化合物A和氢氧化钠的摩尔比为1:(3~8)。
4.阿魏酸葡萄糖苷在化妆品中的用途。
5.根据权利要求4所述的用途,其特征在于,阿魏酸葡萄糖苷的透皮吸收率在40%以上。
6.根据权利要求4所述的用途,其特征在于,阿魏酸葡萄糖苷具有抗衰老作用。
7.根据权利要求6所述的用途,其特征在于,阿魏酸葡萄糖苷在0.2mol/L的浓度时对弹性蛋白酶的抑制率在40%以上。
8.根据权利要求4所述的用途,其特征在于,阿魏酸葡萄糖苷具有美白作用。
9.根据权利要求8所述的用途,其特征在于,阿魏酸葡萄糖苷在0.2mol/L的浓度时对体外酪氨酸酶的抑制率在80%以上。
10.根据权利要求8所述的用途,其特征在于,阿魏酸葡萄糖苷在250μM的浓度时对细胞内酪氨酸酶的抑制率在60%以上。
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