CN104761598A - 二氢黄酮类衍生物及其应用 - Google Patents
二氢黄酮类衍生物及其应用 Download PDFInfo
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- CN104761598A CN104761598A CN201410001917.3A CN201410001917A CN104761598A CN 104761598 A CN104761598 A CN 104761598A CN 201410001917 A CN201410001917 A CN 201410001917A CN 104761598 A CN104761598 A CN 104761598A
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- whitening
- dihydromorin
- cudrania
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Classifications
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
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- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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- A—HUMAN NECESSITIES
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及二氢黄酮类衍生物及其制备方法和应用。该植物活性化合物由下式表示,。本发明提出的植物活性化合物具有非常明显的美白皮肤活性。
Description
技术领域
本发明属于天然产物化学领域,尤其涉及从植物中提取得到的二氢黄酮类衍生物及其应用。
背景技术
近年来人们开始热衷于植物化妆品及回归自然的美容方法。随着人们生活水平和审美标准的提高,越来越多的人追求、渴望白皙及洁润的肌肤。因此,具有防止由太阳光线及其它原因引起的色斑、色素沉着作用的美白类化妆品以及皮肤美白制剂的研究与开发,正日益受到各国化妆品生产商和研究者的重视,美白化妆品已成为护肤类化妆品的主流品种之一。
在人类体内,色素沉着起因于皮肤、毛囊或头发这些角蛋白材料中黑色素的合成和分布。其受多种内部因素(遗传因素)或外部因素(紫外线、废气、活性氧等环境因素)调节。
皮肤和角蛋白纤维的色素沉着起因于特化细胞——黑色素细胞——的代谢活性。这些表皮树突状细胞来源于胚胎发生期间未分化的神经嵴前体——黑色素母细胞。黑色素细胞在称作黑色素小体的细胞器中合成黑色素,该黑色素小体通过黑色素细胞的树突破移至邻近的角质形成细胞。过量生产黑色素导致皮肤成色不均,例如雀斑的生成就是源于此。
祖国医学则认为色素沉着的主要病因是:①肝气郁结;②肾阴不足;③气血淤阻;④劳伤脾土。在治疗上,全身疗法以疏肝、补肾、活血、益气健脾为主,外用以中药面膜和霜、膏剂居多。但此类资料多以临床报道为主,缺乏严密的科研设计、实验室研究和统计学处理。至今为止,也尚末发现开发出治疗“黄褐斑”中药搽剂的文献报道。因此,寻找高效且对人体无副作用或副作用小的美白祛斑制剂已成为目前药学及化妆品领域的一个研究热点。
美白剂的作用是通过抑制酪氨酸酶活性或者阻断酪氨酸生成黑色素的氧化途径,从而减少黑色素生成达到美白皮肤的效果。皮肤美白剂就是作用于皮肤黑色素生成、代谢过程中,抑制黑色素生成且符合规范的物质,但传统的皮肤美白剂,往往采用化学性物质,如具有增白作用的汞盐和祛斑作用的氢醌。这些化合物虽然有快速达到美白之功效,但对皮肤有毒副作用,长期使用会引起接触性皮炎或引起永久脱色等不良作用,在许多国家已被禁用。目前要求的皮肤美白剂应该符合两个标准:一是对酪氨酸酶活性有较高的抑制率,能显著的减少黑色素的生成;二是有较高的安全性,以人体皮肤无毒无刺激。熊果苷、VC及其衍生物和曲酸是目前国内外美白化妆品中较常使用的美白成分。为了开发符合“回归大自然”要求的化妆品,特别是安全,无副作用的美白产品,一些具有很好美白效果的中草药目前越来越受到消费者的青睐。在国际上化妆品发展最有代表性的国家如美国、日本、法国和德国等国家中,中草药因其天然药效温和且不良作用少而被广泛认同,从中了解到近年来崇尚自然,远离化学污染的理念。特别是从日本化妆品工业的发展趋势看,各化妆品公司使用的中草药已达200余种,目前,在日本含天然中草药的化妆品已占整个化妆品市场的50%以上。因此,寻找开发高效且对人体无副作用或副作用小的天然皮肤美白祛斑制剂已成为目前化妆品领域的一个较被重视的课题。
发明内容
本发明的目的在于提供一种由以下通式(1)表示的二氢黄酮类衍生物,
其中,R1为H、烷基或糖基,R2为H或糖基。
所述烷基具体为不饱和烷基(如甲基,乙基,异戊烯基),所述糖基为葡萄糖基、甘露糖基、鼠李糖基中的一种或者任意两种组成的双糖基。
优选R1为CH3,R2为葡萄糖基(Glc-),所述二氢黄酮类衍生物具体为由通式(2)表示的7-甲氧基-二氢桑色素-3-O-β-D-葡萄糖苷:
本发明提供的上述化合物具有显著的美白作用,从而可以抑制黑色素细胞中黑色素的形成。
具体的,本发明提供的上述二氢黄酮类衍生物是首次从柘木植物提取物中分离得到,该化合物也有可能从其他属植物中分离得到。
柘木(拉丁名:Cudrania amboinesis),桑科,柘属植物。国内同属植物还有柘树(拉丁名:Cudrania tricuspidata)、构棘(又名:穿破石)(拉丁名:Cudrania cochichinesis)、柘藤(拉丁名:Cudraniafruticosa)、毛柘藤(拉丁名:Cudrania pubescens)等。柘树在全国分布较广,构棘在我国东南部有较大分布。柘木、柘藤和毛柘藤主要分布在云南南部和中南部地区。
上述活性化合物的制备工艺:采集柘木,将其晒干,粉碎,用有机溶剂室温浸泡后,进行超声处理;滤出提取液之后,向滤渣中再加入有机溶剂,然后进行超声处理并过滤;合并两次提取液,真空浓缩至干,得到柘木提取物;将提取物分散到水中,依次用石油醚、乙酸乙酯、正丁醇萃取。取正丁醇萃取部位,真空减压干燥,得到正丁醇萃取部位;然后用正相、反相和凝胶柱层析法分离精制得到活性化合物;最后通过理化常数和现代波谱学手段鉴定其结构。
所述有机溶剂是指含有羟基或羰基等极性基团的有机溶剂,例如:水、甲酰胺、二甲基甲酰胺、六甲基磷酰胺、四甲基乙二胺、三乙胺、三丁胺、三辛胺、乙酸、三氟乙酸、乙腈、甲酸甲酯、乙酸乙酯、碳酸二甲酯、二甲亚砜、丙酮、甲乙酮、二氧六环、吡啶、四氢呋喃、甲醇、乙醇、醋酸纤维、三氯甲烷、丙三醇、丙二醇、丙烯二醇、异丙醇、正丁醇和乙醚等,中的一种或几种,其中优选乙醇水溶液。
本发明还提供一种上述二氢黄酮类衍生物作为美白剂的用途,尤其涉及7-甲氧基-二氢桑色素-3-O-β-D-葡萄糖苷的美白作用。
附图说明
图1是抑制斑马鱼黑色素产生实验的空白对照图;
图2是熊果苷(0.2mg/ml)抑制斑马鱼黑色素产生实验的效果图;
图3是本发明提供的化合物1(0.1mg/ml)抑制斑马鱼黑色素产生实验的效果图;
图4是本发明提供的化合物2(0.1mg/ml)抑制斑马鱼黑色素产生实验的效果图。
具体实施方式
下面,将结合实施例对本发明作进一步阐述,但这些实施例不对本发明有任何限制。
实施例1活性化合物的制备
取1公斤柘木晒干,粉碎,用6升70%乙醇室温浸泡一天后,超声处理30分钟,滤出提取液之后,向滤渣中再加入5升70%乙醇,超声处理30分钟,过滤,合并两次提取液,真空浓缩至干,得到280g柘木提取物。
取250g柘木提取物加到2升水中进行分散,然后依次用石油醚、乙酸乙酯、正丁醇各1000ml进行萃取。每种溶剂分别萃取三次,并将每种溶剂的三次萃取液合并,最终形成三个部位并浓缩至干:石油醚部位(15g)、乙酸乙酯部位(81g)和正丁醇部位(120g)。
分别检测石油醚部位、乙酸乙酯部位和正丁醇部位的酪氨酸酶活性,以熊果苷为对照品。
试验方法:在样品管和样品对照管中各加入1ml不同浓度的样品溶液,阳性和阴性对照管以磷酸缓冲液代替。在样品管和阳性对照管中加入0.5ml酪氨酸酶溶液(酶活单位125u/ml),样品对照和阴性对照管以0.5ml磷酸缓冲液(pH=6.8)代替,振摇所有试管,使样品和酪氨酸酶充分混匀,37℃水槽孵育10分钟,加入2ml的0.03wt%酪氨酸溶液,反应10分钟,即刻在475nm处测定吸光度。
抑制率I(%)=[1-(T-T0)/(C-C0)]×100%
式中:T0:样品溶剂对照;
T:样品对照;
C:阳性对照;
C0:阳性对照溶剂对照。
计算半数抑制率(IC50)。IC50值定义为抑制率为50%时所需酪氨酸酶抑制剂的浓度。计算方法为以样品的浓度对酪氨酸酶的抑制率作图并进行拟合,读取计算IC50值。试验结果如表1所示:
表1
样品 | IC50(μg/ml) |
柘木提取物 | 300 |
石油醚部位 | 720 |
乙酸乙酯部位 | 240 |
正丁醇部位 | 110 |
熊果苷 | 460 |
由表1可知,乙酸乙酯部位和正丁醇部位均有较强的酪氨酸酶抑制活性,且均优于对照品熊果苷。
取正丁醇部位进行硅胶柱层析,用氯仿:甲醇的体积百分比分别为20∶1;15∶1;10∶1;5∶1;1∶1的比例进行梯度洗脱,分别得到5个部位。将其中氯仿:甲醇为5∶1洗脱的部位再用C18反相制备柱进行层析,用20%甲醇、40%甲醇、60%甲醇、90%甲醇进行梯度洗脱,将其中40%甲醇洗脱的部位再经过Sephadex LH-20凝胶柱层析,用100%乙醇洗脱,得到化合物,通过理化常数和现代波谱学手段(MS、NMR)鉴定结构。
化合物1:为淡黄色粉末,红外图谱(IR):3440显示有羟基存在,1700显示为苯环的特征吸收。ESI-MS(电喷雾质谱)给出准分子离子峰为m/z:465[M-H]-,提示其分子量为466。结合1H NMR和13C NMR,推断其分子式为C21H22O12,不饱和度为10
在1HNMR中,可以观察到5个芳香质子[δ5.88(1H,d,J=2.8Hz);δ5.92(1H,d,J=2.8Hz);δ6.30(1H,d,J=2.8Hz);δ6.30(1H,d,J=8.0Hz);δ7.29(1H,d,J=2.8Hz);],6个葡萄糖基上的质子信号[δ5.10(1H,d,J=8.2Hz),3.90(1H,m);4.05(1H,m);4.21(1H,m);3.92(1H,m);4.27(2H,m)。结合其13C NMR信号:在21个碳信号中,15个归属为黄酮类化合物骨架,6个归属为葡萄糖基。初步推断化合物1为二氢黄酮苷类化合物,根基葡萄糖基异头氢的耦合常数(J=8.2Hz),推断为β-D-葡萄糖苷。
综合文献资料,发现化合物1的1H NMR和13C NMR数据跟从本属植物中分离得到的二氢桑色素非常接近,所不同的是,化合物1多出了明显属于葡萄糖的信号。根据13C NMR的化学位移变化以及相应的HMBC相关点信息(δ4.93H-3/δ101.2葡萄糖的C-1;δ5.10葡萄糖的H-1/δ75.7C-3),可以推断,化合物1中葡萄糖连接在二氢桑色素的C-3位置。因此,化合物1的结构是二氢桑色素-3-O-β-D-葡萄糖苷。
化合物1的结构
化合物1的HMBC关联
化合物2:为淡黄色粉末,红外图谱(IR):3440显示有羟基存在,1700显示为苯环的特征吸收。ESI-MS给出准分子离子峰为m/z:479[M-H]-,提示其分子量为480。结合1H NMR和13C NMR,推断其分子式为C22H24O12,不饱和度为10。
在1H NMR中,可以观察到5个芳香质子[δ5.85(1H,d,J=2.8Hz);δ5.88(1H,d,J=2.8Hz);δ6.35(1H,d,J=2.8Hz);δ6.35(1H,d,J=8.0Hz);δ7.37(1H,d,J=2.8Hz)],6个葡萄糖基上的质子信号[δ5.07(1H,d,J=8.0Hz),δ3.91(1H,m);δ4.05(1H,m);δ4.23(1H,m);δ3.94(1H,m);δ4.25(2H,m)],一个甲氧基信号(δ3.79,3H,s)。结合其13C NMR信号:在22个碳信号中,15个归属为黄酮类化合物骨架,6个归属为葡萄糖基,一个归属为甲氧基碳信号。初步推断化合物1为甲氧基取代二氢黄酮苷类化合物,根基葡萄糖基异头氢的耦合常数(J=8.2Hz),推断为β-D-葡萄糖苷。
综合文献资料,发现化合物2的1HNMR和13C NMR数据跟从本属植物中分离得到的二氢桑色素非常接近,所不同的是,化合物2多出了明显属于葡萄糖的信号以及甲氧基的信号。根据13C NMR的化学位移变化以及相应的HMBC相关点信息[δ4.78(H-3)/δ101.5(葡萄糖的C-1);δ5.10(葡萄糖的H-1)/δ75.7(C-3);δ3.79(甲氧基氢信号)/δ165.3(C-7)],可以推断,化合物2中葡萄糖连接在二氢桑色素的C-3位置,甲氧基连接在二氢桑色素的C-7位。因此,化合物2的结构是7-甲氧基-二氢桑色素-3-O-β-D-葡萄糖苷。
化合物2的结构
化合物2的HMBC关联
化合物1、化合物2和二氢桑色素的HNMR和CNMR数据如表2所示:
表2
在对柘木的分离纯化中(活性跟踪分离纯化),除了分离得到上述化合物1、2外,还另外分离得到4个已知化合物,分别为二氢桑色素-7-O-β-D-葡萄糖苷、二氢桑色素、氧化白藜芦醇和槲皮素。根据文献报道,二氢桑色素-7-O-β-D-葡萄糖苷、二氢桑色素和氧化白藜芦醇均具有非常显著的美白活性。
二氢桑色素-7-O-β-D-葡萄糖苷的化学结构式
二氢桑色素的化学结构式
氧化白藜芦醇的化学结构式
槲皮素的化学结构式。
实施例2对植物活性化合物的美白活性研究
试验样品:由实施例1得到的化合物1和化合物2
对照品:熊果苷
2.1抑制酪氨酸酶活性的研究
试验方法:在样品管和样品对照管中各加入1ml不同浓度的样品溶液,阳性和阴性对照管以磷酸缓冲液代替。在样品管和阳性对照管中加入0.5ml酪氨酸酶溶液(酶活单位125u/ml),样品对照和阴性对照管以0.5ml磷酸缓冲液(pH=6.8)代替,振摇所有试管,使样品和酪氨酸酶充分混匀,37℃水槽孵育10分钟,加入2ml的0.03wt%酪氨酸溶液,反应10分钟,即刻在475nm处测定吸光度。
抑制率I(%)=[1-(T-T0)/(C-C0)]×100%
式中:T0:样品溶剂对照;
T:样品对照;
C:阳性对照;
C0:阳性对照溶剂对照。
计算半数抑制率(IC50)。IC50值定义为抑制率为50%时所需酪氨酸酶抑制剂的浓度。计算方法为以样品的浓度对酪氨酸酶的抑制率作图并进行拟合,读取计算IC50值。试验结果如表3所示:
表3
样品 | IC50(μM) |
化合物1 | 10.2 |
化合物2 | 23.5 |
熊果苷 | 460 |
2.2抑制B16黑色素生成的研究
采用Hosoi等改良方法测定提取物对对黑色素抑制作用。B16黑色素细胞以1×105密度培养在96孔板中,经24h后换液,添加不同浓度的药物,72h后,经PBS洗涤两次,样品经空气干燥,溶于200μ11NNAOH(含1%DMSO),经加热80℃至1h后冷却,选择475nm波长在酶联免疫检测仪上读取吸光度值。
黑色素含量抑制率=[1-(药物孔吸光度值/药物孔细胞密度)(对照孔吸光度值/照孔细胞密度)]×100%
计算半数抑制率(IC50)。IC50值定义为抑制率为50%时所需黑色素抑制剂的浓度。计算方法为以样品的浓度对黑色素的抑制率作图并进行拟合,读取计算IC50值。试验结果如表4所示:
表4
样品 | IC50(μM) |
化合物1 | 25.2 |
化合物2 | 40.3 |
熊果苷 | 346 |
2.3化合物1和化合物2抑制斑马鱼黑色素产生实验
成年斑马鱼饲养于实验室循环水养殖系统中,饲养用水经循环系统过滤并充分曝气,选择形态正常,个体较大和健康的性成熟斑马鱼,在孵化系统按雌雄比1∶2进行配对饲养于玻璃水族箱中。在光照刺激下开始产卵,大约半小时后,开始收集胚胎。将收集的胚胎充分的清洗去除脏物后,在显微镜下挑选出健康发育正常的胚胎用于接下去的实验。
以96孔板作为试验容器,每孔中加入200ul的待测活性物溶液,胚胎发育到9hpf时,按1个胚胎/孔随机分配到96孔板中,每个浓度设置一块板。每个待测活性物设置三个浓度组。每天更换待测活性物暴露液并搅拌,以确保活性成分分布均匀。基于表型的色素沉着评估,于55hpf观察活性物对斑马鱼的黑色素抑制效果。观察前,胚胎用三卡因甲基磺酸盐溶液麻醉后,放入装有3%甲基纤维素的凹玻片上,在倒置显微镜下拍摄。实验结果见图1-4。
从实验结果图片可以看出,化合物1和化合物2均可以非常明显的抑制斑马鱼黑色素的产生,并且其抑制活性明显高于阳性对照熊果苷。化合物1和化合物2在0.1mg/ml的浓度下,其黑色素抑制活性已经高于0.2mg/ml的熊果苷的效果。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (3)
1.一种含有由以下通式表示的二氢黄酮类衍生物,
其中,R1为H、烷基或糖基,R2为H或糖基。
2.根据权利要求1所述的二氢黄酮类衍生物,其特征在于,通式中的R1为CH3,R2为葡萄糖基,化学名为7-甲氧基-二氢桑色素-3-O-β-D-葡萄糖苷。
3.一种根据权利要求1或2所述的二氢黄酮类衍生物的美白用i余。
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