CN116947938A - 马铃薯花色苷衍生物及其应用 - Google Patents
马铃薯花色苷衍生物及其应用 Download PDFInfo
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- CN116947938A CN116947938A CN202310941207.8A CN202310941207A CN116947938A CN 116947938 A CN116947938 A CN 116947938A CN 202310941207 A CN202310941207 A CN 202310941207A CN 116947938 A CN116947938 A CN 116947938A
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- acid
- tyrosinase
- whitening
- anthocyanin
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Abstract
本发明公开了马铃薯花色苷衍生物及其应用,涉及化合物分离技术领域,采用色谱技术对“黑金刚”马铃薯中的花色苷类成分的衍生物进行系统的分离纯化,首次得到马铃薯花色苷衍生物:4‑O‑(p‑coumaryl)rhamnose,本发明分离提取的4‑O‑(p‑coumaryl)rhamnose对酪氨酸酶的活性具有抑制作用。
Description
技术领域
本发明涉及化合物分离技术领域,具体涉及马铃薯花色苷衍生物及其应用。
背景技术
花色苷是花色素与糖以糖苷键结合而成的一类化合物,广泛存在于植物的花、果实、茎、叶和根器官的细胞液中,使其呈现由红、紫红到兰等不同颜色。花色苷是类黄酮——以黄酮核为基础的一类物质中能呈现红色的一族化合物。作用和功效主要包括抗氧化作用、抗炎作用、改善心血管健康等,具体功效因个体差异而有所不同。
可以帮助中和体内的自由基,减少氧化应激对细胞的损伤,有助于预防慢性疾病的发生,如心脏病、癌症和神经退行性疾病。也可以减轻炎症反应,促进炎症的消退,对于炎症相关的疾病如关节炎、炎症性肠病等有一定的缓解作用。花色苷还可以帮助降低血压,改善血液循环,减少心血管疾病的风险。它们可以增强血管弹性,减少血小板聚集,预防动脉硬化和血栓形成。此外,花色苷对大脑健康也有一定的益处,研究表明它们可以改善记忆力、增强学习能力,对于预防和延缓认知功能下降,如老年痴呆症具有一定的保护作用。
花色苷由于其独特的功能性,而被应用于清除体内自由基、增殖叶黄素、抗肿瘤、抗癌、抗炎、抑制脂质过氧化和血小板凝集、预防糖尿病、减肥、保护视力等。作为一种天然色素,安全、无毒,且对人体具有许多保健功能,已被应用于食品、保健品、化妆品、医药等行业。
“黑金刚”马铃薯(Solanum tuberosum L.)是一种良好的粮食作物,因其富含天然活性成分花色苷而越来越受关注。目前,对于黑金刚中花色苷的衍生物的产生和组成研究较少。
发明内容
本发明的目的在于提供马铃薯花色苷衍生物及其应用,采用色谱技术对“黑金刚”马铃薯中的花色苷类成分的衍生物进行系统的分离纯化,得到了花色苷新衍生物(本发明中命名为4-O-(p-coumaryl)rhamnose),同时发现了这一花色苷新衍生物对酪氨酸酶的活性具有抑制作用。
基于上述发现,本发明提供了马铃薯花色苷衍生物,结构如式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物:
式I化合物,即为4-O-(p-coumaryl)rhamnose。
本发明还提供了4-O-(p-coumaryl)rhamnose在制备抑制酪氨酸酶活性产品中的应用。
酪氨酸酶是人体内存在的一种具有双重催化功能的重要生物酶,它参与调控人体内黑色素合成过程,对于人体黑色素形成具有关键作用,当黑色素代谢过程或表皮黑素沉着出现紊乱,即可产生色素性疾病,分为色素脱失和色素沉着过度。
酪氨酸酶又称多酚氧化酶、儿茶酚氧化酶、陈干酪酵素等,是一种种结构复杂的含多亚基的含铜氧化还原酶,广泛存在于微生物、动植物和人体中。酪氨酸酶是一种氧化酶,且是调控黑色素生成的限速酶。
人体黑色素是在黑色素细胞所合成的,形成黑色素,需要两个最基本的物质:第一个是酪氨酸,它是发生反应的一个底物;第二个是酪氨酸酶,是发生反应的催化剂,可以把酪氨酸转换为黑色素,大量的医学研究和临床实验已经证实,酪氨酸酶是黑色素合成的关键酶,如果没有酪氨酸酶的参与,酪氨酸就无法转变为黑色素。
酪氨酸酶活性增加,会大量催化酪氨酸酶向黑色素转变,短时间内大量的黑色素出现,人体代谢不及时,会造成色素沉着,出现如太田痣、雀斑、黄褐斑、老年斑、黑痣等皮肤问题,与人的衰老有密切关系。抑制酪氨酸酶的活性,可以有效降低黑色素的生成,减少皮素色斑的形成。
进一步地,所述的式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物,在制备抑制酪氨酸酶活性产品中的应用。
进一步地,所述产品是抑制黑色素的产品。
进一步地,所述产品为具有美白、祛斑功能的产品。
本发明还提供了一种美白产品,其活性成分至少包括式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物。
进一步地,所述产品选自面膜、面霜、乳液、爽肤水、洗面奶。
本发明中,所述产品的存在形式,包括但不限于药品、化妆品。
本发明中所述“药学上可接受的”是指包括任意不干扰活性成分的生物活性的有效性且对它被给予的宿主无毒性的物质。
本发明所述药学上可接受的辅料,是药物中除主药以外的一切附加材料的总称,辅料应当具备如下性质:(1)对人体无毒害作用,几无副作用;(2)化学性质稳定,不易受温度、pH、保存时间等的影响;(3)与主药无配伍禁忌,不影响主药的疗效和质量检查;(4)不与包装材料相互发生作用。本发明中辅料包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包含糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等;填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等;润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等;崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等;湿润剂包含十二烷基硫酸钠、水或醇等;抗氧剂包含亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等;抑菌剂包含0.5%苯酚、0.3%甲酚、0.5%三氯叔丁醇等;调节剂包含盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸二氢钠和磷酸氢二钠)等;乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68,卵磷酯、豆磷脂等;增溶剂包含吐温-80、胆汁、甘油等。术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。上述酸碱为广义的路易斯酸碱。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物同样可以用于注射制剂。其中,所述注射剂选自液体注射剂(水针)、注射用无菌粉末(粉针)或注射用片剂(系指药物用无菌操作法制成的模印片或机压片,临用时用注射用水溶解,供皮下或肌肉注射之用)。
其中,所述注射用粉剂的中除含有上述化合物外,还至少含有赋形剂。本发明中所述赋形剂,为有意加到药物中的成分,其在所用的量上不应具有药理学特性,但是,赋形剂可以有助于药物的加工、溶解或溶出、通过靶向给药途径递药或有助于稳定性。
本发明的有益效果是:
(1)本发明利用色谱技术首次从马铃薯花色苷衍生物中分离出化合物4-O-(p-coumaryl)rhamnose,并核磁共振确定了化合物4-O-(p-coumaryl)rhamnose的结构,发现了化合物4-O-(p-coumaryl)rhamnose对酪氨酸酶的活性具有抑制作用,添加4-O-(p-coumaryl)rhamnose制备的美白产品,实验证明美白淡斑效果明显。
(2)曲酸,又名曲菌酸,化学命名:5-羟基-2-(羟甲基)-4H-吡喃-4-酮,是一种酪氨酸酶抑制剂。曲菌酸是一种黑色素专属性抑制剂,它进入皮肤细胞后能够与细胞中的铜离子络合,改变酪氨酸酶的立体结构,阻止酪氨酸酶的活化,从而抑制黑色素的形成。本发明的花色苷新衍生物4-O-(p-coumaryl)rhamnose对酪氨酸酶活性均具有较高的抑制效果,且远高于曲酸的抑制效果。
附图说明
图1为马铃薯粗粗提物的液相色谱图;
图2为F2的液相色谱图;
图3为F2-3的液相色谱图;
图4为化合物抑制酪氨酸酶活性的平均斜率图;
图5为实施例3和对比例1效果对比图。
具体实施方式
以下对本发明的技术方案进行清晰、完整地描述,显然,此处所描述的实施例仅是本发明中的一部分,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明的保护范围。
实施例1
马铃薯花色苷衍生物的分离方法,在DAC-HB50分离模块上结合紫外检测器在535nm和280nm处进行制备HPLC(汉邦,中国),使用C18-ODS-A(300毫米×50毫米,5μm,YMC,日本)和XA qua C18半制备柱(4.6×250毫米,5μm,Acchrom,中国)进行分离。
具体包括以下内容:
黑金刚马铃薯粗提物经DAC-HB50色谱柱进行分段得到F1,F2,F3和F4,样品浓度40mg/ml,进样体积20ml,流动相为0.6%三氟乙酸水:乙腈,洗脱梯度条件:0~40min,15%乙腈~35%乙腈,流速50ml/min,如图1所示,Fr.1:25.0~26.5分钟,Fr.2:27.0~29.0分钟,Fr.3:29.3~32.0分钟,Fr.4:32.5~34.5分钟。
F2采用XAqua C18制备柱(5um,100A,20*250mm)进行精细分离,样品浓度为20mg/ml,进样体积为10ml,流动相为0.6%三氟乙酸水:乙腈,洗脱梯度条件0-50-55-60min,15%-27.5%-95%-95%,流速8ml/min,如图2所示,分别得到F2-1~F2-8,其中,F2-3的保留时间为28.5~31.0min。
针对F2-3采用XAqua C18制备柱(5um,100A,20*250mm)进一步纯化,进样体积为10ml,流动相为0.6%三氟乙酸水:乙腈,洗脱梯度条件0-40-100min,16%-16%-16%,流速8ml/min,如图3所示,保留时间39.0~45.0min得到化合物A,保留时间53.5~56.5min得到化合物B。
其中,黑金刚马铃薯粗提物为75%乙醇提取物经大孔树脂的部位,具体包括如下内容:用75%EtOH-BRB(Britton-Robinson缓冲液)提取新鲜的黑金刚马铃薯块茎切片(100kg),减压浓缩,得到提取物(1.58kg),该提取物用D101大孔吸附树脂,依次使用水、EtOH-水(95:5)进行洗脱,收集EtOH-水(95:5)部位得到黑金刚马铃薯粗提物(100.50g)。
EtOH,为乙醇。
化合物B命名为4-O-(p-coumaryl)rhamnose,其结构式如下:
马铃薯花色苷衍生物4-O-(p-coumaryl)rhamnose的核磁共振数据如表1所示。
表1 4-O-(p-coumaryl)rhamnose的核磁共振数据
经表1核磁共振数据确认,及检索对比,确认4-O-(p-coumaryl)rhamnose为:
(2S,3R,4S,5R,6R)-4,5,6-trihydroxy-2-methyltetrahydro-2H-pyran-3-yl(E)-3-(4-hydr oxyphenyl)acrylate,4-O-(p-coumaryl)rhamnose的结构式如下:
实施例2
花色苷新衍生物4-O-(p-coumaryl)rhamnose对酪氨酸酶活性的抑制作用:
1)试剂盒反应液配置
酪氨酸酶底物:用220μL水溶解酪氨酸酶底物冻干粉;
酪氨酸酶:将酪氨酸酶冻干粉溶解在220μL酪氨酸酶测定缓冲液中,分装后-20℃保存,避免反复冻融循环;
酪氨酸酶增强剂:使用时注意避光保护,使用时请置于室温下;
抑制剂对照(曲酸):(1)储备液:加入75μL水制成10mM曲酸原液,混匀。(2)工作液:取配制好的10mM曲酸原液7.5μL中加入92.5μL水,制成0.75mM曲酸工作溶液。
2)样品测定
准备受试样品、抑制剂对照(曲酸)和空白对照制剂。
加入样品:将20μL待测样品(Sample,S)、曲酸对照(IC)或酪氨酸酶测定缓冲液(EC)分别加入96孔板中。96孔板,即96孔细胞培养板、皿系列产品选用进口光学透明纯聚苯乙烯制造。采用特殊工艺而成,使细胞达到最佳吸附状态,所有产品均以伽玛射线灭菌处理。
加入酪氨酸酶溶液:每孔取50μL酪氨酸酶酶液,酪氨酸酶测定缓冲液酪氨酸酶2μL,混合均匀后25℃孵育10分钟。
酪氨酸酶底物加入:每孔取30μL酪氨酸酶底物溶液,酪氨酸酶测定缓冲液23μL、酪氨酸酶底物2μL、酪氨酸酶增强剂5μL,混合均匀。
测量:在510nm处,在动力学模式下测量30和55分钟时的吸光度,得到相应的吸光度值(Abs1,和Abs2)。
3)结果计算:计算所有样本的斜率,包括酶活性控制(EC,缓冲液组),用(Abs2-Abs1)净值ΔAbs除以时间ΔT(T2-T1),计算相对抑制,样本斜率图如图4所示。
根据相对抑制率%=[斜率(EC)-斜率(S)]/斜率(EC)×100%,计算得到花色苷新衍生物4-O-(p-coumaryl)rhamnose的酪氨酸酶抑制活性如表2所示:
表2酪氨酸酶抑制活性
如表2所示,本发明的花色苷新衍生物4-O-(p-coumaryl)rhamnose对酪氨酸酶活性均具有较高的抑制效果,且远高于曲酸的抑制效果。
实施例3
一种添加马铃薯花色苷衍生物4-O-(p-coumaryl)rhamnose的美白面膜的制作工艺:
美白面膜液包括以下重量份原料:羧甲基纤维素钠12份、甘油20份、4-O-(p-coumaryl)rhamnose 2.5份、EDTA二钠0.3份、去离子水50份、聚氧乙烯蓖麻油1份、海藻酸钠3份、积雪草提取液12份、尼泊金甲酯0.4份、甲基异噻唑啉酮0.1份;
面膜液制备工艺具体包括以下步骤:
S1、将羧甲基纤维素钠加入1/2去离子水中溶解形成胶体溶液,然后将甘油、4-O-(p-coumaryl)rhamnose和EDTA二钠加入上述胶体溶液中,搅拌至充分溶解,得到A相组分;
S2、将聚氧乙烯蓖麻油和海藻酸钠加入剩下的1/2去离子水中搅拌均匀得到混合液,然后依次将积雪草提取液加入上述混合液中搅拌至透明稳定,得到B相组分;
S3、将尼泊金甲酯和甲基异噻唑啉酮通过混合机搅拌混合均匀,得到C相组分;
S4、将B相组分缓慢加入A相组分中,边搅拌边升温至50℃,保温20min,然后降温至30℃,加入C相组分继续搅拌至稳定透明,即得到美白面膜液。
上述积雪草提取液为购买成品。
本发明的面膜中马铃薯花色苷衍生物4-O-(p-coumaryl)rhamnose渗润表层斑点,抑制暗沉色素转移,减少色素合成,强韧屏障,焕亮肤色,深入肌肤,渗润基底,阻断黑色素传递,从源头减少黑色素的形成。
对比例1
一种添加烟酰胺的美白面膜的制作工艺:
美白面膜液包括以下重量份原料:羧甲基纤维素钠12份、甘油20份、烟酰胺2.5份、EDTA二钠0.3份、去离子水50份、聚氧乙烯蓖麻油1份、海藻酸钠3份、积雪草提取液12份、尼泊金甲酯0.4份、甲基异噻唑啉酮0.1份;
面膜液制备工艺具体包括以下步骤:
S1、将羧甲基纤维素钠加入1/2去离子水中溶解形成胶体溶液,然后将甘油、烟酰胺和EDTA二钠加入上述胶体溶液中,搅拌至充分溶解,得到A相组分;
S2、将聚氧乙烯蓖麻油和海藻酸钠加入剩下的1/2去离子水中搅拌均匀得到混合液,然后依次将积雪草提取液加入上述混合液中搅拌至透明稳定,得到B相组分;
S3、将尼泊金甲酯和甲基异噻唑啉酮通过混合机搅拌混合均匀,得到C相组分;
S4、将B相组分缓慢加入A相组分中,边搅拌边升温至50℃,保温20min,然后降温至30℃,加入C相组分继续搅拌至稳定透明,即得到美白面膜液。
选取两组测试者,每组50人,分别使用实施例3和对比例1制成的面膜,每次洁面后涂抹,保持20分钟后洗净,每日1次,连续测试30天,统计美白效果,绘制成图,如图5所示。
由图5所示可见,对比例1中含有烟酰胺,烟酰胺的功效是减少黑色素细胞的生成,达到美白淡斑的作用,对比例1具有明显的美白效果;本发明添加马铃薯花色苷衍生物4-O-(p-coumaryl)rhamnose的面膜,在7日、21日和28日测试结果中,发现同样用于接近烟酰胺面膜的美白功效。
Claims (7)
1.如式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物:
2.如权利要求1所述的式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物,在制备抑制酪氨酸酶活性产品中的应用。
3.如权利要求2所述的应用,其特征在于,所述产品为抑制黑色素的产品。
4.如权利要求2所述的应用,其特征在于,所述产品为具有美白、祛斑功能的产品。
5.如权利要求2-4任意一项所述的应用,其特征在于,所述产品为药品、化妆品。
6.一种美白产品,其特征在于,其活性成分至少包括式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物。
7.如权利要求6所述的美白产品,其特征在于,所述产品选自面膜、面霜、乳液、爽肤水、洗面奶。
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