CN111434652B - 双尿嘧啶、其用途及其制备方法 - Google Patents
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- CN111434652B CN111434652B CN201910922805.4A CN201910922805A CN111434652B CN 111434652 B CN111434652 B CN 111434652B CN 201910922805 A CN201910922805 A CN 201910922805A CN 111434652 B CN111434652 B CN 111434652B
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Abstract
本发明涉及一种新型双尿嘧啶(biuracil)、其用途及其制备方法。根据本发明的一方面,该新型双尿嘧啶具有抗老化活性,因此可以有效地应用于化妆品或保健食品组合物中。
Description
相关申请的交叉引用
本申请要求于2019年1月11日提交的韩国专利申请No.10-2019-0003949的优先权和权益,其通过引用合并于此用于所有目的,如同在此完全阐述一样。
技术领域
本发明涉及一种新型双尿嘧啶、其用途及其制备方法。
背景技术
在功能性化妆品技术领域中受主要关注的领域为延缓皮肤老化以帮助改善皱纹的产品、保护皮肤免受紫外线和外部环境影响的产品,以及有助于美白皮肤的产品。其中,为了开发用于延迟皮肤老化的改善皱纹的化妆品,应先行开发能够在皮肤中表现出生理功效的功能性原料。
目前,主要将作为用于抗老化的材料的维生素C、α-生育酚、视黄醇及其衍生物等与化妆品及医药品混合来使用。然而,当将所述材料配制成剂型时,具有发生变臭现象或化学稳定性差的缺点。
一方面,源自微生物的生理活性物质大致为抗菌、抗真菌和抗癌剂的来源,并且由于其优异的稳定性而被开发为用于治疗各种疾病的新药或用作开发新药的模板(template)。
为了克服现有技术的问题,需要研究有关从微生物中分离稳定的新物质。
发明内容
本发明的一方面提供一种新型化合物、其异构体、衍生物、药学上或化妆品学上可接受的盐、水合物或溶剂化物。
本发明的另一方面提供一种生成所述化合物的菌株。
本发明的另一方面提供一种制备所述化合物的方法。
本发明的另一方面提供一种包括所述化合物的用于抗老化的组合物。
另外,本发明的另一方面提供一种包括所述化合物的抗老化方法。
本发明的一方面提供一种包括由化学式1表示的化合物、其异构体、其药学上或化妆品学上可接受的盐、其水合物或其溶剂化物的组合物在制备用于抗老化的化妆品中的用途。
本发明的另一方面提供一种包括由化学式1表示的化合物、其异构体、其药学上或化妆品学上可接受的盐、其水合物或其溶剂化物的组合物在制备用于抗老化的药物中的用途。
本发明的一方面提供一种由化学式1表示的化合物、其异构体、衍生物、药学上或化妆品学上可接受的盐、水合物或溶剂化物。
[化学式1]
所述术语“异构体(isomer)″是指具有相同分子式但在分子中不具有相同的组成原子的连接方法或空间排列的化合物。例如,异构体可以包括结构异构体(structuralisomers)及立体异构体(stereoisomer)。
所述术语“衍生物(derivative)″是指通过用另一个原子或原子团取代上述化合物的一部分结构而获得的化合物。
所述术语“药学上可接受的”表示通过避免在使用常规药学上的服用量时的显著毒性作用而可以从政府或同等监管机构获得或确定获得药物可以用于动物特别是人类的批准,或列举于药典中,或被认为是其他一般药典。
所述术语“药学上可接受的盐”是指化合物的无机和有机酸加成盐。
所述术语“药学上或化妆品学上可接受的盐”是指根据本发明一个方面的盐,其是药学上或化妆品学上可接受的并且具有母体化合物(parent compound)的优选的药理活性。所述盐包括由诸如盐酸、氢溴酸、硫酸、硝酸、磷酸等无机酸形成或由诸如乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)-苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟乙基磺酸、苯磺酸、4-氯代苯磺酸、2-萘磺酸、4-甲基苯磺酸、樟脑磺酸、4-甲基双环[2,2,2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯丙酸、三甲基乙酸、特丁基醋酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸,及粘康酸的有机酸形成的酸加成盐(acidaddition salt);或者存在于母体化合物中的酸性质子被取代时形成的盐。
所述术语“水合物(hydrate)”是指与水结合的化合物,并且是包括在水和化合物之间不具有化学键合力的包合物的广义概念。
所述术语“溶剂化物”是指在溶质的分子或离子与溶剂的分子或离子之间形成的更高级化合物。
所述化合物显示浅棕色性状,分子式表示为C8H6O4N4,并称为1,1′-双尿嘧啶(1,1′-biuracil)。
所述化合物可以通过从表皮葡萄球菌角蛋白菌株提取及净化而获得,并且可以通过有机合成而获得。
所述化合物可以增加原纤维蛋白(fibrillin)的表达,具体而言,可以增加原纤维蛋白的表达来改善皮肤皱纹和增加弹性。
所述化合物可以增加弹性蛋白(elastin)的表达,具体而言,可以增加弹性蛋白的表达来改善皮肤皱纹和增加弹性。
所述化合物可以抑制基质金属蛋白酶3(metalloproteinase 3,MMP3)的表达,具体而言,可以抑制MMP3的的表达来改善皮肤皱纹和增加弹性。
本发明的另一方面提供一种表皮葡萄球菌角蛋白(Epidermidibacteriumkeratini sp.)菌株(保存号:KCCM 11843P)。
所述菌株可以生成所述化学式1的化合物。所述化学式1的化合物如上述的1,1′-双尿嘧啶。
所述菌株包括其变异体。变异体可以是,例如,由天然突变或人为突变引起的变异体。人为突变可以由如紫外线等的物理诱变因素或如碱化合物等的化学诱变因素引起。
所述菌株包括菌株的孢子、菌体,或其培养物。
所述菌株可以从人皮肤分离或衍生自人皮肤。
本发明的另一方面提供一种制备所述化合物的方法,其包括培养表皮葡萄球菌角蛋白(Epidermidibacterium keratini sp.)菌株(保存号:KCCM 11843P)的步骤;以及从所述培养液分离所述化学式1的化合物的步骤。
所述方法包括养表皮葡萄球菌角蛋白(Epidermidibacterium keratini sp.)菌株(保存号:KCCM11843P)的步骤。
所述培养步骤可以是于液体培养基或固体培养基培养菌株。培养基可以包括,例如,葡萄糖、淀粉糖浆、糊精、淀粉、糖蜜、动物油,或植物油作碳源。培养基可以包括,例如,麦糠、大豆粕、小麦、麦芽、棉籽粕、鱼油渣、玉米浆、肉汁、酵母提取物、硫酸铵、硝酸钠,或尿素作氮源。根据需要,培养基可以包括食盐、钾、镁、钴、氯、磷酸、硫酸,或促进其他离子生成的无机盐类。
培养可以在有氧条件下振荡或静置进行。培养温度可以是,例如,约20℃至约37℃,或约26℃至约30℃。
所述方法包括从培养液分离所述化学式1的化合物的步骤。所述化学式1的化合物如上所述。
所述从培养液分离化学式1的化合物的步骤可以包括通过甲醇、乙酸乙酯、水,或其组合提取所述培养液的步骤。所述提取可以使用相同或不同的溶剂进行一次或多次。
所述方法还可以包括通过甲醇、乙酸乙酯、水,或其组合分馏通过所述提取而分配的每个层。
所述从培养液分离化学式1的化合物的步骤可以包括对培养液进行浓缩、离心、过滤或色谱法的步骤。色谱法可以是,例如,根据固定相的状态的柱色谱法、平面色谱法(planar chromatography)、纸色谱法、分取色谱法,或薄层色谱法。色谱法可以是,例如,根据流动相的物理特性的气相色谱法、液相色谱法,或亲和色谱法。液相色谱法可以是,例如,高效液相色谱法(HPLC)。色谱法可以是,例如,根据分离方法的离子交换色谱法或尺寸排阻色谱法。色谱法可以是,例如,正相色谱法或反相色谱法。
术语“培养液”是指通过培养菌株获得的培养液本身、其浓缩物或冻结干燥物,或者从培养液除去菌株而获得的培养上清液、其浓缩物或冻结干燥物。所述培养液可以包括诸如在培养表皮葡萄球菌角蛋白(Epidermidibacterium keratini sp.)菌株过程中产生的蛋白质的有用的活性成分。
本发明的另一方面提供一种用于抗老化的组合物,其包括由化学式1表示的化合物、其异构体、衍生物、药学上或化妆品学上可接受的盐、水合物或溶剂化物。
所述由化学式1表示的化合物、其异构体、衍生物、药学上或化妆品上可接受的盐、水合物或溶剂化物如上所述。
所述由化学式1表示的化合物可以是具有抑制老化作用的抗老化剂。
术语“抗老化”可以是改善、防止和/或预防(anti-aging)皮肤老化。例如,防止皮肤老化可以是预防或改善皮肤皱纹、增加皮肤弹性、预防或改善皮肤老化或色素沉着,或促进皮肤再生。
术语“皮肤老化”是指随着年龄的增长皮肤上出现的有形和无形的变化的统称,例如,表皮厚度变薄、真皮细胞数量或血管数量、恢复DNA损伤的能力、细胞更换周期、伤口愈合、皮肤屏障功能、表皮的水分维持、汗液分泌、皮脂分泌、维生素D产生、物理损伤防护、化学物质去除能力、免疫反应感觉功能和体温调节的减少。所述由化学式1表示的化合物可以用于改善外源因素或内源因素引起的皮肤老化。所述外源因素是指各种外在因素,如紫外线(光),所述內源因素是指时间因素,主要由时间过去而引起。即,所述皮肤老化具体地不仅是由紫外线、公害、香烟烟雾、化学物质等外部刺激引起的初期老化症状,更包括因年龄增长而减少皮肤细胞增殖使自然老化现象发生,并且包括如皱纹、弹性降低减少、皮肤耷拉和干燥现象。此外,皱纹包括由内源因素和外源因素的变化引起的刺激改变组成皮肤组织的成分而引起的皱纹。
所述老化可以是光老化。术语“光老化(photoaging)”是由外部环境因素引起的现象,紫外线是最典型的因素。紫外线导致蛋白裂解酶的活性化和基质蛋白质的链断裂及异常交叉耦合等的生物组件受损,这些机制重复导致明显的皮肤老化。
术语“皱纹”是指皮肤弹性丧失而松弛的状态,例如,皮肤可以折叠。色素沉着是指体内色素的量异常或色素出现的地方有异常状态,例如,斑点和雀斑等。所述″皮肤皱纹预防或改善”可以指抑制这些皱纹相关因子的表达以预防或改善皱纹,或者增加胶原蛋白的总量的所有作用。
术语“改善”可以指与缓和或治疗病症相关的参数,例如,至少可以减轻症状的程度的所有行动。
术语“预防″可以指通过施用所述组合物抑制或延迟皮肤光老化、色素沉着或皱纹的任何行动。
所述组合物可以是化妆品组合物、保健食品组合物或药物组合物。
除了上述组合物之外,所述化妆品组合物可以包括常规用于化妆品组合物中的成分作为有效成分,例如稳定剂、溶剂、维生素、颜料和香料等的常规助剂及载体。
在所述组合物中,由化学式1表示的化合物可以制备成包括以下的剂型:化妆水(润肤液)、爽肤水(toner)、收敛剂(Astringent)、乳液、牛奶润肤露(milk lotion)、保湿乳液、营养液、按摩霜、营养霜、保湿霜、手霜、粉底、精华、营养精华、膜、肥皂、洁面泡沫、洁面乳、洁面霜、身体乳液、身体清洁液、悬浮液、凝胶、粉末、粘膏(paste)、面膜或片装面膜或喷雾组合物。可根据本领域常规方法制备所述剂型的组合物。所述化妆品组合物可以进一步包括保存剂、稳定剂、表面活性剂、溶剂、保湿剂、润肤剂、紫外线吸收剂、防腐剂、杀菌剂、抗氧化剂、pH调节剂、有机和无机颜料、香料、冷感剂或止汗剂。在不损害本发明的目的和效果的范围内,本领域技术人员可以容易地选择诸如上述保湿剂等的附加成分的混合量,该混合量可以是基于组合物的总重量的0.001重量百分比至5重量百分比,具体而言,0.01重量百分比至3重量百分比。
此外,所述组合物可以制剂成皮肤外用剂。在本公开中,所述皮肤外用剂可以是乳膏、凝胶、软膏、皮肤乳化剂、皮肤悬浮液、经皮传递性贴片、含药绷带、乳液或其组合。所述皮肤外用剂可以根据需要适当混合于通常用于化妆品或药物等的皮肤外用剂的成分,例如,水性成分、油性成分、粉末成分、醇类、保湿剂、增稠剂、紫外线吸收剂、美白剂、防腐剂、抗氧化剂、表面活性剂、香料、着色剂、各种皮肤营养剂,或其组合。所述皮肤外用剂可以适当混合乙二胺四乙酸二钠、乙二胺四乙酸三钠、柠檬酸钠、多聚磷酸钠、偏磷酸钠、葡萄糖酸等的金属螯合剂、咖啡因、单宁、戊脉安、甘草提取物、光甘草定、大蓟果实的热水提取物、各种生药、生育酚乙酸酯、甘草酸、氨甲环酸及其衍生物或其盐等药剂、维生素C、抗坏血酸磷酸酯镁、抗坏血酸葡糖苷、熊果苷、曲酸、葡萄糖、果糖、海藻糖等的糖类。
所述保健食品组合物可以单独使用由化学式1表示的化合物,或可以与其他食品或食品成分一起使用,并且可以根据常规方法适当地使用。根据使用目的(预防、保健或治疗处理)适当地决定有效成分的混合量。通常,在制造食品或饮料时,本说明书的组合物可以以基于原料不超过15重量份的量添加。所述保健食品的种类没有特别限制。在各种保健食品中,饮料组合物可以含有如普通饮料的各种香味剂或天然碳水化合物作为附加成分。所述天然碳水化合物是如葡萄糖和果糖的单糖、如麦芽糖及蔗糖的二糖,以及如糊精及环式糊精的多糖以及如木糖醇、山梨糖醇,及赤藓糖醇等的糖醇。作为甜味剂,可以使用如索马甜和甜菊糖提取物的天然甜味剂以及如糖精和阿斯巴甜的合成甜味剂。所述保健食品组合物还可含有营养剂、维生素、电解质、调味剂、着色剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、碳酸饮料中使用的碳酸化剂,或其组合。所述保健食品组合物还可含有天然果汁、果汁饮料、用于制造蔬菜饮料的果肉,或其组合。
本发明的另一方面提供一种改善个体的皮肤的方法,其包括向个体施用所述组合物的步骤。所述组合物如上所述。
具体地,所述方法可以是预防或改善个体的皮肤老化,或者预防或改善皮肤皱纹的方法。
术语“应用的”、“施用的”、″导入的″和“移植的”等可以互换使用,并且可以指将根据一个实施例的组合物带到所需位点的至少局部部分的方法,或者将根据一个实施例的组合物通过途径布置到个体体内。包括根据一个实施例的化合物的组合物中的至少一部分可以通过任何传送至活体中的期望位置的合适途径来施用。
所述个体可以是哺乳动物,例如:人、牛、马、猪、狗、绵羊、山羊或猫。所述个体可以是需要改善皮肤状况,如改善皮肤老化或改善皮肤皱纹的个体。
附图说明
被包括以提供对本发明的进一步理解并且被并入且构成本说明书的一部分的附图例示本发明的示例性实施例,并且与说明书一起用于解释本发明构思。
图1显示1,1′-双尿嘧啶的1H-NMR(600MHz,DMSO-d6,δH)光谱的结果。
图2显示1,1′-双尿嘧啶的13C-NMR(125MHz,DMSO-d6,δC)光谱的结果。
图3显示1,1′-双尿嘧啶的COSY(600MHz,DMSO-d6)光谱的结果。
图4显示1,1′-双尿嘧啶的HSQC(DMSO-d6)光谱的结果。
图5显示1,1′-双尿嘧啶的HMBC(DMSO-d6)光谱的结果。
图6显示以RT-PCR确认化学式1化合物对通过UV照射的Hs68细胞的原纤维蛋白1(FBN)基因表达的影响的结果。***p<0.0001vs.(-)对照组,#p<0.001vs.UV对照组,##p<0.0001vs.UV对照组。
图7显示以RT-PCR确认化学式1化合物对通过UV照射的Hs68细胞的MMP3基因表达的影响的结果。***p<0.0001vs.(-)对照组,#p<0.05vs.UV对照组,##p<0.005vs.UV对照组
具体实施方式
在下文中,将通过实施例更详细地描述本公开。然而,这些实施例是为了描述本公开,本公开的范围不限于这些实施例。
实施例1:鱼孢菌科(Sporichthyaceae family)菌株的分离
从用无菌蒸馏水洗涤健康的女性皮肤来从得到的样品中分离出对应于鱼孢菌科的菌株(以下称为“EPI-7”)。在进行所述菌株的16S rRNA同源性分析和系统分析的结果,确认了所述EPI-7菌株是属于鱼孢菌科(Sporichthyaceae)的新型表皮葡萄球菌,而到目前为止,尚未见有关报道。
将所述表皮葡萄球菌角蛋白菌株于2016年6月8日保存于韩国生命工学研究院生物资源中心,并获得保存号KCCM 11843P。
实施例2:菌株的培养
将R2A培养基以每1公升3g溶于无菌蒸馏水中,并在121℃下灭菌15分钟后冷却至25℃,然后接种分离的EPI-7种菌。在培养条件为28℃的恒温室中培养,并以100rpm搅拌。培养120小时后,终止培养。
实施例3:化合物的分离及净化
50L的于R2A培养基培养的EPI-7T培养液在4℃下以4000rpm离心7分钟后收集上清液,且剩余的残余物用80%甲醇(MeOH,500mL)提取3次。将所述两种溶液在减压下浓缩,获得总共144g的提取物。将获得的提取物用乙酸乙酯(EtOAc,2.2L)和水(H2O,2.2L)分配提取3次,且使用n-丁醇(n-BuOH,2.0L)再次将水层分配提取3次。将分配的每个层在减压下浓缩来获得EtOAc馏分(EPE,10.7g)、n-BuOH(EPB,42.8g),及H2O馏分(EPH,90.5g)。
对获得的EPE馏分10.7g实施SiO2柱(Φ5.5X 35.0cm,EtOAc-n-BuOH-H2O=20∶3∶1→7∶3∶1,各2.0L)以在每150mL进行分取。通过TLC(EtOAc-n-BuOH-H2O=7∶3∶1)确认每个分取液,且将相似的部分合并在一起并浓缩,以获得12个馏分(EPE-1至EPE-12)。在所述馏分之中,对EPE-3馏分(168.0mg,Ve/Vt 0.20-0.25)实施ODS c.c.(Φ2.0X 10.0cm,MeOH-H2O=2∶1,400.0mL)来获得4个馏分(EPE-3-1至EPE-3-4),其中,分离了1,1′-双尿嘧啶(EPE-3-1,20.5mg,Ve/Vt 0.000-0.225,SiO2 TLC Rf 0.70EtOAc-n-BuOH-H2O=15∶3∶1,ODS TLC Rf0.88 MeOH-H2O=2∶1)。
实施例4:化合物的结构分析
通过核磁共振(Nuclear Magnetic Resonance,NMR)光谱及质谱(mass spectrum,MS)分析1,1′-双尿嘧啶的结构。
1,1′-双尿嘧啶:性状(浅棕色);1H-NMR及12C-NMR,参考以下表1及表2;LC-MS(ESI+/triple quadrupole)m/z 113[M/2+1]+,223[M+1]+,267[M+2Na-H]+;分子式,C8H6O4N4;分子量,222.
【表1】
1H-NMR(600MHz,DMSO-d6,δH)10.963,(2H,br.s,NH-3,3′),7.378(2H,d,J=7.2Hz,H-6,6′),5.401(2H,d,J=7.2Hz,H-5,5′)
【表2】
尿嘧啶 | 1,1′-双尿嘧啶 | D | |
2 | 151.984 | 151.535 | 0.449 |
4 | 164.799 | 164.349 | 0.450 |
5 | 100.689 | 100.194 | 0.495 |
6 | 142.658 | 142.245 | 0.413 |
13C-NMR(125MHz,DMSO-d6,δC)164.349(s,C-4,4′),151.535(s,C-2,2′),142.245(d,C-6,6′),100.194(d,C-5,5′)
从LC/MS谱中的分子离子峰m/z 223[M+1]+决定分子量为222,且预测分子式为C8H6N4O4。因此,所述化合物的不饱和度为8。
图1显示1,1′-双尿嘧啶的1H-NMR(600MHz,DMSO-d6,δH)光谱的结果。
在1H-NMR光谱(600MHz,DMSO-d6,δH)中,观察到一个有关胺的质子信号(amineproton signal)于δH 10.963处的宽单峰(broad singlet,bs)。由于观察到胺信号,因此推测胺的质子和进行氢键合的氧位于附近。另外,分别于δH 7.378(1H,d,J=7.2Hz)及5.401(1H,d,J=7.2Hz)处观察到有关芳香族的质子信号(aromatic proton signal),且从耦合常数(coupling constant,J=7.2Hz)彼此显示了3J耦合(3J coupling)。从分子量、分子式、不饱和度和上述1H-NMR数据推定1,1′-双尿嘧啶是由三个双键和一个环组成的杂环化合物,并且推定是两个相同分子键合的二聚体(dimer)。
图2显示1,1′-双尿嘧啶的13C-NMR(125MHz,DMSO-d6,δC)光谱的结果。
于13C-NMR(125MHz,DMSO-d6,δC)处观察到总共四个信号。于δC 164.349及δC151.535处显示两个4级碳,推定前者是酰胺碳,而从非常高磁性的观点来推定后者是位于胺和胺之间的羰基碳。另外,于δC 142.245及δC 100.194处也出现2个烯烃次甲基(olefinmethine)碳。可以得知氮结合于在2个烯烃次甲基碳中于低磁区δC 142.245。
在上述MS数据中观察到m/z 223的分子离子峰,且从NMR数据结果推定1,1′-双尿嘧啶是两个尿嘧啶结合的化合物,其中,所述尿嘧啶是核酸的嘧啶碱基之一。在尿嘧啶的情况下,于l1ppm附近观察到两个与碳结合的胺的质子信号,两个烯烃次甲基质子信号分别分成ddd和dd。相反,在1,1′-双尿嘧啶的情况下,观察到一个胺衍生的质子,且所有烯烃次甲基质子信号分成d。从所述质子数据的角度来看,可以看出尿嘧啶分别连接一次。
图3显示1,1′-双尿嘧啶的COSY(600MHz,DMSO-d6)光谱的结果。
在相关光谱(COSY)中,于δH 7.378和δH 5.401中低磁区所观察到的前者确认为是H-6,6,而后者是H-5,5′。
图4显示1,1′-双尿嘧啶的HSQC(DMSO-d6)光谱的结果。
在异核单量子相干(HSQC)光谱中,于13C-NMR观察到的两个烯烃次甲基质子信号δH7.738(H-6,6′)和δH 5.401(H-5,5′)及分别显示交叉峰(cross peak)的δC 142.245和δC100.194碳信号分别被鉴定为C-6,6′和C-5,5′。
图5显示1,1′-双尿嘧啶的HMBC(DMSO-d6)光谱的结果。
在异核多键相关(HMBC)光谱中,在两个羰基碳信号中,δC 164.349(C-4,4′)与δH7.738(H-6,6′)质子信号显示了3J耦合,且与δH 5.401(H-5,5′)质子信号显示了2J偶合,根据δC151.535(C-2,2′)仅显示与δH7.738(H-6,6′)质子信号的3J耦合,确认所述化合物具有尿嘧啶结构,并且通过MS数据得知所述化合物为尿嘧啶的二聚体。
当将所述化合物与尿嘧啶的1H-NMR进行比较时,该事实显示出于NH-3的化学位移(chemical shift)具有估计约0.03ppm的差异。当看耦合模式时,可以得知H-5及H-6分裂成双峰,与尿嘧啶不同。另外,当比较13C-NMR的化学位移时,可以确认C-5的碳向高磁场移动约0.04ppm,而C-6的碳向低磁场移动约0.04ppm。
因此,获得以下最终结构:
实验例1:评估化合物的原纤维蛋白基因表达的诱导效果
通过以下实验确认所述化合物对原纤维蛋白基因表达的影响。将人成纤维细胞细胞株((Human dermal fibroblast,Hs68)以3.5x105个分株到6孔板后,在37℃和5%CO2的培养基下培养24小时。然后,除去培养基并加入杜氏磷酸缓冲液(DPBS),然后用12mJ/cm2的UVB照射或不照射。UVB照射后立即除去DPBS,且以无胎牛血清(FBS)的培养基替换后,处理0.1ppm、lppm,及10ppm的1,1′-双尿嘧啶,并附外培养24小时。之后,在每个样品的细胞中使用Trizol提取试剂(RNA iso,DAKARA,日本)分离RNA后,用纳米微滴于260nm处定量RNA,然后分别使用2μg的RNA于放大器中合成(CDNAC1000 Thermal Cycler,Bio-Rad,美国)。使用TGFβ1(1ng/ml)及尿嘧啶(0.1,10ppm)作为对照组。
使用于合成的cDNA添加对作为靶基因的原纤维蛋白1(fibrillin 1:FBN)的引物(正向:AATGTCAGACGAAGCCAGGG(序列号1)、反向:GATTTGGTGACGGGGTTCCT(序列号2)以及作为花青燃料的赛博格林(SYBR Green supermix,Applied Biosystems,美国)的混合物于实时(real-time)PCR机器中进行实时聚合酶链反应,以确认了原纤维蛋白基因的表达程度。最后通过有关β肌动蛋白基因(正向:GGCCATCTCTTGCTCGAAGT(序列号3)、反向:GACACCTTCAACACCCCAGC(序列号4)的校正来最终分析基因的表达量。
图6显示以RT-PCR确认化学式1化合物对通过UV照射的Hs68细胞的原纤维蛋白1基因表达的影响的结果。***p<0.0001vs.(-)对照组,#p<0.001vs.UV对照组,##p<0.0001vs.UV对照组.
如图6所示,可以确认在1,1′-双尿嘧啶处理组中,通过UVB照射而减少的原纤维蛋白表达显着增加。所述原纤维蛋白表达的增加效果依赖于1,1′-双尿嘧啶的浓度。
从以上结果,可以确认本发明的1,1′-双尿嘧啶通过增加原纤维蛋白的表达来改善皮肤中产生的皱纹并改善弹性以显示抗老化效果。
实验例2:评估化合物的MMP3基因表达的诱导效果
通过以下实验确认所述化合物对MMP3基因表达的影响。将人成纤维细胞细胞株((Hs68)以3.5x105个分株到6孔板后,在37℃和5%CO2的培养基下培养24小时。然后,除去培养基并加入DPBS,然后用12mJ/cm2的UVB照射。UVB照射后立即除去DPBS,且以无FBS的培养基替换后,处理0.1ppm、1ppm,及10ppm的1,1′-双尿嘧啶,并附外培养24小时。之后,在每个样品的细胞中使用Trizol提取试剂(RNA iso,DAKARA,日本)分离RNA后,用纳米微滴于260nm处定量RNA,然后分别使用2μg的RNA于放大器中合成CDNAC1000 Thermal Cycler,Bio-Rad,美国)。
使用于合成的cDNA添加对作为靶基因的MMP-3引物(正向:ATTCCATGGAGCCAGGCTTTC(序列号5)、反向:CATTTGGGTCAAACTCCAACTGTG(序列号6)以及作为花青染料的赛博格林(SYBR Green master mix,Applied Biosystem,美国)的混合物于实时(real-time)PCR机器中进行实时聚合酶链反应,以确认了MMP-3基因的表达程度。通过有关β-肌动蛋白基因的校正来最终分析基因的表达量,且分析结果显示在图7中。
图7显示以RT-PCR确认化学式1化合物对通过UV照射的Hs68细胞的MMP3基因表达的影响的结果。***p<0.0001vs.(-)对照组,#p<0.05vs.UV对照组,##p<0.005vs.UV对照组
如图7所示,当UVB照射皮肤细胞株时,由UVB增加的MMP-3的表达通过处理化学式1化合物而显着减少。特别是,比使用作为对照组的TGFβ1处理的情沉更显着减少。
因此,可以确认本发明的1,1′-双尿嘧啶通过减少MMP-3的表达来改善皮肤中产生的皱纹并改善弹性以显示具有抗老化活性。
【保存号】
保存机关名称:韩国微生物保存中心(国外)
保存号:KCCM11843P
保存日期:20160608
根据本发明的一方面,新型双尿嘧啶具有抗老化活性,因此可以有效地应用于化妆品或保健食品组合物中。
虽然已在此描述了某些示例性实施例和实施方式,但是根据该描述,其它实施例和修改将是明显的。因此,本发明构思不限于这些实施例,而是限于所附权利要求的更宽范围,并且对于本领域普通技术人员来说,各种显而易见的修改和等同布置将是明显的。
<110> 科丝美诗株式会社
<120> 新型双尿嘧啶,其用途及其制备方法
<130> PX059094
<150> KR 10-2019-0003949
<151> 2019-01-11
<160> 6
<170> KoPatentIn 3.0
<210> 1
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 原纤维蛋白 1 正向引物
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aatgtcagac gaagccaggg 20
<210> 2
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 原纤维蛋白 1 反向引物
<400> 2
gatttggtga cggggttcct 20
<210> 3
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> β肌动蛋白正向引物
<400> 3
gacaccttca acaccccagc 20
<210> 4
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> β肌动蛋白反向引物
<400> 4
gacaccttca acaccccagc 20
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<213> 人工序列
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<211> 24
<212> DNA
<213> 人工序列
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Claims (10)
2.根据权利要求1所述的化合物或其药学上或化妆品学上可接受的盐,所述化合物为表皮葡萄球菌角蛋白菌株(Epidermidibacterium keratini sp.)产生的化合物,表皮葡萄球菌角蛋白菌株的保藏号为KCCM 11843P。
3.一种制备根据权利要求1所述的化合物的方法,包括:
培养保藏号为KCCM 11843P的表皮葡萄球菌角蛋白菌株的步骤;以及
从培养液中分离根据权利要求1所述的化合物的步骤。
5.根据权利要求4所述的组合物,所述组合物为化妆品组合物。
6.根据权利要求4所述的组合物,所述组合物为保健食品组合物。
7.根据权利要求4所述的组合物,所述化合物增加原纤维蛋白的表达。
8.根据权利要求4所述的组合物,所述化合物减少基质金属蛋白酶3的表达。
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