CN109715217B - 米诺地尔和肽的结合物 - Google Patents
米诺地尔和肽的结合物 Download PDFInfo
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- CN109715217B CN109715217B CN201780057559.XA CN201780057559A CN109715217B CN 109715217 B CN109715217 B CN 109715217B CN 201780057559 A CN201780057559 A CN 201780057559A CN 109715217 B CN109715217 B CN 109715217B
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- minoxidil
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Abstract
本发明涉及一种用于防脱发的组合物,更具体来说,本发明涉及一种具有米诺地尔和肽以化学方式连接的结构的化合物,并涉及包含该化合物的防脱发或促进毛发生长的药物组合物或化妆品组合物。根据本发明的具有米诺地尔和肽以化学方式连接的结构的化合物不仅具有如减少脱发、促进毛发生长或促进细胞生长等良好的生理活性,而且在水中具有优异的稳定性,因此可以用作防脱发和促进毛发生长的组合物。
Description
技术领域
本发明涉及一种米诺地尔和肽的结合物,更具体地说,本发明涉及这样一种米诺地尔和肽的结合物,该结合物中的米诺地尔和肽在保持各自性质的同时,各自的活性相互协同。
背景技术
作为哺乳动物皮肤特有器官的毛囊是由原始表皮的下部生长并延伸进入更深的皮肤层中而形成的。毛囊基部存在着被称为小囊或真皮乳头的细胞塞(plug of cell),并且真皮乳头对于毛囊的正常循环及毛干的生长而言是必需的。毛干具有由紧密附着的上皮细胞形成的螺纹状结构,该上皮细胞由角蛋白丝和纤丝聚集蛋白(filament-aggregatingprotein)构成。
人类的毛发周期性地重复生长期、退化期和休止期,并经过脱发和再生的过程。毛发生长周期是由激素调节和许多生长因子共同决定的,而严重的压力或营养不良会使毛发经由退化期提前进入休止期,从而引起严重的脱发症状。
头发从头皮脱落的现象称为脱发,并且影响脱发的因素可能包括气候、暴露于光或热等环境因素,以及疾病、生育、激素分泌及变化、药物使用、营养状况等内在因素。脱发还可能由除了酶促作用以外的营养缺乏、头皮干燥、压力等引起。在由于这些原因导致脱发的情况中,可以通过补充足够的营养、进行头皮治疗和摄入或施用抗氧化剂来抑制脱发,同时促进毛发生长。
为了治疗这种脱发现象,到目前为止,已经将各种各样的物质用作药物,但是它们的缺点是价格太贵或者疗效的个体差异太大。对于其他化妆品,他们使用的是比较便宜但低效的植物提取物,所以效果不显著。用于治疗脱发的药物的一个典型例子是米诺地尔。米诺地尔已获得美国FDA的批准,并有报道称,米诺地尔除了作为一种独特的钾通道开放剂而具有血管舒张功能外,还具有从毛发周期的休止期诱导至生长期和维持毛发周期的诱导性生长期的活性。然而,虽然米诺地尔在使用时可能延缓脱发,但是实际上并不能诱导新毛囊的再生。此外,米诺地尔在水中溶解度低,从而会析出且难以使用。为了解决这些问题,专利文献1(韩国待审查专利公开No.10-2012-0011632)公开了一种使用米诺地尔时添加表面活性剂的技术。
同时,在毛发的生长和退化过程中,有许多因素是相互关联的。例如,有研究报道了使用一系列生长因子,通过促进角质形成细胞的生长因子、促进血管内皮细胞生长因子的活性、促进WINT通路和抑制BMP通路所涉及的蛋白的活性的方式,从而促进毛发生长。然而,虽然生长因子是非常有效的,但是需要额外的步骤和时间以进行重折叠,从而获得天然生长因子,并且在纯化过程中,也需要复杂的纯化步骤,以除去来自大肠杆菌(E.coli)的污染物,并且由于其稳定性和高分子量,所以无法轻易穿过毛发的保护膜,再结合其高昂的价格,因此不太有用。
于是,本发明的发明人已经开发出了这样的肽,该肽能够实现与天然生长因子相同或相似功能或用作天然生长因子,但是其比天然生长因子有更好的稳定性并且可以克服由天然生长因子的大分子量所造成的问题,即,由SEQ ID NO:3的氨基酸序列构成的Nokkin肽(专利文献2:韩国待审查专利公开No.10-2010-0085407)、由SEQ ID NO:2的氨基酸序列构成的Keramin2肽(专利文献3:韩国待审查专利公开No.10-2009-0108323)和由SEQ IDNO:1的氨基酸序列构成的WINT肽(专利文献4:韩国专利公开No.10-2011-0023991)。
然而,常规使用的米诺地尔或由SEQ ID NO:1至SEQ ID NO:3的氨基酸序列构成的肽在预防脱发和提高毛发生长促进性能、减少副作用以及提高在水中的溶解度方面仍需改进。
为解决这些问题,本发明的发明人通过将米诺地尔与SEQ ID NO:1至SEQ ID NO:3的氨基酸序列构成的肽以化学方式结合,从而分别制备了米诺地尔-Nokkin肽、米诺地尔-Keramin 2肽和米诺地尔-WINT肽,并证实了上述化合物能够促进与毛发生长相关的血管内皮细胞生长因子的活性,促进WINT通路,并抑制主要的BMP通路中涉及脱发的蛋白的活性,从而完成了本发明。
发明内容
技术问题
本发明旨在解决常规生发液的问题,因此本发明的技术目的在于提供这样一种物质,该物质在与常规生发液(如天然生长因子、由SEQ ID No:1至SEQ ID No:3的氨基酸序列构成的肽或米诺地尔)相比具有相同或更优异的预防脱发和/或促进毛发生长功能的同时,还具有优异的生理特性,如水中稳定性。
技术方案
为了实现上述目的,本发明提供了一种化合物,该化合物具有米诺地尔和肽以化学方式结合的结构。
根据本发明的一个实施方案,所述肽可以由2至30个氨基酸构成,优选由5至20个氨基酸构成,更优选由8至15个氨基酸构成,还更优选由10至12个氨基酸构成,但不限于此。
根据本发明的另一个实施方案,所述肽优选为水溶性肽,但不限于此。根据本发明的一个优选实施方案,水溶性肽中含有亲水性侧链的氨基酸的比例为至少50%,优选至少60%,更优选至少70%,更优选至少80%,更优选至少90%,并且最优选100%。根据本发明的另一个优选实施方案,水溶性肽具有至多5个具有亲水性侧链的氨基酸,优选至多4个具有亲水性侧链的氨基酸,更优选至多3个具有亲水性侧链的氨基酸,更优选至多2个具有亲水性侧链的氨基酸,更优选至多1个具有亲水性侧链的氨基酸,并且最优选不具有氨基酸。
根据本发明的另一个实施方案,所述肽可以但不限于是由SEQ ID NO:1的氨基酸序列构成的Nokkin肽、由SEQ ID NO:2的氨基酸序列构成的Keramin2肽或由SEQ ID NO:3的氨基酸序列构成的WINT肽。
此外,本发明提供了一种用于预防脱发或促进毛发生长的药物组合物,其包含上述公开的化合物中的任一者。
此外,本发明提供了一种用于预防脱发或促进毛发生长的化妆品组合物,其包含上述公开的化合物中的任一者。
根据本发明的一个实施方案,所述化妆品组合物可以为但不限于是例如以下制剂:润肤美容液、滋养美容液、滋养霜、按摩霜、精华素、眼霜、清洁霜、清洁泡沫、洁肤水、面膜、喷雾、粉、生发油、发乳、洗发液、洗发香波、染发液、护发素、发胶、头发喷雾、润发油、溶胶凝胶、乳液、油、蜡和气溶胶。
有益效果
根据本发明的化合物具有米诺地尔和肽以化学方式结合的结构,其不仅具有如改善脱发、促进毛发生长和促进细胞生长等优异的生理活性,而且还具有优异的水中稳定性以及优异的皮肤渗透率,因此可以用作用于减少脱发和促进毛发生长的组合物。
但是,本发明的效果不限于上述效果,并且可以通过下面的说明使本领域的技术人员清楚地理解其他未提及的效果。
附图说明
图1为示出本发明的化合物和米诺地尔在水中的溶解度的照片。
图2为示出利用本发明的化合物处理时,人脐静脉内皮细胞(HUVEC)的细胞增殖程度的图。
图3为示出利用本发明的化合物处理时,人毛发真皮乳头细胞(HHDPC)的细胞增殖程度的图。
图4至图6示出了确认利用本发明的化合物处理时,VEGF的mRNA和TGFβ1数量的结果。
图7示出了确认利用本发明的化合物处理时,VEGF蛋白量的结果。
图8和图9为示出利用本发明的化合物处理时,血管形成程度的图。
图10和图11示出了确认本发明的化合物对作为WINT的信号通路的β-连环蛋白转位到细胞核中效果的结果。
图12和图13示出了确认本发明的化合物是否能通过抑制磷酸-Smad1/5/8的活化(从细胞质向细胞核迁移)来抑制作为脱发的主要因素的BMP信号通路的结果。
图14和图15为确认利用本发明的化合物处理时,毛发生长程度的结果。
具体实施方式
为了实现上述目标,本发明提供了一种化合物,其具有米诺地尔和肽以化学方式结合的结构。
米诺地尔是6-氨基-1,2-二氢-1-羟基-2-亚氨基-4-苯氧基嘧啶,其结构由以下式1表示:
[式1]
下文将详细说明本发明。
在本发明中,术语“肽”是指通过氨基酸残基形成的直链分子,该氨基酸残基通过肽键连接在一起。肽可以根据本领域公知的常规的生物或化学合成法来制备,特别是通过固相合成技术来制备(Merrifield,J.Amer.Chem.Soc.,85:2149-54(1963))。
肽旨在提高米诺地尔的水溶性。在这方面,所述肽优选为水溶性肽,但不限于此。根据本发明的一个实施方案,所述肽由2至30个氨基酸序列构成,优选由5至20个氨基酸序列构成,更优选由8至15个氨基酸序列构成,还更优选由10至12个氨基酸序列构成。根据本发明的优选的实施方案,所述肽中含有亲水性侧链的氨基酸的比例为优选至少50%,优选至少60%,更优选至少70%,更优选至少80%,更优选至少90%,并且最优选100%。另一方面,所述肽中含有疏水性侧链的氨基酸的比例为小于50%,优选至多40%,更优选至多30%,更优选至多20%,更优选至多10%,且最优选0%。如本文所用,“含有亲水性侧链的氨基酸”是指精氨酸(Arg)、组氨酸(His)、赖氨酸(Lys)、天冬氨酸(Asp)、谷氨酸(Glu)、丝氨酸(Ser)、苏氨酸(Thr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、半胱氨酸(Cys)、硒代半胱氨酸(Sec)、甘氨酸(Gly)和脯氨酸(Pro),而“含有疏水性侧链的氨基酸”是指丙氨酸(Ala)、缬氨酸(Val)、异亮氨酸(Ile)、亮氨酸(Leu)、甲硫氨酸(Met)、苯丙氨酸(Phe)、酪氨酸(Tyr)和色氨酸(Trp),但不限于此,除了上述存在于自然界的氨基酸以外,也可以使用它们的经修饰的产物等而没有限制。根据本发明的优选的实施方案,含有疏水性侧链的氨基酸在所述肽中的存在量为至多5个,优选至多4个,更优选至多3个,更优选至多2个,更优选至多1个,最优选0个。根据本发明的一个实施方案,所述肽优选但不限于是由SEQ ID No:1的氨基酸序列构成的Nokkin肽、由SEQ ID No:2的氨基酸序列构成的Keramin2肽或者由SEQ ID No:3的氨基酸序列构成的WINT肽。
根据本发明的一个实施方案,本发明的化合物对人脐静脉内皮细胞(HUVEC)和人毛发真皮乳头细胞(HHDPC)具有促进细胞生长的能力。根据本发明的另一个实施方案,本发明的化合物具有激活WNT信号转导途径的功能。根据本发明的另一个实施方案,本发明的化合物使β-连环蛋白转位到细胞核中。根据本发明的另一个实施方案,本发明的化合物阻断了作为脱发主要因素的BMP信号通路。
本发明的化合物本身具有优异的稳定性,但其稳定性可以通过修饰构成与该化合物结合的肽的任意氨基酸来进一步提高。根据本发明的一个实施方案,所述肽的N-末端可以与以下保护基结合,从而进一步提高稳定性,所述保护基选自由乙酰基、芴基甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂酰基和聚乙二醇(PEG)组成的组中。根据本发明的另一个实施方案,所述肽可以与以下保护基结合,从而进一步提高稳定性,所述保护基选自由乙酰基、芴基甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂酰基和聚乙二醇(PEG)组成的组中。
上述氨基酸的修饰在大幅提高本发明化合物的稳定性方面起作用。如本文所用,术语“稳定性”旨在包括“体内”稳定性以及“体外”稳定性,如储存稳定性(例如,在室温下的储存稳定性)。此外,上述保护基在保护本发明的化合物免受体内和体外的蛋白水解酶攻击方面起作用。
此外,本发明提供了用于治疗或改善脱发的组合物,其包含作为有效成分的所述化合物。根据本发明的另一个实施方案,本发明提供了用于改善皮肤状况的组合物,其包含作为有效成分的所述肽。在本发明中,组合物可以是药物组合物或保健食品的形式,但不限于此。
由于本发明的组合物包含作为有效成分的本发明的上述化合物,所以省略了两者共同的内容,以避免本说明书过于复杂。
根据本发明的一个实施方案,由本发明的化合物治疗或改善脱发是指促进毛发生长或使毛发生长。根据本发明的优选的实施方案,本发明的化合物能够促进HUVEC和HHDPC细胞生长,促进β-连环蛋白信号转导途径,这是WNT蛋白的代表性信号转导途径。根据本发明的另一个实施方案,本发明的化合物阻断了作为脱发主要因素的BMP信号通路。基于这些结果的动物实验表明,本发明的化合物显著地促进毛发生长。因此,本发明的组合物在改善毛发生长和皮肤状况方面非常有效。
此外,根据本发明的一个实施方案,由本发明的化合物改善皮肤状况为改善皱纹、改善皮肤弹性、防止皮肤老化、改善皮肤保湿能力、治疗伤口或使皮肤再生。
由于本发明的组合物包含作为有效成分的本发明的上述化合物,所以省略了两者共同的内容,以避免本说明书过于复杂。
根据本发明的优选的实施方案,本发明的组合物是包含(a)药学上有效量的本发明的前述化合物和(b)药学上可接受的载体的药物组合物。
如本文所用,术语“药学上有效量”是指足以实现本发明化合物的效力或活性的量。
本发明的药物组合物所含的药学上可接受的载体包括通常用于制剂的制备的载体,并且包括例如(但不限于)乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石、硬脂酸镁、矿物油等。除了上述成分之外,本发明的药物组合物可以进一步包含润滑剂、湿润剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。合适的药学上可接受的载体和制剂的详细内容描述于韩国待审查专利公开No.2017-0027312中。
本发明的药物组合物可以根据本发明所属领域的普通技术人员容易实施的方法,利用药学上可接受的载体和/或赋形剂以制成单位剂量形式或通过插入多剂量容器,从而进行制备。在这种情况下,制剂可以是油性介质或水性介质中的溶液、悬浮液或者乳液的形式,或者也可以是提取物、粉末、颗粒、片剂、胶囊或者凝胶(例如,水凝胶)的形式,并且可以进一步包含分散剂或者稳定剂。
根据本发明的药物组合物在临床施用时可以口服施用或者胃肠外施用,并且可以以一般药物制剂的形式使用。即,在实际临床施用时,本发明的药物组合物可以作为各种剂型通过口服和胃肠外施用,并且当配制本发明的药物组合物时,可以使用常用的稀释剂或赋形剂,如填料、增量剂、粘合剂、润湿剂、崩解剂和表面活性剂。用于口服施用的固体制剂包括片剂、丸剂、粉末、颗粒或胶囊,并且固体制剂可通过将草药提取物或发酵的草药提取物与如淀粉、碳酸钙、蔗糖、乳糖或明胶等的一种或多种赋形剂混合来制备。除了简单的赋形剂之外,还可以使用如硬脂酸镁或滑石之类的润滑剂。用于口服施用的液体制剂(包括悬浮液、内服用液体、乳液、糖浆等)可包括诸如水或液体石蜡之类的简单稀释剂,以及诸如湿润剂、调味剂、芳香剂或防腐剂之类的各种赋形剂。用于肠胃外施用的制剂可包括无菌水溶液、非水溶剂、悬浮剂、乳液、冻干剂或栓剂。非水溶液和悬浮液可为丙二醇、聚乙二醇、植物油(如橄榄油)、可注射用酯类(如油酸乙酯)。栓剂的基质可为witepsol、聚乙二醇(Macrogol)、吐温61、可可油、月桂油、甘油、明胶等。
剂量单位可包括(例如)单剂量的1、2、3或4倍或单剂量的1/2、1/3或1/4。单剂量包含在单次剂量中施用的活性药物的量,并且通常对应于每日剂量的全部、一半、三分之一或四分之一。
本发明的药物组合物可以根据本发明所属领域的普通技术人员可以容易地实施的方法,利用药学上可接受的载体和/或赋形剂以制成单位剂量形式或通过插入多剂量容器,从而进行制备。在这种情况下,制剂可以是油性介质或水性介质中的溶液、悬浮液或乳液的形式,或者可以是提取物、粉末、颗粒、片剂、胶囊或凝胶(例如,水凝胶)的形式,并且可另外包含分散剂或稳定剂。
根据本发明的优选的实施方案,本发明的组合物是化妆品组合物,其包含(a)化妆品学上有效量的如上所述的本发明的化合物;和(b)化妆品学上可接受的载体。
如本文所用,术语“化妆品学上有效量”是指足以实现本发明组合物的改善皮肤状况的效果的量。
本发明的化妆品组合物还可以制备成在本领域中通常制备的任意剂型,(例如)包括溶液、悬浮液、乳液、糊剂、凝胶、乳膏、洗剂、粉末、肥皂、含表面活性剂的清洗剂、油、粉末粉底、乳液粉底、蜡粉底及喷雾剂等,但不限于此。更详细而言,本发明的化妆品组合物可以制备成各种形式,如润肤美容液、营养美容液、滋养霜、按摩霜、精华素、眼霜、清洁霜、清洁泡沫、洁肤水、面膜、喷雾、粉、生发油、发乳、洗发液、洗发香波、染发液、护发素、发胶、头发喷雾、润发油和凝胶等溶液、溶胶凝胶、乳液、油、蜡、气溶胶等,但不限于此。
本发明的糊剂、乳膏或者凝胶制剂可包含作为载体成分的动物油、植物油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅、膨润土、二氧化硅、滑石或者氧化锌。
本发明的粉末或者喷雾制剂可包含作为载体成分的乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或者聚酰胺粉末,特别地,喷雾制剂可另外包含(但不限于)氯氟烃、丙烷/丁烷或者二甲醚等推进剂。
本发明的溶液或者乳液制剂可包含(但不限于)作为载体成分的溶剂、增溶剂或者乳化剂,如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇油、丙三醇脂肪族酯、聚乙二醇或者山梨糖醇的脂肪酸酯。
本发明的悬浮制剂可包含(但不限于)作为载体成分的诸如水、乙醇和丙二醇之类的液相稀释剂、诸如乙氧基异硬脂醇、聚氧乙烯山梨醇酯及聚氧乙烯山梨聚糖酯之类的悬浮剂、微晶性纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶。
如果本发明的制剂是含表面活性剂的清洗剂,则该制剂可包含作为载体成分的脂肪醇硫酸盐、脂肪醇醚硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑鎓盐(imidazolium)衍生物、甲基牛磺酸、肌氨酸盐、脂肪酸酰胺醚硫酸盐、烷基酰胺甜菜碱、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物或者羟乙基化甘油脂肪酸酯,但不限于此。
如果本发明的制剂是洗发香波,则将用于形成洗发香波的基础成分(例如增稠剂、表面活性剂、粘度调节剂、保湿剂、pH调节剂、防腐剂、精油等)与本发明的化合物混合。CDE可用作增稠剂,表面活性剂可为阴离子表面活性剂LES和两性表面活性剂椰油甜菜碱,粘度调节剂可为聚季铵盐(Polyquater),保湿剂可为甘油,pH调节剂可为柠檬酸或氢氧化钠,并且防腐剂可为葡萄柚提取物。此外,可以添加精油(如杉木、薄荷和迷迭香)和蚕丝氨基酸、戊醇和维生素E。根据本发明的一个实施方案,基于100重量份的本发明的化合物,洗发香波可以包含(但不限于)5至10重量份的CDE、30至40重量份的LES、10至20重量份的椰油甜菜碱、0.1至0.2重量份的聚季铵盐、5至10重量份的甘油、0.1至1.01重量份的葡萄柚提取物、0.5至1重量份的蚕丝氨基酸、0.5至1重量份的戊醇、0.5至2重量份的维生素E、以及0.01至0.1重量份的作为精油的杉木、薄荷、迷迭香中的任意一者。
除了作为有效成分的本发明的化合物和载体成分之外,通常用于化妆品组合物中的成分包括(但不限于)常规的佐剂,如抗氧化剂、稳定剂、增溶剂、维生素、色素和香料。
此外,本发明提供了一种预防脱发或促进毛发生长的方法,该方法包括向患有脱发的受试者的患处经皮施用所述化合物的步骤。
经皮施用可以为(但不限于)局部涂敷或注射。
患处可包括但不限于选自由头皮、面部、胡须、头部、唇上胡须、身体、眉毛和眼睑部分组成的组中的至少一者。
患有脱发的受试者可能是患有选自由下列组成的组中的任意一种脱发病症的患者:雄激素脱发、秃斑、系统性脱发、退行性脱发、拔毛发癖、休止期脱发、生长期脱发、疤痕性脱发、瘢痕性脱发、薄头皮、发根营养不良、传染性毛发疾病、遗传性疾病及化疗、荷尔蒙失调、霉菌感染和药物摄入性脱发。
下文将结合实施例和实验例对本发明进行详细说明。
但是,以下实施例和实验例仅用于解释本发明,而本发明的范围不受以下实施例和实验例的限制。
<实施例1>本发明的化合物的合成与溶解度评价
<1-1>肽的合成
<1-1-1>SEQ ID No:3的肽的合成
将700mg的氯三苯甲基氯树脂(CTL树脂;Nova biochem[0064]分类No.01-64-0021)放置在反应器中,并向反应器中添加10ml的二氯甲烷(MC),而后搅拌3分钟。除去溶液并向反应器中添加10ml的二甲基甲酰胺(DMF)。搅拌3分钟后,再次除去溶剂。向反应器中添加10ml的二氯甲烷(DCM),并随后添加200mmol的Fmoc-Cys(trt)-OH(Bachem,Swiss)和400mmol的二异丙基乙胺(DIEA),进行搅拌从而充分溶解,并在搅拌下反应1小时。反应之后,进行洗涤,并将甲醇和DIEA(2:1)溶于DCM中,反应10分钟,并用过量的DCM/DMF(1:1)洗涤。除去溶液,并向反应器中添加10ml的二甲基甲酰胺(DMF)。搅拌3分钟后,再次除去溶剂。向反应器中添加10ml的脱保护溶液(20%哌啶/DMF),在室温下搅拌10分钟,然后除去该溶液。添加相同量的脱保护溶液,并将反应保持10分钟。然后,除去溶液,并用DMF洗涤两次、用MC洗涤一次并用DMF洗涤一次,各3分钟,从而得到Cys(trt)-CTL树脂。
向新的反应反应器中添加10ml的DMF,添加200mmol的Fmoc-His(trt)-OH(Bachem,Swiss)、200mmol的HoBt和200mmol的Bop,搅拌并充分溶解。向反应容器中添加两个部分的400mmol的DIEA,然后搅拌至少5分钟直到所有的固体溶解。将溶解的氨基酸混合物溶液放置在含有脱保护树脂的反应器中,并在室温下搅拌1小时以进行反应。除去反应溶液,并用DMF溶液搅拌3次,各5分钟,然后除去DMF溶液。取出少量的反应树脂并利用Kaiser试验(Nihydrine试验)检查反应的程度。以如上所述相同的方式,利用脱保护溶液进行脱保护两次,制备了His(trt)-Cys(trt)-CTL树脂。用DMF和MC充分洗涤并再次进行Kaiser试验后,如上所述进行以下氨基酸粘附实验。
根据所选择的氨基酸序列,以Fmoc-Cys(trt)、Fmoc-Arg、Fmoc-Gln(trt)、Fmoc-Val、Fmoc-Arg、Fmoc-Thr、Fmoc-Gln(trt)和Fmoc-Arg(pbf)的顺序进行链反应。通过与脱保护溶液反应2次,各10分钟,然后充分洗涤,从而除去Fmoc-保护基。添加乙酸酐、DIEA和HoBt并进行乙酰化一小时,然后将制备的肽基树脂洗涤3次,每次用DMF、MC和甲醇。使氮气缓慢流动并干燥,然后在真空下、P2O5存在下,彻底地进行干燥。然后,在添加30ml的离去溶液[95%的三氟乙酸、2.5%的蒸馏水、2.5%的苯硫基甲烷]后,在室温下将反应保持间歇振动2小时。过滤树脂并用少量TFA溶液洗涤树脂,然后与母液合并。利用减压进行蒸馏,以使总体积留下约一半,并添加50ml的冷乙醚以产生沉淀。通过离心收集沉淀物,并用冷乙醚洗涤两次。除去母液并在氮气下充分干燥,从而得到0.65g的未纯化的NH2-Arg-Gln-Thr-Arg-Val-Gln-Arg-Cys-His-Cys-OH肽(SEQ ID No:3)(产率:92.6%)。当使用分子量分析仪测定时,得到分子量为1287.1(理论值:1286.5)。
<1-1-2>SEQ ID No:1和SEQ ID No:2的肽的合成
使用与实施例<1-1-1>中相同的方法合成SEQ ID No:1的肽(Glu-Leu-Ile-Glu-His-Gly-Gly-Gly-Arg-Pro-Ala-Asp:ELIEHGGGRPAD)和SEQ ID No:2的肽(Ac-Tyr-Lys-Ser-Lys-Lys-Gly-Gly-Trp-Thr-His:Ac-YKSKKGGWTH)。
[表1]
<1-2>本发明化合物的合成
将肽反应器中的肽基树脂(1mmol)和3.9g(3mmol,3.0当量)N,N'-二异丙基乙胺(DIPEA)溶于10mL的1-甲基-2-吡咯烷酮(NMP)中,然后添加200mg(2mmol,2.0当量)琥珀酸酐,并在室温下反应2小时。将溶剂滤掉,并用新制备的NMP(5mL X 2)洗涤,以得到肽基树脂-琥珀酸结合物。将270mg(0.2mmol,2.0当量)1-羟基苯并三唑(HOBt)和759mg(0.2mmol,2.0当量)N,N,N',N'-四甲基-O-(1H-苯并三唑-1-基)六氟磷酸脲(HBTU)溶于10mL二甲基亚砜(DMSO)中,并反应30分钟。添加388mg(0.3mmol,3当量)N,N-二异丙基乙胺(DIPEA)、41.8mg(0.2mM)米诺地尔类似物和肽基树脂-琥珀酸结合物(0.1mmol),并在室温下反应72小时,并过滤以得到反应过的肽基树脂。使所得的树脂与裂解溶液在室温下反应2小时,以去除树脂和保护基,并用10mL(10mmol)乙醚结晶,从而得到米诺地尔杂合肽。
[反应图解1]米诺地尔和肽的结合物的反应图解
[反应图解2]米诺地尔-Nokkin结合物的反应图解
[反应图解3]米诺地尔-Keramin2结合物的反应图解
[反应图解4]米诺地尔-WINT结合物的反应图解
<1-3>溶解度的评价
将实施例1-1中制备的米诺地尔-CG-Nokkin、米诺地尔-CG-Keramin2和米诺地尔-CG-WINT以10mg/ml的浓度分别溶解于DW中。米诺地尔用作对照。
作为结果,可以确认米诺地尔在相同浓度下几乎不溶于水,因此处于不透明状态,而本发明的全部三种化合物均完全溶于水(参见图1)。
<实施例2>在本发明的化合物处理时细胞增殖程度的评价
<2-1>对于人脐静脉内皮细胞(HUVEC)的细胞增殖的评价
为了确认实施例1中合成的本发明的化合物的功能,用本发明的化合物对HUVEC进行处理,以确定增殖程度。将3000个HUVEC置于96孔板的每个孔中,并在CO2培养箱中培养24小时。24小时后,将培养基更换为无血清的DMEM培养基,并将实施例1中合成的本发明的三种化合物和米诺地尔分别以0.5uM、5uM和50uM的浓度添加到细胞中,培养72小时。培养完成后,去除培养上清液,并用乙醇固定细胞,并用PBS(磷酸盐缓冲液)洗涤三次。去除洗涤液后,用比色SRB溶液处理细胞,并用1%醋酸彻底洗涤。然后用显微镜观察细胞,以观察细胞的活性。向经染色的细胞中添加10mM Trizma碱(pH 10.5)溶液,以洗脱SRB,然后用560nm波长的紫外光测量吸光度,从而测定细胞活性。
作为结果,经确认在本发明的三种化合物在低浓度的情况中,细胞增殖表现为与对照组、米诺地尔的情况相似,但是随着浓度增大,细胞增殖程度与米诺地尔相比有显著的增加(参见图2)。
<2-2>对于人毛发真皮乳头细胞(HHDPC)的细胞增殖的评价
将3000个HHDPC置于96孔板的每个孔中,并在CO2培养箱中培养24小时。将培养基更换为无血清的DMEM培养基,并将本发明的三种化合物和米诺地尔分别以0.5uM、5uM和50uM的浓度添加到细胞中,培养72小时。培养完成后,用与实施例2-1相同的方法对细胞进行染色,洗脱SRB,以量化细胞增殖的程度。
作为结果,经确认本发明的三种化合物的细胞增殖程度均高于米诺地尔,且细胞增殖程度以与处理浓度成比例的方式显著增加(参见图3)。
<实施例3>本发明化合物对VEGF和TGFβ1表达的影响的评价
因为VEGF在血管生成和扩张功能中起作用并且TGFβ1影响脱发,所以对用本发明的化合物处理时,VEGF和TGFβ1的表达水平进行确认。
<3-1>mRNA的量(转录水平)的评价
VEGF由HUVEC表达,而TGFβ1由毛发真皮乳头细胞表达。将两种细胞以1×105个细胞/孔的比例放置在6孔板的每个板中。在CO2培养箱中培养24小时后,将培养基更换为无血清的DMEM培养基。将本发明的三种化合物和米诺地尔分别以5uM和50uM的浓度添加到细胞中,并且培养24小时。收获经培养的细胞后,使用RNA提取试剂盒来提取RNA,并进行RT-PCR,从而确认VEGF和TGFβ1的表达程度。用于RT-PCR的引物示于表2中。
表2
引物类型 | 序列 | SEQ ID No |
VEGF正向 | (5')CCATGAACTTTCTGCTGTCTT(3') | 4 |
VEGF反向 | (5')TCGATCGTTCTGTATCAGTCT(3') | 5 |
TGFβ1正向 | (5')GCCCTGGATACCAACTATTGC(3') | 6 |
TGFβ1反向 | (5')TCAGCACTTGCAGGAGTAGCG(3') | 7 |
GAPDH正向 | (5')GGAGCCAAAAGGGTCATCAT(3') | 8 |
GAPDH反向 | (5')GTGATGGCATGGACTGTGGT(3') | 9 |
作为结果,与米诺地尔的VEGF表达相比,本发明的三种化合物显示出更高的VEGF表达,尤其是,在米诺地尔-Nokkin和米诺地尔-Keramin2的情况中,VEGF表达均明显高于米诺地尔的VEGF表达(参见图4至图6)。此外,在本发明的三种化合物的情况中,TGFβ1的表达低于米诺地尔的TGFβ1表达,特别是在米诺地尔-Nokkin的情况中,TGFβ1的表达水平明显低于同一浓度下的米诺地尔的TGFβ1表达(图4至图6)。从这些结果可以看出,由于本发明的三种化合物具有高表达量在血管生成和扩张功能中起作用的VEGF和低表达量的与脱发有关的TGFβ1,因此本发明的三种化合物可用于预防或改善脱发。
<3-2>蛋白质的量(翻译水平)的评价
将HUVEC以1×105个细胞/孔放置在6孔板的每个孔中。在CO2培养箱中培养24小时。将培养基更换为无血清的DMEM培养基后,将本发明的三种化合物和米诺地尔分别以5uM和50uM的浓度添加到细胞中,然后培养24小时。采用蛋白质提取试剂盒提取蛋白质并进行蛋白质印迹。制备12%的SDS-PAGE后,将15ug蛋白质上样到制备好的SDS-PAGE上,并转移到PVDF膜上。在室温下,用5%脱脂乳溶液封闭1小时。在室温下,将一抗(抗-VEGF抗体,抗-α微管蛋白抗体)以1/3000的浓度附着2小时。用PBST进行3次洗涤,每次10分钟,并在室温下,将二抗以1/5000的浓度附着1小时。用BST洗涤三次(每次15分钟)后,进行检测。
作为结果,发现关于VEGF的表达水平,本发明的三种化合物与米诺地尔相似,或高于米诺地尔(参见图7)。由于本发明的三种化合物能够提高在血管生成和扩张功能中起作用的VEGF的表达,因此本发明的三种化合物可用于预防或改善脱发。
<实施例4>本发明的化合物的血管生成程度的评价
将200μl基质胶放置在24孔板的每个孔中,并且培养1小时。各基质胶中放置1×105个HUVEC。将本发明的三种化合物和米诺地尔分别以5uM和50uM的浓度添加到接种有细胞的基质胶中。用作阳性对照的VEGF以50nM和100nM的浓度进行处理。6小时后,通过显微镜观察HUVEC血管生成程度。
作为结果,当用本发明的三种化合物进行处理时,血管生成的程度非常好,特别是优于米诺地尔,并且血管形成的程度与VEGF处理的程度相似(参见图8)。当将每个实验组中的血管生成程度与某一单位面积内完全形成的血管的数量进行比较时,与米诺地尔相比,本发明的三种化合物表现出了相对良好的血管生成(参见图9)。
<实施例5>确认本发明的米诺地尔-WINT是否参与作为WINT信号通路的β-连环蛋
白的细胞核转位
将HUVEC以1×105个细胞/孔放置在6孔板的每个孔中。在CO2培养箱中培养24小时。将培养基更换为无血清的DMEM培养基后,分别将米诺地尔、米诺地尔-WINT和WINT以5uM和50uM的浓度添加到细胞中,然后培养24小时。使用蛋白质提取试剂盒提取蛋白(提取每个细胞核蛋白/细胞质蛋白)。以与实施例3-2相同的方式进行蛋白质印迹,不同之处在于,使用抗-β-连环蛋白抗体、抗-HADC抗体、抗-α微管蛋白抗体作为一抗。
作为结果,证实了在相同浓度下,本发明的化合物米诺地尔-WINT表现出了β-连环蛋白转位到细胞核中,而单独的米诺地尔的β-连环蛋白转位到细胞核的程度显著较低(参见图10)。据发现,米诺地尔-WINT转位到的细胞核是单独的米诺地尔的至少2.8倍(参见图11)。从这些结果可以看出,由于本发明的化合物米诺地尔-WINT可以将作为WINT的信号通路的β-连环蛋白转移到细胞核中,并且与米诺地尔相比,β-连环蛋白转位到细胞核转位程度更高,因而本发明的化合物可用于促进毛发生长或预防脱发。
<实施例6>确认本发明的米诺地尔-Nokkin是否参与作为Nokkin信号通路的磷酸-
Smad1/5/8转位到细胞核中
确认本发明的米诺地尔-Nokkin是否能够通过抑制磷酸-Smad1/5/8活化(从细胞质向细胞核迁移)从而抑制作为脱发主要因素的BMP信号通路。以与实施例5相同的方式进行实验,不同的是在BMP2存在的情况下,使用米诺地尔-Nokkin代替米诺地尔-WINT,并使用抗-P-Smad1/5/8抗体和抗-HDAC1抗体作为一抗。
作为结果,证实了与用米诺地尔处理相比,在用米诺地尔-Nokkin处理的情况中,P-Smad1/5/8向细胞核内的递送减少,并且随着米诺地尔-Nokkin的浓度增加,细胞核中的P-Smad1/5/8会进一步降低(参见图12和图13)。从这些结果可以看出,由于本发明的米诺地尔-Nokkin能够阻断会导致脱发的BMP信号通路,因此本发明的米诺地尔-Nokkin可以用于促进毛发生长或预防脱发。
<实施例7>当用本发明的化合物处理时毛发生长的鉴定
将本发明的米诺地尔-Nokkin用于6只7周龄雄性C57BL小鼠,以测定毛发生长的程度。使用脱毛膏除去7周龄C57BL/6小鼠的背部毛发。分别将米诺地尔和米诺地尔-Nokkin以100ug/ml的浓度添加到PBS中,以制备样品。将样品均匀涂抹于小鼠的背部皮肤,每天一次。在观察到小鼠的背部皮肤上是否生长毛发之后,从背部皮肤的颜色开始变黑的点开始拍摄照片。对于组织学检查,处死小鼠,收集小鼠的背部皮肤,固定于4%PFA中,并用石蜡包埋。将包埋块切成4μm,用H&E染色并观察毛囊。
作为结果,证实了当涂抹本发明的化合物时,毛发生长速度明显快于未使用样品处理的对照组或使用米诺地尔处理的组的毛发生长速度(参见图14)。当通过H&E试验检查毛囊时,证实了与对照组或经米诺地尔处理的组相比,在使用本发明的化合物处理的组的情况中,毛囊位于皮肤深处并且毛囊的数量更多,并且以毛囊中的发根生长变长并生长到皮肤表面的形式促进了毛囊的生长和发育(参见图15)。从以上结果可以看出,本发明的化合物能够用于促进毛发生长或预防脱发。
<制剂例>
制剂例1:润肤美容液
根据常规美容液的制备方法制备包含上述实施例1-2中制备的本发明化合物并具有以下成分的润肤美容液。
表3:
制剂例2.滋养霜
根据常规滋养霜的制备方法制备包含上述实施例1-2中制备的本发明化合物并具有以下成分的滋养霜。
表4:
成分 | 含量(重量%) |
本发明的化合物 | 2.5 |
白芒花籽油 | 3 |
鲸蜡硬脂醇 | 1.5 |
硬脂酸 | 1.5 |
硬脂酸甘油酯 | 1.5 |
液体石蜡 | 10 |
蜂蜡 | 2 |
聚山梨醇酯60 | 0.6 |
失水山梨糖醇倍半油酸酯 | 2.5 |
角鲨烷 | 3 |
1,3-丁二醇 | 3 |
丙三醇 | 5 |
三乙醇胺 | 0.5 |
生育酚乙酸酯 | 0.5 |
防腐剂、着色剂 | 适量 |
香料 | 适量 |
纯净水 | 余量 |
总计 | 100 |
制剂例3.滋养美容液
根据常规美容液的制备方法制备包含上述实施例1-2中制备的本发明化合物并具有以下成分的滋养美容液。
表5:
成分 | 含量(重量%) |
本发明的化合物 | 2.5 |
1,3-丁二醇 | 4 |
丙三醇 | 4 |
鲸蜡硬脂醇 | 0.8 |
硬脂酸甘油酯 | 1 |
三乙醇胺 | 0.13 |
生育酚乙酸酯 | 0.3 |
液体石蜡 | 5 |
角鲨烷 | 3 |
澳洲胡桃油 | 2 |
聚山梨醇酯60 | 1.5 |
失水山梨糖醇倍半油酸酯 | 0.5 |
羧基乙烯基聚合物 | 1 |
防腐剂、着色剂 | 适量 |
香料 | 适量 |
纯净水 | 余量 |
总计 | 100 |
制剂例4.精华素
根据常规精华素的制备方法制备包含上述实施例1-2中制备的本发明化合物并具有以下成分的精华素。
表6:
制剂例5.头发精华
根据常规头发精华的制备方法制备包含上述实施例1-2中制备的本发明化合物并具有以下成分的头发精华。
表7:
制剂例6.染发剂
根据常规染发剂的制备方法制备包含上述实施例1-2中制备的本发明化合物并具有以下成分的染发剂。
表8:
成分 | 含量(重量%) |
本发明的化合物 | 1 |
丙三醇 | 2 |
1,3-丁二醇 | 2 |
PEG 1500 | 2 |
尿囊素 | 0.1 |
DL-泛醇 | 0.3 |
EDTA-2Na | 0.02 |
透明质酸钠 | 8 |
羧基乙烯基聚合物 | 0.2 |
三乙醇胺 | 0.18 |
乙醇 | 10 |
香料、防腐剂、着色剂 | 适量 |
纯净水 | 余量 |
总计 | 100 |
虽然本发明的优选实施方案已通过例子的形式加以说明,但本发明的范围不限于上述具体实施方案。本领域技术人员将领会到,在不脱离本发明权利要求的范围的情况下可做出各种修改。
SEQUENCE LISTING
<110> 凯尔格恩有限公司
<120> 米诺地尔和肽的结合物
<130> 2017-OPA-9196
<150> KR 10-2016-0105707
<151> 2016-08-19
<160> 9
<170> KopatentIn 2.0
<210> 1
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> WINT肽
<400> 1
Glu Leu Ile Glu His Gly Gly Gly Arg Pro Ala Asp
1 5 10
<210> 2
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Keramin2肽
<400> 2
Tyr Lys Ser Lys Lys Gly Gly Trp Thr His
1 5 10
<210> 3
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Nokkin肽
<400> 3
Arg Gln Thr Arg Val Gln Arg Cys His Cys
1 5 10
<210> 4
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VEGF正向引物
<400> 4
ccatgaactt tctgctgtct t 21
<210> 5
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VEGF反向引物
<400> 5
tcgatcgttc tgtatcagtc t 21
<210> 6
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> TGFb1正向引物
<400> 6
gccctggata ccaactattg c 21
<210> 7
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> TGFb1反向引物
<400> 7
tcagcacttg caggagtagc g 21
<210> 8
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> GAPDH正向引物
<400> 8
ggagccaaaa gggtcatcat 20
<210> 9
<211> 20
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<213> 人工序列(Artificial Sequence)
<220>
<223> GAPDH反向引物
<400> 9
gtgatggcat ggactgtggt 20
Claims (11)
2.根据权利要求1所述的化合物,其中所述水溶性肽中含有亲水性侧链的氨基酸的比例为至少70%。
3.根据权利要求2所述的化合物,其中所述水溶性肽的含有亲水性侧链的氨基酸的比例为至少90%。
4.根据权利要求1所述的化合物,其中所述水溶性肽具有5个以下含有疏水性侧链的氨基酸。
5.根据权利要求4所述的化合物,其中所述水溶性肽具有3个以下含有疏水性侧链的氨基酸。
6.根据权利要求4所述的化合物,其中所述含有疏水性侧链的氨基酸选自由丙氨酸(Ala)、缬氨酸(Val)、异亮氨酸(Ile)、亮氨酸(Leu)、甲硫氨酸(Met)、苯丙氨酸(Phe)、酪氨酸(Tyr)和色氨酸(Trp)所组成的组中。
7.根据权利要求1所述的化合物,其中所述肽选自由SEQ ID NO:1的氨基酸序列构成的Nokkin肽、由SEQ ID NO:2的氨基酸序列构成的Keramin2肽和由SEQ ID NO:3的氨基酸序列构成的WINT肽所组成的组中。
8.一种防脱发或促进毛发生长的药物组合物,其包含权利要求1至7中任一项所述的化合物。
9.一种防脱发或促进毛发生长的化妆品组合物,其包含权利要求1至7中任一项所述的化合物。
10.根据权利要求9所述的化妆品组合物,其中所述化妆品组合物为选自由滋养霜、按摩霜、粉、生发油、洗发香波、染发液、护发素、发胶、头发喷雾、润发油和蜡组成的组中的制剂。
11.根据权利要求9所述的化妆品组合物,其中所述化妆品组合物为选自由精华素、发乳和洗发液组成的组中的制剂。
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