CN116496345A - 多肽神经酰胺及其合成方法和应用 - Google Patents
多肽神经酰胺及其合成方法和应用 Download PDFInfo
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- CN116496345A CN116496345A CN202310479134.5A CN202310479134A CN116496345A CN 116496345 A CN116496345 A CN 116496345A CN 202310479134 A CN202310479134 A CN 202310479134A CN 116496345 A CN116496345 A CN 116496345A
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- polypeptide
- ceramide
- hexapeptide
- acid
- reaction
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- 229940106189 ceramide Drugs 0.000 title claims abstract description 58
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 57
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 55
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 55
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- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 title claims abstract description 50
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 title claims abstract description 50
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 title claims abstract description 47
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 claims abstract description 26
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 claims abstract description 25
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
本发明属于生物医药技术领域,公开了一种多肽神经酰胺,其具有通式I的结构或通式I的异构体:其中,M为R1或所述R1为多肽缩合后的残基,所述多肽由2~10个氨基酸缩合而成。本发明还公开了多肽神经酰胺的合成方法和应用。本发明使用短链多肽作为起始原料,通过与鞘氨醇碱反应,构建了一类结构新颖的多肽神经酰胺,多肽神经酰胺具有优异的保湿效果,可以用于保健品、化妆品和药品领域。
Description
技术领域
本发明属于生物医药技术领域,具体涉及多肽神经酰胺及其合成方法和应用。
背景技术
神经酰胺(Ceramide,又称分子钉)天然存在于皮肤中,是皮肤屏障(角质层)非常重要的组成部分,含量高达40~50wt%,神经酰胺是一类由鞘氨醇类长链碱基与脂肪酸组成的神经鞘氨脂质,其中的鞘氨醇部分、脂肪酸部分的碳链长度、不饱和度和羟基数目都是可以变化的,神经酰胺代表了一类化合物。神经酰胺在调控皮肤屏障功能,恢复皮肤水分以及增强皮肤角质细胞之间的粘着力等方面表现出优异的性能。
神经酰胺的量如果减少将导致皮肤的干燥症,失去皮肤表面的防御机能,使外来物质更容易侵入并引起皮肤的二次感染,从而引起皮肤排斥反应。具体地,侵入物导致细胞因子从表层细胞的角质形成细胞、朗格汉斯细胞和黑素细胞等细胞释放,从而引起炎症现象等。因此,为了维持和改善皮肤屏障,皮肤的保湿作用是很重要的,并且与普通的保湿剂相比,含有神经酰胺类化合物的生理脂质混合物能够促进受损的皮肤恢复屏障机能,临床试验结果表明,其在特应性皮炎患者的症状改善中,与中等以上的外用类固醇制剂呈现相似的效果。
由于神经酰胺的重要性,许多化妆品和制药公司正在研究、开发相应的产品。然而,由于天然神经酰胺不易萃取、成本高昂而不适合商业化等因素,故而难以大规模生产天然神经酰胺,一些公司正在努力开发神经酰胺,其结构与皮肤中存在的神经酰胺相似,且在机能上可以提供相同的效果。
因此,考虑到市场上对于功能性神经酰胺的广泛需求,通过使用天然来源且易得的原料构建新建的神经酰胺化合物,解决其供应不足的问题,并增强其功效是非常有必要的。
发明内容
本发明的目的是提供一种结构新颖的多肽神经酰胺化合物,其由多肽与鞘氨醇碱类化合物或连接了丁二酸的鞘氨醇碱类化合物经缩合反应而成。
本发明的另一目的是提供多肽神经酰胺化合物的合成方法,其利用多肽与鞘氨醇碱类化合物或连接了丁二酸的鞘氨醇碱类化合物作为原料。
本发明的另一目的是提供多肽神经酰胺化合物的用途。
为达到上述目的之一,本发明采用以下技术方案:
一种多肽神经酰胺,其具有通式I的结构或通式I的异构体:
其中,M为R1或所述R1为多肽缩合后的残基,所述多肽由2~10个氨基酸缩合而成;
R2选自以下结构之一:-C15H29、-C15H31、-C15H27、-CHOHC14H27、-CHOHC14H29。
缩合后的残基是指相应的多肽的羧基与鞘氨醇碱的氨基缩合形成肽键,或者多肽的氨基与连接了丁二酸的鞘氨醇碱的羧基缩合形成肽键之后,残余的多肽片段R,如双甘肽/>缩合后的残基为/>四肽-5H2N-(β-Ala)-His-Ser-His-OH缩合后的残基为(β-Ala)-His-Ser-His-OH。
进一步地,所述R1选自二肽、四肽、六肽、八肽、九肽缩合后的残基。
二肽是一种由两个氨基酸借由一个肽键组成的多肽;四肽是是一种由四个氨基酸借由三个肽键组成的多肽;六肽是一种由六个氨基酸借由五个肽键组成的多肽;八肽是一种由八个氨基酸借由七个肽键组成的多肽;九肽是一种由九个氨基酸借由八个肽键组成的多肽。
氨基酸选自:丙氨酸、苏氨酸、脯氨酸、天冬酰胺、谷氨酰胺、亮氨酸、色氨酸、丝氨酸、缬氨酸、蛋氨酸、酪氨酸、组氨酸、L-天冬氨酸-4-叔丁基酯、L-天冬氨酸-1-叔丁基酯、甘氨酸、异亮氨酸、苯丙氨酸、赖氨酸、精氨酸、半胱氨酸、L-谷氨酸-5-叔丁基酯、L-谷氨酸-1-叔丁基酯。
进一步地,所述R1选自双甘肽、蛇毒肽中间体、丙氨酰-L-酪氨酸、四肽-5、六肽-1、六肽-8、六肽-9、八肽-3、九肽-1缩合后的残基。
双甘肽结构式
蛇毒肽中间体(二肽-1)结构式丙氨酰-L-酪氨酸(二肽-2)结构式/>四肽-5结构式H-(b-Ala)-His-Ser-His-OH。
六肽-1结构式H-Nle-Ala-His-(D-Phe)-Arg-Trp-NH2。
六肽-8结构式H-Glu-Glu-Met-Gln-Arg-Arg-NH2。
六肽-9结构式H-Gly-Pro-Gln-Gly-Pro-Gln-OH。
八肽-3结构式H-Glu-Glu-Met-Gln-Arg-Arg-Ala-Asp-NH2。
九肽-1结构式H-Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Pro-Val-NH2。
进一步地,所述R2选自以下结构之一:
进一步地,所述R2选自以下结构之一:
分别对应鞘氨醇、二氢鞘氨醇、植物鞘氨醇。
进一步地,所述R1选自双甘肽缩合后的残基。
进一步地,所述R1选自蛇毒肽中间体缩合后的残基。
进一步地,所述R1选自丙氨酰-L-酪氨酸缩合后的残基。
进一步地,所述R1选自四肽-5缩合后的残基。
进一步地,所述R1选自六肽-1缩合后的残基。
进一步地,所述R1选自六肽-8缩合后的残基。
进一步地,所述R1选自六肽-9缩合后的残基。
进一步地,所述R1选自八肽-3缩合后的残基。
进一步地,所述R1选自九肽-1缩合后的残基。
进一步地,所述R1选自L-天冬氨酸-4-叔丁基酯或L-天冬氨酸-1-叔丁基酯缩合后的残基。
进一步地,多肽神经酰胺选自以下化合物之一:
一种多肽神经酰胺的合成方法,包括以下步骤:
当M为R1时,
步骤S1:将Boc保护的多肽、鞘氨醇碱缩合剂、偶联剂反应,得到化合物C;
步骤S2:化合物C脱去保护基Boc得到产物;
当M为时,将Fmoc保护的多肽脱去保护基Fmoc后与丁二酸相连的鞘氨醇碱/>缩合剂反应得到产物。
当M为R1时,所述缩合剂为EDCI或DCC,所述偶联剂为N-羟基丁二酰亚胺,所述Boc保护的多肽、鞘氨醇碱、缩合剂、偶联剂的摩尔比为(1~1.5):1:(1~2):(1~2),所述反应的溶剂为DCM。
当M为时,所述缩合剂为HOBt和DIC,所述多肽、丁二酸相连的鞘氨醇碱HOBt、DIC的摩尔比为(1~1.5):1:(1~2):(1~2),所述反应的溶剂为DMF。
S1具体为:原料A、N-羟基丁二酰亚胺溶于二氯甲烷中,加入缩合剂(EDCI或DCC),常温下反应过夜,加入鞘氨醇碱,常温搅拌反应直至TCL检测鞘氨醇碱反应完全为止。后处理:加入DCM稀释,过滤去除固体,滤液再分别用水、饱和食盐水各洗一次,收集到的水相再用二氯甲烷萃取一次,合并有机相,用无水硫酸钠干燥,过滤,减压旋蒸后得粗产物,经柱层析纯化得到产物。
S2具体为:将上一步得到的产物溶于DCM,再加入TFA,室温反应搅拌过夜直至TLC检测原料反应完全为止。后处理:先旋干反应液,再加入饱和碳酸钠溶液调节反应体系的pH值到10左右,加入DCM后分液,有机相加入水洗两次,合并的水相用DCM回萃一次,合并有机相,用无水硫酸钠干燥,过滤后减压旋蒸得产物粗品,粗产品用甲醇重结晶后过滤得纯化的白色固体产品。
当M为时,具体步骤为:在树脂上合成好多肽之后,加入哌啶脱去多肽的Fmoc保护基,称取/>和HOBt并用DMF溶剂,冰浴下加入DIC活化后导入反应柱,常温下反应,用DCM、DMF、甲醇洗涤树脂后,所得到的粗肽树脂放入真空干燥箱烘干;裂解与分离:干燥树脂置于裂解液(TFA:EDT:TIPS:H2O=92.5:2.5:2.5:2.5),在室温下裂解,加入冰冻后的异丙醚沉降,析出白色固体,将白色固体抽滤烘干,用水和乙腈溶解,使用半制备分离仪器在30-70(流动相为1/‰三氟乙酸水和乙腈)的梯度下分离得到产物。
当M为时,合成方法还包括鞘氨醇碱/>和丁二酸酐反应的步骤:
该反应加入有机碱DIPEA,以四氢呋喃THF为溶剂,鞘氨醇碱和丁二酸酐、DIPEA的摩尔比为1:(1~1.5):(1.5~3)。具体步骤为:在单口瓶中加入丁二酸酐和鞘氨醇,加入THF将其溶解,然后加入DIPEA,室温下搅拌反应直至TCL检测反应完全为止。使用二氯甲烷和盐酸水溶液萃取两次,二氯甲烷和饱和食盐水溶液萃取一次。合并有机相,使用柱层析纯化得到白色固体产品。
多肽神经酰胺在制备具有保湿作用的化妆品、药品或保健品中的用途。
一种具有保湿作用的组合物,其包含作为活性成分的多肽神经酰胺、其异构体、其药学上可接受的盐、其水合物或其溶剂合物。
该组合物含有可接受的辅料,包括增溶剂、防腐剂、抗氧剂、pH调节剂、促渗剂、脂质体、保湿剂、增稠剂、螯合剂、肤感调节剂、表面活性剂、乳化剂、香精及色素中的一种或多种;该组合物为霜剂、乳剂、溶液剂、膜剂、气雾或喷雾形式。
本文使用的“异构体”包括互变异构体和立体异构体,互变异构体是指具有不同能量的可通过低能垒互相转化的结构异构体;立体异构体是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体等。
本文使用的“药学上可接受的盐”意指,药学上可接受的且具有母体化合物的所期望的药理活性的本发明一方面的盐。这种盐包括:(1)与无机酸或有机酸形成的酸加成盐,无机酸例如有氢氯酸、氢溴酸、硫酸、硝酸、磷酸等,而有机酸例如有醋酸、丙酸、己酸、环戊基丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸、羟基丁二酸、顺丁烯二酸、反丁烯二酸、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-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基二环[2,2,2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡萄糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸及粘康酸;或(2)当所述母体化合物中存在的酸性质子被取代而生成的盐。
本文使用的“水合物”意指一种与水结合的化合物。所述化合物与水之间的结合包括非共价结合。
本文使用的“溶剂合物”意指一种由溶质分子或离子与溶剂分子或离子所形成的配合物。
除非另有说明,否则术语“本发明的化合物”包括该化合物本身、其药学上可接受的盐、其水合物、其溶剂合物、其异构物。
本发明具有以下有益效果:
本发明使用短链多肽作为起始原料,通过与鞘氨醇碱反应,构建了一类结构新颖的多肽神经酰胺,多肽神经酰胺具有优异的保湿效果,可以用于保健品、化妆品和药品领域。
附图说明
图1是实施例4所得化合物的质谱图;
图2是实施例5所得化合物的质谱图;
图3是实施例6所得化合物的质谱图;
图4是实施例7所得化合物的质谱图;
图5是实施例8所得化合物的质谱图;
图6是实施例9所得化合物的质谱图;
图7是实施例10所得化合物的质谱图;
图8是实施例11所得化合物的质谱图;
图9是实施例12所得化合物的质谱图;
图10是实施例13所得化合物的质谱图;
图11是实施例14的81%环境湿度时透明质酸的吸湿率-时间曲线;
图12是实施例14的81%环境湿度时双甘肽-植物鞘氨醇的吸湿率-时间曲线;
图13是实施例14的81%环境湿度时蛇毒肽-植物鞘氨醇的吸湿率-时间曲线;
图14是实施例14的81%环境湿度时二肽-2-植物鞘氨醇的吸湿率-时间曲线;
图15是实施例14的81%环境湿度时四肽-5-植物鞘氨醇的吸湿率-时间曲线;
图16是实施例14的81%环境湿度时四肽-5-鞘氨醇的吸湿率-时间曲线;
图17是实施例14的81%环境湿度时六肽-1-植物鞘氨醇的吸湿率-时间曲线;
图18是实施例14的81%环境湿度时六肽-1-鞘氨醇的吸湿率-时间曲线;
图19是实施例14的81%环境湿度时六肽-8-植物鞘氨醇的吸湿率-时间曲线;
图20是实施例14的81%环境湿度时六肽-9-植物鞘氨醇的吸湿率-时间曲线;
图21是实施例14的81%环境湿度时六肽-9-鞘氨醇的吸湿率-时间曲线;
图22是实施例14的81%环境湿度时八肽-3-植物鞘氨醇的吸湿率-时间曲线;
图23是实施例14的81%环境湿度时九肽-1-植物鞘氨醇的吸湿率-时间曲线;
图24是实施例14的81%环境湿度时九肽-1-鞘氨醇的吸湿率-时间曲线;
图25是实施例14的43%环境湿度时透明质酸的吸湿率-时间曲线;
图26是实施例14的43%环境湿度时双甘肽-植物鞘氨醇的吸湿率-时间曲线;
图27是实施例14的43%环境湿度时蛇毒肽-植物鞘氨醇的吸湿率-时间曲线;
图28是实施例14的43%环境湿度时二肽-2-植物鞘氨醇的吸湿率-时间曲线;
图29是实施例14的43%环境湿度时四肽-5-植物鞘氨醇的吸湿率-时间曲线;
图30是实施例14的43%环境湿度时四肽-5-鞘氨醇的吸湿率-时间曲线;
图31是实施例14的43%环境湿度时六肽-1-植物鞘氨醇的吸湿率-时间曲线;
图32是实施例14的43%环境湿度时六肽-1-鞘氨醇的吸湿率-时间曲线;
图33是实施例14的43%环境湿度时六肽-8-植物鞘氨醇的吸湿率-时间曲线;
图34是实施例14的43%环境湿度时六肽-9-植物鞘氨醇的吸湿率-时间曲线;
图35是实施例14的43%环境湿度时六肽-9-鞘氨醇的吸湿率-时间曲线;
图36是实施例14的43%环境湿度时八肽-3-植物鞘氨醇的吸湿率-时间曲线;
图37是实施例14的43%环境湿度时九肽-1-植物鞘氨醇的吸湿率-时间曲线;
图38是实施例14的43%环境湿度时九肽-1-鞘氨醇的吸湿率-时间曲线。
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。
所有反应在氮气气氛下进行。除非另有说明,化学品均购自商业化产品并且不经进一步纯化。实验中使用的二氯甲烷、四氢呋喃、吡啶、N,N-二甲基甲酰胺均为无水溶剂。薄层色谱分析(TLC)使用60F254硅胶板。硅胶柱层析使用青岛海洋硅胶(粒径0.040-0.063mm)。TLC显色采用UV光(254nm)或碘。NMR图谱使用Bruker DPX 400核磁共振仪表征,1H NMR为400MHz,溶剂为氘代甲醇,氘代DMSO或氘代四氢呋喃,以四甲基硅烷(TMS)为内标。化学位移的单位是ppm,耦合常数的单位是Hz。在1H NMR中,δ表示化学位移,s表示单峰,d表示双峰,t表示三重峰,q表示四重峰,m表示多重峰。
EDCI指1-乙基-(3-二甲基氨基丙基)碳二亚胺,HOBt指1-羟基苯并三唑,DCC指N’N-二环己基碳二亚胺,DIC指N'N-二异丙基碳二亚胺,SuOH指N-羟基丁二酰亚胺,DCM指二氯甲烷,THF指四氢呋喃,DMF指N,N-二甲基甲酰胺,Boc指叔丁氧羰基,Fmoc指9-芴基甲氧基羰基,TFA指三氟乙酸,EA指乙酸乙酯,MeOH指甲醇,DIPEA指N,N-二异丙基乙基胺。
实施例1
双甘肽-植物鞘氨醇神经酰胺的合成
第一步:将Boc保护的双甘肽(1.0eq,50mmol)和N-羟基丁二酰亚胺(1.5eq,75mmol)溶于100mL二氯甲烷中,常温下加入DCC(1.5eq,75mmol),常温下反应过夜后加入植物鞘氨醇(1eq,50mmol),搅拌反应直至TCL检测植物鞘氨醇反应完全为止。
后处理:加入80mL的DCM稀释,过滤去除固体,滤液再分别用80mL水、80mL饱和食盐水各洗一次,收集到的水相再用80mL二氯甲烷萃取一次,合并有机相,用无水硫酸钠干燥,过滤,减压旋蒸后得粗产物,经柱层析纯化得到产物。
第二步:将上一步得到的产物(1eq,30mmol)溶于30mL DCM,再加入15mL TFA,室温反应搅拌过夜,直至TLC检测原料反应完全为止。
后处理:先旋干反应液,再加入饱和碳酸钠溶液调节反应体系的pH值到10左右,加入30mL DCM后分液,有机相加入30mL水洗两次,合并的水相用20mL DCM回萃一次,合并有机相,用无水硫酸钠干燥,过滤后减压旋蒸得产物粗品。粗产品用甲醇重结晶后过滤得纯化的白色固体产品。
1H NMR(400MHz,Methanol-d4)δ4.15(dt,J=6.3,4.7Hz,1H),3.91(d,J=1.3Hz,2H),3.78(dd,J=11.2,4.4Hz,1H),3.73–3.62(m,1H),3.57–3.45(m,2H),3.33(s,2H),1.67(td,J=9.5,8.7,5.1Hz,1H),1.52(d,J=14.9Hz,1H),1.30–1.26(m,24H),0.89(t,J=6.7Hz,3H)。
实施例2
二肽-1-植物鞘氨醇(蛇毒肽-植物鞘氨醇)神经酰胺的合成
第一步:将Boc保护的二肽-1(1.0eq,30mmol),EDCI(1.5eq,45mmol)和N-羟基丁二酰亚胺(1.5eq,45mmol)溶于60mL二氯甲烷中,常温下反应30min后,加入植物鞘氨醇(1eq,45mmol),常温搅拌反应直至TCL检测植物鞘氨醇反应完全为止。
后处理:加入50mL水稀释,分液,有机相再分别用80mL水、80mL饱和食盐水洗,水相再用60mL二氯甲烷萃取一次,合并有机相,用无水硫酸钠干燥,过滤,减压旋蒸后得粗产物,经柱层析纯化得到产物。
第二步:将上一步得到的产物(1eq,10mmol)溶于10mL DCM,再加入5mL TFA,室温反应搅拌过夜,直至TLC检测原料反应完全为止。
后处理:先旋干反应液,再加入饱和碳酸钠溶液调节反应体系的pH值到10左右,加入30mL DCM后分液,有机相加入30mL水洗两次,合并的水相用20mL DCM回萃一次,合并有机相,用无水硫酸钠干燥,过滤后减压旋蒸得产物粗品。粗产品经柱层析纯化得到二肽-1-植物鞘氨醇神经酰胺产物。
1H NMR(400MHz,Methanol-d4)δ4.44(dd,J=8.5,3.9Hz,1H),4.10(td,J=5.9,4.1Hz,1H),3.94–3.42(m,6H),3.11–3.08(m,2H),2.70(dt,J=8.7,6.0Hz,2H),2.24(td,J=8.2,4.9Hz,1H),2.15–1.88(m,3H),1.73–1.50(m,2H),1.32–1.29(s,24H),0.92(t,J=6.7Hz,3H)。
实施例3
二肽-2-植物鞘氨醇神经酰胺的合成
参照二肽-1-植物鞘氨醇神经酰胺的方法合成得到。
1H NMR(400MHz,Chloroform-d)δ7.07(d,J=8.3Hz,2H),6.69(d,J=8.3Hz,2H),4.55(dd,J=8.7,5.9Hz,1H),4.12–4.03(m,1H),3.70(dtd,J=21.7,10.7,10.2,3.6Hz,2H),3.49(ddd,J=22.8,9.6,5.7Hz,3H),3.03(td,J=14.6,14.2,6.4Hz,1H),2.82(dd,J=13.7,9.0Hz,1H),1.67–1.49(m,2H),1.28–1.24(m,J=9.8Hz,27H),0.89(t,J=6.7Hz,3H)。
实施例4
六肽-1-鞘氨醇神经酰胺的合成
第一步:鞘氨醇与丁二酸酐的合成
在1L单口瓶中加入丁二酸酐(3.78g,37.8mmol)和鞘氨醇(9.5g,31.5mmol),将其溶于100mL THF溶液中,加入DIPEA(8.2g,63mmol),室温下搅拌反应直至TCL检测反应完全为止。使用二氯甲烷和盐酸水溶液萃取两次,二氯甲烷和饱和食盐水溶液萃取一次,合并有机相,使用柱层析纯化得到白色固体产品I(8.1g)。
第二步:六肽-1序列合成
1、MBHA Linker的合成
称取MBHA树脂7mmol,(10g,上样量:0.69mmol/g),100mL DMF溶胀2h,抽干。用100mL干燥DMF洗涤3次,抽干。
称取7.5g Fmoc-Linker、2.2g HOBT,用100mL DMF溶解,在冰浴下加入2.6mL DIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。
2、Fmoc-Trp(Boc)-OH的合成
加入20%的哌啶/DMF溶液脱保护两次,100mL/次,10min+10min脱保护完毕,DMF洗涤6次,100mL/次/3min,抽干,印三酮检测,K+。
称取8.9g Fmoc-Trp(Boc)-OH、2.2g HOBT,用100mL DMF溶解,在冰浴下加入2.6mLDIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。
3、Fmoc-Arg(Pbf)-OH的合成
加入20%的哌啶/DMF溶液脱保护两次,100mL/次,10min+10min脱保护完毕,DMF洗涤6次,100mL/次/3min,抽干,印三酮检测,K+。
称取9.1g Fmoc-Arg(Pbf)-OH和2.2g HOBT,用100mL DMF溶解,在冰浴下加入2.6mL DIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。
4、Fmoc-D-Phe-OH的合成
加入20%的哌啶/DMF溶液脱保护两次,100mL/次,10min+10min脱保护完毕,DMF洗涤6次,100mL/次/3min,抽干,取样检测。
称取8.1g Fmoc-D-Phe-OH和2.2g HOBT,用100mL DMF溶解,在冰浴下加入2.6mLDIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。
5、Fmoc-His(Trt)-OH的合成
加入20%的哌啶/DMF溶液脱保护两次,100mL/次,10min+10min脱保护完毕,DMF洗涤6次,100mL/次/3min,抽干,取样检测。
称取12.8g Fmoc-His(Trt)-OH和2.2g HOBT,用100mL DMF溶解,在冰浴下加入2.6mL DIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。
6、Fmoc-Ala-OH的合成
加入20%的哌啶/DMF溶液脱保护两次,100mL/次,10min+10min脱保护完毕,DMF洗涤6次,100mL/次/3min,抽干,取样检测。
称取5.2g Fmoc-Ala-OH和2.3g HOBT,用100mL DMF溶解,在冰浴下加入2.6mLDIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。
7、Fmoc-Nle-OH的合成
加入20%的哌啶/DMF溶液脱保护两次,100mL/次,10min+10min脱保护完毕,DMF洗涤6次,100mL/次/3min,抽干,取样检测。
称取7.4g Fmoc-Nle-OH和2.3g HOBT,用100mL DMF溶解,在冰浴下加入2.6mLDIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。
第三步:化合物I与六肽-1序列合成六肽-1-鞘氨醇神经酰胺
加入20%的哌啶/DMF溶液脱保护两次,100mL/次,10min+10min脱保护完毕,DMF洗涤6次,100mL/次/3min,抽干,取样检测。
称取5.8g第一步合成的化合物I和2.3g HOBt,用100mL DMF溶解,在冰浴下加入2.6mL DIC,于溶液中活化约5min,导入反应柱中,室温下反应1h,取样检测;用DMF洗涤树脂3次,100mL/1次/3min,抽干。用甲醇洗涤树脂3次,100mL/1次/3min,抽干。得到粗肽树脂,将其放入真空干燥箱烘干。化合物I与六肽-1序列的合成的产品命名为hexapeptide-1-399。
hexapeptide-1-399的裂解与制备分离:将真空干燥后得到的干燥树脂称重约为17.8g。配置200mL裂解液(TFA:EDT:TIPS:H2O=92.5:2.5:2.5:2.5)室温下裂解2h。加入2L冰冻后的异丙醚沉降,析出白色固体,将白色固体抽滤烘干,用之后用水和乙腈溶解。使用半制备分离仪器在30-70(流动相为1‰三氟乙酸水和乙腈)的梯度下分离,得到合格液减压浓缩冻干,所得化合物质谱测试如图1所示。
实施例5
六肽-1-植物鞘氨醇神经酰胺的合成
第一步:植物鞘氨醇与丁二酸酐的合成
在1L单口瓶中加入丁二酸酐(3.78g,37.8mmol)和植物鞘氨醇(10g,31.5mmol),将其溶于100mL THF溶液中,加入DIPEA(8.2g,63mmol),室温下搅拌反应直至TCL检测反应完全为止。使用二氯甲烷和盐酸水溶液萃取两次,二氯甲烷和饱和食盐水溶液萃取一次,合并有机相,使用柱层析纯化得到白色固体产品I(8.2g)。
第二步;化合物II与六肽-1序列合成六肽-1-植物鞘氨醇神经酰胺
参照实施例4第三步,所得化合物质谱测试如图2所示。
实施例6
六肽-8-植物鞘氨醇神经酰胺的合成
六肽-8序列合成参照六肽-1的合成方法。
参照实施例5进行,所得化合物质谱测试如图3所示。
实施例7
六肽-9-鞘氨醇神经酰胺的合成
六肽-9序列合成参照六肽-1的合成方法。
参照实施例4进行,所得化合物质谱测试如图4所示。
实施例8
六肽-9-植物鞘氨醇神经酰胺的合成
参照实施例5进行,所得化合物质谱测试如图5所示。
实施例9
四肽-5-鞘氨醇神经酰胺的合成
四肽-5序列合成参照六肽-1的合成方法。
参照实施例4进行,所得化合物质谱测试如图6所示。
实施例10
四肽-5-植物鞘氨醇神经酰胺的合成
参照实施例5进行,所得化合物质谱测试如图7所示。
实施例11
八肽-3-植物鞘氨醇神经酰胺的合成八肽-3序列合成参照六肽-1的合成方法。
参照实施例5进行,所得化合物质谱测试如图8所示。
实施例12
九肽-1-鞘氨醇神经酰胺的合成
九肽-1序列合成参照六肽-1的合成方法。
参照实施例4进行,所得化合物质谱测试如图9所示。
实施例13
九肽-1-植物鞘氨醇神经酰胺的合成
参照实施例5进行,所得化合物质谱测试如图10所示。
实施例14
保湿性能测试
仪器:恒温恒湿隔水式培养箱、温度湿度计、密闭干燥器、容量瓶、万分之一电子天平、烘干箱。
试剂:透明质酸(HA)、实施例1~13合成的化合物、干微粉硅胶、碳酸钾、硫酸铵。
溶液配制:饱和碳酸钾溶液(湿度43%),饱和硫酸铵溶液(湿度81%)。
吸湿率:称量瓶贴上标签,装入样品,铺满整个称量瓶的底部,将称量瓶放入真空干燥箱,干燥1h。取出称量瓶分别在电子天平上称重,记录0h时的初始重量。将称量瓶及饱和硫酸铵溶液放入干燥箱内密封,放入隔水式培养箱(20-25℃),分别在4、8、12、24h取出称量瓶进行称重,记录数据。透明质酸(HA)溶液做对照样品同法测试。把饱和硫酸铵溶液更换为饱和碳酸钾溶液,重复上述步骤。
计算:吸湿率(%)=(M-M0)÷M0×100%
M:吸湿后样品重量
M0:干燥恒重后样品重量
图11~24是透明质酸、实施例1~13神经酰胺在81%环境湿度时的吸湿率-时间曲线,图25~38是透明质酸、实施例1~13神经酰胺在43%环境湿度时的吸湿率-时间曲线。在两种湿度环境下,多肽神经酰胺原料均具有良好的吸湿功效。
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)
1.一种多肽神经酰胺,其具有通式I的结构或通式I的异构体:
其中,M为R1或所述R1为多肽缩合后的残基,所述多肽由2~10个氨基酸缩合而成;
R2选自以下结构之一:-C15H29、-C15H31、-C15H27、-CHOHC14H27、-CHOHC14H29。
2.根据权利要求1所述的多肽神经酰胺,其特征在于,所述R1选自二肽、四肽、六肽、八肽、九肽缩合后的残基。
3.根据权利要求2所述的多肽神经酰胺,其特征在于,所述R1选自双甘肽、蛇毒肽中间体、丙氨酰-L-酪氨酸、四肽-5、六肽-1、六肽-8、六肽-9、八肽-3、九肽-1缩合后的残基。
4.根据权利要求1所述的多肽神经酰胺,其特征在于,所述R2选自以下结构之一:
5.根据权利要求4所述的多肽神经酰胺,其特征在于,所述R2选自以下结构之一:
6.根据权利要求1所述的多肽神经酰胺,其特征在于,选自以下化合物之一:
7.一种权利要求1~6任意一项所述的多肽神经酰胺的合成方法,其特征在于,包括以下步骤:
当M为R1时,将Boc保护的多肽、鞘氨醇碱缩合剂、偶联剂反应,得到化合物C,然后化合物C脱去保护基Boc得到产物;
当M为时,将Fmoc保护的多肽脱去保护基Fmoc后与丁二酸相连的鞘氨醇碱缩合剂反应得到产物。
8.根据权利要求7所述的合成方法,其特征在于,当M为R1时,所述缩合剂为EDCI或DCC,所述偶联剂为N-羟基丁二酰亚胺,所述Boc保护的多肽、鞘氨醇碱、缩合剂、偶联剂的摩尔比为(1~1.5):1:(1~2):(1~2),所述反应的溶剂为DCM;当M为时,所述缩合剂为HOBt和DIC,所述多肽、丁二酸相连的鞘氨醇碱/>HOBt、DIC的摩尔比为(1~1.5):1:(1~2):(1~2),所述反应的溶剂为DMF。
9.权利要求1~6任意一项所述的多肽神经酰胺在制备具有保湿作用的化妆品、药品或保健品中的用途。
10.一种具有保湿作用的组合物,其包含作为活性成分的权利要求1~6任意一项所述的多肽神经酰胺、其异构体、其药学上可接受的盐、其水合物或其溶剂合物。
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