CN115894270A - 一种新型的神经酰胺及其制备方法和应用 - Google Patents
一种新型的神经酰胺及其制备方法和应用 Download PDFInfo
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- CN115894270A CN115894270A CN202211238109.XA CN202211238109A CN115894270A CN 115894270 A CN115894270 A CN 115894270A CN 202211238109 A CN202211238109 A CN 202211238109A CN 115894270 A CN115894270 A CN 115894270A
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- ceramide
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- inhibition rate
- acid
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Abstract
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种新型的神经酰胺及其制备方法和应用。
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%。从化学结构上来说,神经酰胺是一种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,因此神经酰胺分子不是唯一的,它指的是一类化合物。
神经酰胺在皮肤中的分布尤其广泛,目前已知的有9种天然神经酰胺,应用于护肤品中的神经酰胺也有不同的种类。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屏障机能的恢复,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短链片段快速合成神经酰胺,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神经酰胺。
本发明的另一目的是提供神经酰胺的合成方法,其利用易得的10-羟基葵酸作为原料。
本发明的另一目的是提供神经酰胺的用途。
为达到上述目的之一,本发明采用以下技术方案:
一种神经酰胺,其具有式I的结构或其对映异构体、非对映异构体:
神经酰胺的合成方法,包括以下步骤:
化合物S1和TBDPSCl反应得到化合物S2;
化合物S2和对硝基三氟乙酸苯酯反应得到化合物S3;
化合物S3脱保护得到化合物S4;
化合物S4和亚油酰氯反应得到化合物S5;
化合物S5和植物鞘氨醇反应得到神经酰胺。
进一步地,所述化合物S1和TBDPSCl的摩尔比为1:(1~3)。
进一步地,所述化合物S2和对硝基三氟乙酸苯酯的摩尔比为1:(1~3)。
进一步地,所述化合物S4和亚油酰氯的摩尔比为1:(1~3)。
进一步地,所述化合物S5和植物鞘氨醇的摩尔比为1:(1~2)。
神经酰胺可以用于化妆品、保健品或药品领域。
第一方面,神经酰胺具有组织修复作用,神经酰胺在浓度0.0625mM时,细胞活力在114%以上,神经酰胺在浓度0.5mM时,细胞活力在120%以上。
第二方面,神经酰胺具有抗炎修复作用,原理是其抑制IL-6细胞因子表达,神经酰胺在浓度0.1mM时,对细胞因子IL-6的抑制率在46%以上,神经酰胺在浓度0.2mM时,对细胞因子IL-6的抑制率在73%以上,神经酰胺在浓度0.4mM时,对细胞因子IL-6的抑制率在86%以上,神经酰胺在浓度0.8mM时,对细胞因子IL-6的抑制率在94%以上,神经酰胺在浓度1.0mM时,对细胞因子IL-6的抑制率在97%以上。抗炎修复是发明人对神经酰胺进行生物活性研究之后发现的独有功效,现有的神经酰胺未见报道具有抗炎修复功效。
第三方面,神经酰胺具有组织愈合作用,神经酰胺在浓度0.08mM时,细胞愈合率在74%以上。
第四方面,神经酰胺具有保湿作用,原理是其提升AQP3水通道蛋白的表达量,神经酰胺在浓度0.4mM时,AQP3水通道蛋白的表达量相比溶剂控制组为112%以上,神经酰胺在浓度0.8mM时,AQP3水通道蛋白的表达量相比溶剂控制组为133%以上,神经酰胺在浓度1.6mM时,AQP3水通道蛋白的表达量相比溶剂控制组为147%以上。
第五方面,神经酰胺具有抗衰作用,原理是其提升弹性蛋白酶抑制率,神经酰胺在浓度0.4mM时,弹性蛋白酶抑制率在18%以上,神经酰胺在浓度0.8mM时,弹性蛋白酶抑制率在22%以上,神经酰胺在浓度1.0mM时,弹性蛋白酶抑制率在25%以上。抗衰是发明人对神经酰胺进行生物活性研究之后发现的独有功效,现有的神经酰胺未见报道具有抗衰功效。
一种组合物,其包含作为活性成分的神经酰胺、其异构体、其药学上可接受的盐、其水合物或其溶剂合物,该组合物具有组织修复、抗炎修复、组织愈合、保湿或抗衰作用。
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。
本文使用的“异构体”意指,本发明的化合物或其盐具有相同化学式或分子式但具有不同光学性质或空间性质。
除非另有说明,否则术语“本发明的化合物”或“神经酰胺”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:
本发明使用天然来源、可以商业化购买、价格低廉的10-羟基羧酸作为起始原料,构建了一种结构新颖的神经酰胺,避免使用难以商业化获得的原料;合成路线简洁方便,适合放大生产;得到的神经酰胺在组织修复、抗炎修复、组织愈合、保湿、抗衰方面均表现出优异的功效,比已知的神经酰胺3和神经酰胺3效果更好,尤其是抗炎和抗衰的独特功效是该类化合物少有报道的,可以用于保健品、化妆品和药品领域。
说明书附图
图1是本发明神经酰胺细胞增殖活力检测结果柱形图;
图2是神经酰胺3细胞增殖活力检测结果柱形图;
图3是神经酰胺3B细胞增殖活力检测结果柱形图;
图4是本发明神经酰胺抗炎修复功效检测结果柱形图;
图5是实施例3不同神经酰胺抗炎修复功效检测结果柱形图;
图6是实施例4组织愈合能力检测结果柱形图;
图7是本发明神经酰胺保湿功效检测结果柱形图;
图8是实施例5不同神经酰胺保湿功效检测结果柱形图;
图9是本发明神经酰胺抗衰功效检测结果柱形图;
图10是实施例6不同神经酰胺抗衰功效检测结果柱形图。
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。
EA指乙酸乙酯,DCM指二氯甲烷,DMF指N,N-二甲基甲酰胺,Py.指吡啶,Im.指咪唑,TBDPSCl指叔丁基二苯基氯硅烷,TBAF指4-正丁基氟化铵。
实施例1
神经酰胺的合成
将1.0eq(160mmol)的S1和2.0eq(320mmol)的咪唑溶于100mL DMF,冰浴下冷却,滴加2.0eq(320mmol)TBDPSCl和50mL DMF的混合液,滴加完毕后升温至40℃反应,至TLC检测原料S1反应完全。
后处理:加入400mL EA稀释,加入250mL饱和NH4Cl洗两次,300mL饱和NaCl洗两次,有机相加入无水Na2SO4干燥,过滤并真空浓缩。由此获得的残余物通过硅胶柱纯化到79.4g产物S2。
将1.0eq(160mmol)的S2和1.0eq(160mmol)的对硝基三氟乙酸苯酯溶于150mL吡啶,室温下搅拌反应至TLC检测原料S2反应完全。
后处理:加入300mL EA稀释,加入150mL稀盐酸洗两次,300mL水洗两次,200mL饱和NaCl洗一次,有机相加入无水Na2SO4干燥,过滤并真空浓缩得到油状产物通过硅胶柱纯化到67.4g产物S3。
将1.0eq(124mmol)的S3溶于100mL THF中,冰浴下冷却,将1.2eq(149mmol)的TBAF溶于40mL THF中滴加到上述反应液中,滴加完毕后在室温下反应至TLC检测原料S3反应完全。
后处理:加入200mL EA稀释,加入100mL稀盐酸洗一次,100mL饱和NaCl洗一次,有机相加入无水Na2SO4干燥,过滤并真空浓缩得到油状产物通过硅胶柱纯化到21.6g产物S4。
1H NMR(400MHz,Methanol-d4)δ8.34–8.23(m,2H),7.39–7.30(m,2H),3.54(t,J=6.6Hz,2H),2.63(t,J=7.4Hz,2H),1.73(t,J=6.8Hz,2H),1.53(t,J=6.8Hz,2H),1.46–1.26(m,10H)。
将1.0eq(71mmol)的S4溶于200mL吡啶中,冰浴下冷却,滴加4.0eq(284mmol)的亚油酰氯,滴加完毕后在室温下反应至TLC检测原料S4反应完全。
后处理:加入400mL DCM稀释,加入600mL稀HCl洗两次,500mL饱和NaCl洗两次,有机相加无水Na2SO4干燥。旋干得到黑色油状物通过硅胶柱纯化到30g产物S5。
1H NMR(400MHz,Methanol-d4)δ8.32–8.25(m,2H),7.37–7.29(m,2H),5.41–5.31(m,4H),3.64(t,J=6.6Hz,2H),2.53(t,J=7.4Hz,2H),2.29(t,J=7.6Hz,2H),2.26–2.19(m,4H),2.08(q,J=6.9Hz,4H),1.63(t,J=6.8Hz,4H),1.43(t,J=6.8Hz,4H),1.46–1.26(m,20H),0.86(t,J=6.9Hz,3H)。
将1.0eq(53mmol)的S5和1.0eq(53mmol)的植物鞘氨醇溶于100mL吡啶中,升温至45℃度反应至TLC检测原料植物鞘氨醇反应完全。
后处理:加入200mL THF稀释,加入200mL稀盐酸洗两次,200mL饱和NaCl洗两次,有机相加无水Na2SO4干燥。旋干得到粗产品通过硅胶柱纯化到15g产物。
1H NMR(400MHz,Chloroform-d)δ6.37(d,J=7.5Hz,1H),5.36(tddt,J=10.7,5.4,3.7,1.6Hz,4H),4.15(dt,J=7.2,2.6Hz,1H),4.05(t,J=6.8Hz,2H),3.91(t,J=6.8Hz,2H),3.73(s,2H),3.67–3.51(m,2H),2.88–2.70(m,3H),2.29(t,J=7.6Hz,2H),2.26–2.19(m,2H),2.05(q,J=6.9Hz,4H),1.80–1.70(m,1H),1.61(p,J=6.9Hz,6H),1.55–1.44(m,2H),1.39–1.21(m,47H),0.88(td,J=6.9,4.0Hz,6H)。
实施例2
MTT法检测细胞增殖活力:将HaCaT细胞以1×104个/孔的密度种于96孔板,培养箱内过夜。24h后弃去上清液,加入含不同浓度样品(实施例1所得产物)或空白的培养基100μL,继续孵育24h后除去培养基,每孔中加入100μL噻唑蓝(MTT),测定450nm处吸光度,计算细胞存活率=A给药孔/A空白孔×100%。
结果如图1所示,化合物浓度0.0625mM时细胞活力达到114.7%,浓度在0.5mM时,细胞活力达到122.3%,表现出明显的促进细胞增殖效果,具备组织修复潜力。同时,在高达1mM的浓度范围内,无细胞毒性,表现出较好的生物安全性。
神经酰胺3和神经酰胺3B的细胞增殖活力检测结果如图2、图3所示,本发明的神经酰胺和神经酰胺3B具有较好的细胞愈合和组织修复的能力。
实施例3
LPS诱导细胞法检测抗炎修复功效
将B16小鼠黑色素瘤细胞以密度1×104个/孔种于96孔板,置于培养箱内贴壁过夜,24h后弃去上清液,加入100μL经DMEM培养基稀释的不同浓度样品(实施例1所得产物),阴性对照组为不含样品的DMEM培养基,每组3个复孔,在质量分数5%CO2、37℃环境中孵育。给药2h后脂多糖模型组与实验组加入10μg/mL LPS并共同孵育至24h。反应结束后取细胞上清液50μL,使用IL-6ELISA试剂盒检测细胞内IL-6基因表达。
结果如图4所示,LPS成功对细胞进行了炎症造模,模型细胞内的IL-6炎症因子表达高达控制组的23.14倍;本发明的化合物具有优异的抑制IL-6细胞因子表达效果。在浓度分别为0.1,0.2,0.4,0.8,1.00mM时,IL-6因子的表达相比控制组分别为12.37,6.15,3.04,1.31和0.65倍;相比LPS模型组,分别抑制了46.54%、73.42%、86.86%、94.30%和97.19%。因此,化合物具有良好的抗炎效果,有望促进炎症受损皮肤的修复。
用1mmol/L的神经酰胺3、神经酰胺3B和本发明的神经酰胺进行对比,结果如图5所示,这三种神经酰胺均有效抑制IL-6炎症因子表达,本发明的神经酰胺对IL-6炎症因子的抑制效果最为显著。
实施例4
划痕法检测组织愈合能力
原理:当细胞长到融合成单层状态时,在融合的单层细胞上划痕工具制造一个空白区域,空白区域的细胞被机械力去除掉了,通过一段时间的培养,观察细胞向无细胞区域迁移的情况,通过测量细胞的迁移距离反映细胞的迁移能力。
操作:1.培养板划线。首先使用Marker笔在6孔板背后,用直尺比着,均匀的划横线,大约每隔0.5~1cm一道,横穿过孔,每孔至少穿过5条线,划线时注意线不要太粗。
2.铺细胞。在孔中加入约5×105个细胞(不同的细胞数量有所不同,根据细胞的生长快慢调整),接种原则为过夜后融合率达到100%。
3.细胞划线。第二天用枪头,垂直于细胞平面,沿着头一天划在平板背面的线在细胞层上进行划痕(不同孔之间最好使用同一只枪头)。
4.洗细胞。划痕完成后,使用无菌PBS洗细胞3次,洗去不贴壁的细胞,即划线时划线的细胞,划线后留下的间隙清晰可见,然后更换新鲜无血清培养基。
5.细胞培养、观察。样品(实施例1化合物、神经酰胺3、神经酰胺3B)用培养基稀释后(浓度为0.08mM)加入细胞培养皿,将细胞放入37℃、5wt%CO2培养箱培养,在24h取出细胞,显微镜观察并测量划痕的宽度,并拍照,用Image J软件计算愈合率。
结果如图6所示,溶剂控制组在24h后的自愈率为35.74%,神经酰胺在24h后的愈合率为74.48%,比神经酰胺3和神经酰胺3B具有更好的组织愈合能力。本发明的化合物明显提升了细胞愈合速率,具备良好的皮肤组织修复活性。
实施例5
AQP3细胞法检测保湿功效
水通道蛋白3(AQP3)是细胞膜上负责水、甘油及尿素等物质运输的转运蛋白因子,主要表达于角质形成细胞和皮肤成纤维细胞。AQP3不仅参与皮肤水合、屏障功能,同时在皮肤损伤和修复、愈合方面,均发挥着重要的作用,是皮肤正常形态和功能维持的重要保障。
将HaCat细胞以密度1×104个/孔种于96孔板,置于培养箱内贴壁过夜,24h后弃去上清液,加入100μL经DMEM培养基稀释的不同浓度样品(实施例1所得产物),阴性对照组为不含药的DMEM培养基,每组3个复孔,在质量分数5%CO2、37℃环境中孵育。给药2h后脂多糖模型组与实验组加入10μg/mL LPS并共同孵育至24h。反应结束后取细胞上清液50μL,使用AQP3试剂盒检测细胞内AQP3基因表达。
结果如图7所示,本发明的化合物有效提升了AQP3水通道蛋白的表达量,呈浓度依赖性。浓度0.4、0.8、1.6mM时,其表达量分别为溶剂控制组的1.12、1.33和1.47倍。
用2.5mmol/L的神经酰胺3、神经酰胺3B和本发明的神经酰胺进行对比,结果如图8所示,这三种神经酰胺均不同程度提升了AQP3水通道蛋白的表达量,本发明的神经酰胺的效果最为显著,表现出最好的保湿性能。
实施例6
弹性蛋白酶抑制方法检测抗衰功效
取2mg/mL弹性蛋白酶溶液2mL,加入不同浓度样品,充分涡旋混匀,在37℃、400r/min摇床振荡20min,立即加入pH6.0的0.5mol/L磷酸盐缓冲液5mL,涡旋混匀,取混匀液适量至2mL离心管内,在9391×g下离心10min,精密吸取上清液200uL至96孔板内,在波长495nm处酶标仪测定吸光度,同时进行400~800nm光谱扫描。
以底物加酶溶液为空白对照组,底物加酶和样品(实施例1所得产物)溶液为酶抑制组,底物加样品不加酶溶液作扣背景用。每组均设3复孔。抑制率(%)=[1–(An–An′)/(A0–A0′)]×100%,式中,A0为加酶不加样品的吸光度,A0′为仅加底物不加样品和酶的吸光度,An为仅加样品溶液的吸光度,An′为加样品不加酶的吸光度。若An′>An,则表现为促进作用,促进率(%)=[1–(An′–An)/(A0–A0′)]×100%。
结果如图9所示,本发明的化合物有效提升弹性蛋白酶抑制率,呈浓度依赖性。浓度0.4、0.8、1.0mM时,其抑制率分别为18.21%、22.07%和25.37%,表明其可抑制弹性蛋白酶表达,保护弹性蛋白,维持或提升肌肤弹性。
用1mmol/L的神经酰胺3、神经酰胺3B和本发明的神经酰胺进行对比,结果如图10所示,本发明的神经酰胺的效果远远优于神经酰胺3和神经酰胺3B,表现出最好的弹性蛋白酶抑制效果。
本发明全面测试了神经酰胺的细胞修复、增殖、抗炎、保湿、抑制弹性蛋白酶的功效,对比市售神经酰胺3和神经酰胺3B,本发明的神经酰胺的各项指标最为优异和全面,尤其体现在抗炎、组织愈合、抑制弹性蛋白酶方面。
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)
3.根据权利要求2所述的合成方法,其特征在于,所述化合物S1和TBDPSCl的摩尔比为1:(1~3);所述化合物S2和对硝基三氟乙酸苯酯的摩尔比为1:(1~3);所述化合物S4和亚油酰氯的摩尔比为1:(1~3);所述化合物S5和植物鞘氨醇的摩尔比为1:(1~2)。
4.权利要求1所述的神经酰胺在化妆品、保健品或药品中的用途。
5.根据权利要求4所述的用途,其特征在于,所述神经酰胺具有组织修复作用;所述神经酰胺在浓度0.0625mM时,细胞活力在114%以上,和/或所述神经酰胺在浓度0.5mM时,细胞活力在120%以上。
6.根据权利要求4所述的用途,其特征在于,所述神经酰胺具有抗炎修复作用;所述神经酰胺在浓度0.1mM时,对细胞因子IL-6的抑制率在46%以上,和/或所述神经酰胺在浓度0.2mM时,对细胞因子IL-6的抑制率在73%以上,和/或所述神经酰胺在浓度0.4mM时,对细胞因子IL-6的抑制率在86%以上,和/或所述神经酰胺在浓度0.8mM时,对细胞因子IL-6的抑制率在94%以上,和/或所述神经酰胺在浓度1.0mM时,对细胞因子IL-6的抑制率在97%以上。
7.根据权利要求4所述的用途,其特征在于,所述神经酰胺具有组织愈合作用;所述神经酰胺在浓度0.08mM时,细胞愈合率在74%以上。
8.根据权利要求4所述的用途,其特征在于,所述神经酰胺具有保湿作用;所述神经酰胺在浓度0.4mM时,AQP3水通道蛋白的表达量相比溶剂控制组为112%以上;所述神经酰胺在浓度0.8mM时,AQP3水通道蛋白的表达量相比溶剂控制组为133%以上;所述神经酰胺在浓度1.6mM时,AQP3水通道蛋白的表达量相比溶剂控制组为147%以上。
9.根据权利要求4所述的用途,其特征在于,所述神经酰胺具有抗衰作用;所述神经酰胺在浓度0.4mM时,弹性蛋白酶抑制率在18%以上,所述神经酰胺在浓度0.8mM时,弹性蛋白酶抑制率在22%以上,所述神经酰胺在浓度1.0mM时,弹性蛋白酶抑制率在25%以上。
10.一种组合物,其包含作为活性成分的权利要求1的神经酰胺、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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