CN116444393A - 一种抗糖化氨基酸衍生物及其合成方法和应用 - Google Patents

一种抗糖化氨基酸衍生物及其合成方法和应用 Download PDF

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CN116444393A
CN116444393A CN202310479251.1A CN202310479251A CN116444393A CN 116444393 A CN116444393 A CN 116444393A CN 202310479251 A CN202310479251 A CN 202310479251A CN 116444393 A CN116444393 A CN 116444393A
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amino acid
glycation
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butyl ester
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杨超文
叶柳
刘良先
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Shenzhen Dikeman Biotechnology Co ltd
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Abstract

本发明属于生物医药技术领域，公开了一种抗糖化氨基酸衍生物，其具有通式I的结构或通式I的异构体：其中，R1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‑叔丁基酯缩合后的残基，R2选自以下结构之一：‑C15H29、‑C15H31、‑C15H27、‑CHOHC14H27、‑CHOHC14H29。本发明还公开了抗糖化氨基酸衍生物的合成方法和应用。该类化合物提高了氨基酸类化合物的脂溶性，有利于渗透到皮肤，其在抗氧化、抗糖化、皮肤屏障修复、组织愈合等方面表现出优异的功效。

Description

一种抗糖化氨基酸衍生物及其合成方法和应用
技术领域
本发明属于生物医药技术领域，具体涉及一种抗糖化氨基酸衍生物及其合成方法和应用。
背景技术
糖化反应又叫美拉德反应，是指蛋白质与糖类一起结合反应，先生成希夫碱，进而形成复杂的美拉德中间物，并经过长期的演变，生成晚期糖基化终末产物AGEs的过程。而AGEs加合物会随年龄的增长而不断累积。更让人不安的是，生成的AGEs加合物，使得蛋白质变色，原来没有颜色的蛋白质被糖化后变黄。糖化不仅会引起表皮皮肤发黄，还能在真皮中发生，比如细胞外的弹性蛋白、胶原蛋白和细胞内的细胞骨架蛋白、波形蛋白发生糖化后，皮肤弹性下降，甚至产生皱纹，糖化对皮肤的损伤是全方位的。
抗糖化的方式主要包括两个方面：一方面可以采用保护的方式来抑制糖化反应的产生，比如保护胶原蛋白、弹性蛋白，清除还原糖或抗氧化来清除自由基；另一方面可以减少糖基化终末产物AGE的形成，甚至逆转已经初期糖化的胶原蛋白，从而达到抗糖化效果。
由于抗糖化在护肤上的重要性，许多化妆品公司和制药公司正在研究、开发相应的产品，考虑到市场上对于抗糖化产品的广泛需求，有必要开发新型的抗糖化化合物。
发明内容
本发明的目的是提供一种结构新颖的抗糖化氨基酸衍生物，其由氨基酸与鞘氨醇碱类化合物对接生成。
本发明的另一目的是提供抗糖化氨基酸衍生物的合成方法，其利用氨基酸与鞘氨醇类长链碱基作为原料。
本发明的另一目的是提供抗糖化氨基酸衍生物的用途。
为达到上述目的之一，本发明采用以下技术方案：
一种抗糖化氨基酸衍生物，其具有通式I的结构或通式I的异构体：
其中，R1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-叔丁基酯缩合后的残基，
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氨基酸RCOOH的羧基与鞘氨醇碱的氨基缩合形成肽键之后，残余的氨基酸片段R，如丙氨酸缩合后的残基为/>苏氨酸缩合后的残基为/>
进一步地，所述R1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-叔丁基酯或L-天冬氨酸-1-叔丁基酯缩合后的残基。
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选自丙氨酸缩合后的残基。
进一步地，所述R1选自苏氨酸缩合后的残基。
进一步地，所述R1选自脯氨酸缩合后的残基。
进一步地，所述R1选自天冬酰胺缩合后的残基。
进一步地，所述R1选自谷氨酰胺缩合后的残基。
进一步地，所述R1选自亮氨酸缩合后的残基。
进一步地，所述R1选自色氨酸缩合后的残基。
进一步地，所述R1选自丝氨酸缩合后的残基。
进一步地，所述R1选自缬氨酸缩合后的残基。
进一步地，所述R1选自蛋氨酸缩合后的残基。
进一步地，所述R1选自酪氨酸缩合后的残基。
进一步地，所述R1选自组氨酸缩合后的残基。
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，抗糖化氨基酸衍生物选自以下化合物之一：
抗糖化氨基酸衍生物的合成方法，包括以下步骤：
S1、Boc或Fmoc保护的氨基酸和鞘氨醇碱缩合剂、偶联剂反应，得到化合物A；
S2、化合物A脱去保护基Boc或Fmoc。
进一步地，所述缩合剂为EDCI或DIC，所述偶联剂为N-羟基丁二酰亚胺。
进一步地，所述Boc或Fmoc保护的氨基酸、鞘氨醇碱、缩合剂、偶联剂的摩尔比为(1～1.5)：1：(1～2)：(1～2)。
进一步地，所述S1反应的溶剂为二氯甲烷。
S1具体为：Boc或Fmoc保护的氨基酸、缩合剂(EDCI或DIC)、N-羟基丁二酰亚胺溶于二氯甲烷中，常温下反应一定时间，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：加入水稀释，分液，有机相分别用水、饱和食盐水洗涤，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。
S2具体为：对于Boc保护基，将粗产物溶于MeOH，缓慢滴加6N盐酸，加热到50℃反应直至TLC检测粗产物原料反应完全为止；后处理：旋干MeOH，用饱和碳酸钠溶液调反应液的pH值到9左右，加入饱和食盐水稀释，再用二氯甲烷萃取，收集得到的有机相用无水硫酸钠干燥，过滤，减压旋蒸后得粗产物。
对于Fmoc保护基，将粗产物溶于THF，缓慢滴加二乙基胺，常温下反应直至TLC检测粗产物反应完全为止；后处理：旋干THF，加饱和食盐水稀释，再用二氯甲烷萃取，收集得到的有机相，用无水硫酸钠干燥，过滤，减压旋蒸后得粗产物。
抗糖化氨基酸衍生物的合成方法还包括步骤S3：粗产品用甲醇重结晶后，过滤得产物；或者粗产物经柱层析纯化得到产物。
抗糖化氨基酸衍生物具有皮肤屏障修复、组织愈合、抗氧化、抗糖化功效中的至少一种，可以用于化妆品、保健品、药品，尤其是化妆品精华油或者化妆品无水配方体系。
一种组合物，其包含作为活性成分的抗糖化氨基酸衍生物、其异构体、其药学上可接受的盐、其水合物或其溶剂合物，该组合物具有皮肤屏障修复、组织愈合、抗氧化或抗糖化作用。
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：
本发明使用天然来源的氨基酸作为起始原料，通过与带有长烷基链的鞘氨醇碱反应构建了一类结构新颖的氨基酸衍生物，该类化合物提高了氨基酸类化合物的脂溶性，有利于渗透到皮肤，其在抗氧化、抗糖化、皮肤屏障修复、组织愈合等方面表现出优异的功效，可以用于保健品、化妆品和药品领域。化合物的脂溶性增强，更合适在以油护肤的配方体系中，解决非修饰的多肽无法应用在油相体系中的问题。
附图说明
图1～12是实施例1、2、3、4、6、7、8、9、10、11、13、14的化合物的抗氧化实验结果的柱形图；
图13～24分别是实施例1、2、3、4、6、7、8、9、10、11、13、14的化合物的抗糖化实验结果的柱形图。
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，DIC指N'N-二异丙基碳二亚胺，DCM指二氯甲烷，THF指四氢呋喃，Boc指叔丁氧羰基，Fmoc指9-芴基甲氧基羰基，MeOH指甲醇。
方法A
缩合反应：将Boc保护的氨基酸(1.0eq,50mmol)，EDCI(1.5eq,75mmol)和N-羟基丁二酰亚胺(1.5eq,75mmol)溶于100mL二氯甲烷中，常温下反应30min后，加入植物鞘氨醇(1eq,50mmol)，常温搅拌反应直至TCL检测植物鞘氨醇反应完全为止。
Boc保护的氨基酸的用量可以调整为50～75mmol(1～1.5eq.)，EDCI和N-羟基丁二酰亚胺的用量可以调整为50～100mmol(1～2eq.)；植物鞘氨醇可以替换为鞘氨醇或者二氢鞘氨醇。
后处理：加入50mL的水稀释，分液，有机相再分别用100mL的水、100mL的饱和食盐水洗一次，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。
脱保护基反应：将粗产物(1eq,30mmol)溶于100mL MeOH，缓慢滴加6N盐酸(4eq,120mmol)，加热到50℃反应直至TLC检测粗产物原料反应完全为止。
后处理：旋干MeOH，用饱和碳酸钠溶液调反应液的pH值到9左右。加100mL饱和食盐水稀释，再用80mL二氯甲烷萃取，收集得到的有机相用无水硫酸钠干燥，过滤，减压旋蒸后得粗产物。
粗产物精制过程：粗产品用甲醇重结晶后过滤得纯化的白色固体产品。
方法B
缩合反应：将Boc保护的氨基酸(1.3eq,50mmol)和N-羟基丁二酰亚胺(1.5eq,75mmol)溶于100mL二氯甲烷中，常温下滴加DIC(1.5eq,75mmol)，常温下反应过夜后加入植物鞘氨醇(1eq,50mmol)，常温搅拌反应直至TCL检测植物鞘氨醇反应完全为止。
Boc保护的氨基酸的用量可以调整为50～75mmol(1～1.5eq.)，DIC和N-羟基丁二酰亚胺的用量可以调整为50～100mmol(1～2eq.)；植物鞘氨醇可以替换为鞘氨醇或者二氢鞘氨醇。
后处理：加入80mL的水稀释，分液，有机相再分别用80mL的水、80mL的饱和食盐水洗一次，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。
脱保护基反应：将粗产物(1eq,30mmol)溶于100mL MeOH，缓慢滴加6N盐酸(4eq,120mmol)，加热到50℃反应直至TLC检测粗产物反应完全为止。
后处理：旋干MeOH，用饱和碳酸钠溶液调反应液的pH值到9左右。加100mL饱和食盐水稀释，再用80mL二氯甲烷萃取，收集得到的有机相用无水硫酸钠干燥，过滤，减压旋蒸后得粗产物。
粗产物精制过程：粗产品用甲醇重结晶后过滤得白色固体产品，再用二氯甲烷打浆后过滤得到纯化的产品。
方法C
缩合反应：将Fmoc保护的氨基酸(1.3eq,50mmol)和N-羟基丁二酰亚胺(1.5eq,75mmol)溶于100mL二氯甲烷中，常温下滴加DIC(1.5eq,75mmol)，常温下反应过夜后加入植物鞘氨醇(1eq,50mmol)，常温搅拌反应直至TCL检测植物鞘氨醇反应完全为止。
Fmoc保护的氨基酸的用量可以调整为50～75mmol(1～1.5eq.)，DIC和N-羟基丁二酰亚胺的用量可以调整为50～100mmol(1～2eq.)；植物鞘氨醇可以替换为鞘氨醇或者二氢鞘氨醇。
后处理：加入80mL的水稀释，分液，有机相再分别用80mL的水、80mL的饱和食盐水洗一次，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。
脱保护基反应：将粗产物(1eq,20mmol)溶于20mL THF，缓慢滴加二乙基胺(4eq,80mmol)，常温下反应直至TLC检测粗产物反应完全为止。
后处理：旋干THF，加60mL饱和食盐水稀释，再用80mL二氯甲烷萃取，收集得到的有机相用无水硫酸钠干燥，过滤，减压旋蒸后得粗产物。粗产物经柱层析纯化得到产物。
实施例1
丙氨酸植物鞘氨醇神经酰胺经方法A合成得到。
1H NMR(400MHz,Methanol-d4)δ4.14(dt,J＝6.5,4.5Hz,1H),3.79(dd,J＝11.2,4.3Hz,1H),3.68(dd,J＝11.3,6.5Hz,1H),3.58–3.43(m,2H),2.93(t,J＝6.5Hz,2H),2.48–2.32(m,2H),1.74–1.62(m,1H),1.57(s,1H),1.29(d,J＝9.3Hz,24H),0.89(t,J＝6.7Hz,3H)。
实施例2
苏氨酸植物鞘氨醇神经酰胺经方法B合成得到。
1H NMR(400MHz,Methanol-d4)δ4.15(dt,J＝5.9,4.4Hz,1H),4.01(qd,J＝6.4,4.5Hz,1H),3.82–3.68(m,2H),3.57–3.48(m,2H),3.16(d,J＝4.5Hz,1H),1.69(dd,J＝12.3,9.3Hz,1H),1.54(d,J＝10.9Hz,1H),1.34–1.29(s,24H),1.20(d,J＝6.4Hz,3H),0.90(t,J＝6.7Hz,3H)。
实施例3
脯氨酸植物鞘氨醇神经酰胺经方法A合成得到。
1H NMR(400MHz,Methanol-d4)δ4.09(q,J＝5.1Hz,1H),3.80–3.70(m,2H),3.67(dd,J＝8.7,5.3Hz,1H),3.58–3.44(m,2H),3.02–2.87(m,2H),2.18–2.05(m,1H),1.86–1.62(m,4H),1.60–1.45(m,1H),1.30(d,J＝8.6Hz,25H),0.90(t,J＝6.7Hz,3H)。
实施例4
天冬酰胺植物鞘氨醇神经酰胺经方法B合成得到。
1H NMR(400MHz,Methanol-d4)δ4.17–4.09(m,1H),3.79(dd,J＝11.3,4.4Hz,1H),3.76–3.64(m,2H),3.56–3.45(m,2H),2.66(dd,J＝15.3,5.1Hz,1H),2.49(dd,J＝15.3,7.8Hz,1H),1.76–1.64(m,1H),1.54(d,J＝11.3Hz,1H),1.30(d,J＝8.5Hz,25H),0.90(t,J＝6.7Hz,3H)。
实施例5
谷氨酰胺植物鞘氨醇神经酰胺经方法B合成得到。
1H NMR(400MHz,Chloroform-d)δ4.65(d,J＝5.5Hz,1H),4.54(t,J＝5.5Hz,1H),4.37(d,J＝6.5Hz,1H),4.03(dd,J＝8.5,4.3Hz,1H),3.98–3.84(m,1H),3.52(dq,J＝10.9,5.2Hz,1H),2.30–1.99(m,3H),1.86(ddd,J＝12.3,9.0,4.6Hz,1H),1.55–1.34(m,2H),1.23–1.18(s,24H),0.85(t,J＝6.6Hz,3H)。
实施例6
亮氨酸植物鞘氨醇神经酰胺经方法A合成得到。
1H NMR(400MHz,Methanol-d4)δ4.08(td,J＝5.8,4.2Hz,1H),3.81–3.68(m,2H),3.56(t,J＝5.9Hz,1H),3.51(ddd,J＝8.7,5.9,2.5Hz,1H),3.34(tt,J＝6.3,3.1Hz,1H),1.75–1.49(m,4H),1.42–1.20(m,25H),0.98–0.91(m,6H),0.91–0.86(m,3H)。
实施例7
色氨酸植物鞘氨醇神经酰胺经方法A合成得到。
1H NMR(400MHz,Methanol-d4)δ7.62(d,J＝7.9Hz,1H),7.34(d,J＝8.0Hz,1H),7.12(s,1H),7.09(ddd,J＝8.2,6.9,1.2Hz,1H),7.04–6.97(m,1H),4.09(q,J＝5.1Hz,1H),3.72–3.61(m,3H),3.44(ddd,J＝9.0,6.3,2.5Hz,1H),3.39(dd,J＝6.4,5.0Hz,1H),3.22(dd,J＝14.2,5.6Hz,1H),2.95(dd,J＝14.2,7.8Hz,1H),1.63(ddt,J＝12.4,10.2,2.4Hz,1H),1.51(q,J＝7.7Hz,1H),1.29(d,J＝10.1Hz,24H),0.96–0.83(m,3H)。
实施例8
丝氨酸植物鞘氨醇神经酰胺经方法B合成得到。
1H NMR(400MHz,Methanol-d4)δ4.17(q,J＝4.8Hz,1H),3.85–3.66(m,4H),3.59–3.49(m,2H),3.44(t,J＝5.5Hz,1H),1.77–1.63(m,1H),1.56(d,J＝11.3Hz,1H),1.33–1.30(m,24H),0.92(t,J＝6.7Hz,3H)。
实施例9
缬氨酸植物鞘氨醇神经酰胺经方法A合成得到。
1H NMR(400MHz,Methanol-d4)δ4.19–4.11(m,1H),3.81(dd,J＝11.3,4.3Hz,1H),3.74(dd,J＝11.3,5.9Hz,1H),3.61–3.50(m,2H),3.17(d,J＝5.7Hz,1H),2.01(dq,J＝13.4,6.8Hz,1H),1.73–1.50(m,2H),1.40–1.24(m,24H),1.00(d,J＝6.8Hz,3H),0.96(d,J＝6.9Hz,3H),0.92(t,J＝6.7Hz,3H)。
实施例10
蛋氨酸植物鞘氨醇神经酰胺经方法B合成得到。
1H NMR(400MHz,Methanol-d4)δ4.15(td,J＝5.8,4.2Hz,1H),3.82(dd,J＝11.3,4.2Hz,1H),3.74(dd,J＝11.3,6.1Hz,1H),3.61–3.49(m,3H),2.58(dd,J＝8.6,6.6Hz,2H),2.12(s,3H),2.08–1.97(m,1H),1.86(dt,J＝14.0,7.1Hz,1H),1.66(d,J＝11.1Hz,1H),1.57(d,J＝12.1Hz,1H),1.46–1.23(m,24H),0.92(t,J＝6.8Hz,3H)。
实施例11
酪氨酸植物鞘氨醇神经酰胺经方法B合成得到。
1H NMR(400MHz,Methanol-d4)δ7.12(d,J＝8.5Hz,2H),6.81–6.74(m,2H),4.17(dt,J＝6.5,4.5Hz,1H),4.01(dd,J＝8.3,6.2Hz,1H),3.83(dd,J＝11.3,4.3Hz,1H),3.69(dd,J＝11.3,6.6Hz,1H),3.49–3.38(m,2H),3.12(dd,J＝14.1,6.3Hz,1H),2.91(dd,J＝14.1,8.3Hz,1H),1.72–1.60(m,1H),1.54(d,J＝10.5Hz,1H),1.28(s,24H),0.90(t,J＝6.8Hz,3H)。
实施例12
组氨酸植物鞘氨醇神经酰胺经方法B合成得到。
1H NMR(400MHz,Methanol-d4)δ7.61(s,1H),6.92(s,1H),4.13(dt,J＝6.4,4.6Hz,1H),3.79(dd,J＝11.3,4.3Hz,1H),3.74–3.63(m,2H),3.52–3.40(m,2H),3.02(dd,J＝14.7,5.3Hz,1H),2.88(dd,J＝14.6,7.4Hz,1H),1.75–1.63(m,1H),1.55(s,1H),1.28(s,24H),0.90(t,J＝6.7Hz,3H)。
实施例13
L-天冬氨酸-4-叔丁酯植物鞘氨醇神经酰胺经方法C合成得到。
1H NMR(400MHz,Methanol-d4)δ4.10(q,J＝5.0Hz,1H),3.75(qd,J＝11.3,5.1Hz,2H),3.63(dd,J＝7.2,5.4Hz,1H),3.59–3.47(m,2H),2.70(dd,J＝16.5,5.4Hz,1H),2.52(dd,J＝16.5,7.2Hz,1H),1.73–1.60(m,1H),1.54(t,J＝8.0Hz,1H),1.46(s,9H),1.28(s,24H),0.90(t,J＝6.7Hz,3H)。
实施例14
L-天冬氨酸-1-叔丁酯植物鞘氨醇神经酰胺经方法C合成得到。
1H NMR(400MHz,Methanol-d4)δ4.14(dt,J＝6.3,4.4Hz,1H),3.79(ddd,J＝9.4,4.3,1.7Hz,2H),3.68(dd,J＝11.5,6.3Hz,1H),3.57–3.46(m,2H),2.71(dd,J＝15.4,4.3Hz,1H),2.60(dd,J＝15.5,7.9Hz,1H),1.71–1.67(m,1H),1.59–1.51(m,1H),1.48(s,9H),1.36–1.22(m,24H),0.90(t,J＝6.7Hz,3H)。
实施例15
丙氨酸鞘氨醇神经酰胺经方法A合成得到。
1H NMR(400MHz,Methanol-d4)δ5.70–5.61(m,1H),5.52–5.40(m,1H),4.06(t,J＝7.4Hz,1H),3.89–3.82(m,1H),3.68(d,J＝5.0Hz,2H),2.93(t,J＝6.5Hz,2H),2.48–2.32(m,2H),2.15(t,J＝7.6Hz,2H),1.76–1.64(m,1H),1.59–1.55(m,1H),1.28–1.22(m,20H),0.91(t,J＝6.8Hz,3H)。
实施例16
丙氨酸二氢鞘氨醇神经酰胺经方法A合成得到。
1H NMR(400MHz,Methanol-d4)δ4.12(td,J＝6.1,4.1Hz,1H),3.91–3.81(m,2H),3.79–3.74(m,1H),2.91(t,J＝6.5Hz,2H),2.51–2.34(m,2H),1.47–1.39(m,3H),1.28–1.22(m,25H),0.88(t,J＝6.8Hz,3H)。
实施例17
抗氧化实验：选择氮自由基清除剂DPPH和氧自由基清除剂PTIO
DPPH自由基清除率测定
将对应浓度样品分别与0.1mol/L DPPH、无水乙醇溶液按1:1的体积比例混合，空白组以DPPH与无水乙醇1：1等体积混合，室温避光反应30min后于517nm处测吸光值。DPPH与不同浓度样品反应液的吸光度记作A1，无水乙醇与不同浓度样品反应液的吸光度记作A2，DPPH与无水乙醇反应液的吸光度记作A3，则样品的DPPH清除率＝[1-(A1-A2)/A3]×100％。
PTIO自由基清除率测定
将对应浓度样品分别与0.6mmol/L PTIO、无水乙醇溶液按1:2的体积比例混合，空白组以PTIO与无水乙醇1：2等体积混合，室温避光反应30min后于557nm处测吸光值。PTIO与不同浓度样品反应液的吸光度记作A1，无水乙醇与不同浓度样品反应液的吸光度记作A2，PTIO与无水乙醇反应液的吸光度记作A3，则样品的PTIO清除率＝[1-(A1-A2)/A3]×100％。
图1～12分别是实施例1、2、3、4、6、7、8、9、10、11、13、14的化合物的抗氧化实验结果的柱形图；本发明的氨基酸神经酰胺化合物具有良好的抗氧化性能，对氧自由基的清除性能要好于氮自由基。
实施例18
抗糖化实验
在无菌条件下，向无菌瓶中加入用除菌膜除菌后的牛血清白蛋白溶液和葡萄糖溶液各4mL，混合均匀后，加入不同浓度样品溶液和磷酸缓冲液各4mL，于37℃恒溫避光孵育10天。以氨基胍代替样品做阳性对照组，磷酸代替样品做空白对照组。于反应第10天进行AGEs含量测定。每组平行测试三次。
AGEs测试方法是：取糖基化物质3mL，测定糖基化终产物在激发波长340nm和发射波长420nm处的荧光值Fs,即代表总荧光AGEs的含量；磷酸溶液所测得为F0。
计算抑制率％＝(F0-Fs)/F0×100
图13～24分别是实施例1、2、3、4、6、7、8、9、10、11、13、14的化合物的抗糖化实验结果的柱形图；本发明的氨基酸神经酰胺化合物都具有良好的抗糖化效果。
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 (11)

1.一种抗糖化氨基酸衍生物，其具有通式I的结构或通式I的异构体：
其中，R1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-叔丁基酯缩合后的残基，
R2选自以下结构之一：-C15H29、-C15H31、-C15H27、-CHOHC14H27、-CHOHC14H29。
2.根据权利要求1所述的抗糖化氨基酸衍生物，所述R1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-叔丁基酯或L-天冬氨酸-1-叔丁基酯缩合后的残基。
3.根据权利要求1所述的抗糖化氨基酸衍生物，所述R2选自以下结构之一：
4.根据权利要求1所述的抗糖化氨基酸衍生物，所述R2选自以下结构之一：
5.根据权利要求1所述的抗糖化氨基酸衍生物，其特征在于，选自以下化合物之一：
6.一种权利要求1～5任意一项所述的抗糖化氨基酸衍生物的合成方法，其特征在于，包括以下步骤：
S1、Boc或Fmoc保护的氨基酸和鞘氨醇碱缩合剂、偶联剂反应，得到化合物A；
S2、化合物A脱去保护基Boc或Fmoc。
7.根据权利要求6所述的合成方法，其特征在于，所述缩合剂为EDCI或DIC，所述偶联剂为N-羟基丁二酰亚胺；所述Boc或Fmoc保护的氨基酸、鞘氨醇碱、缩合剂、偶联剂的摩尔比为(1～1.5)：1：(1～2)：(1～2)。
8.权利要求1～5任意一项所述的抗糖化氨基酸衍生物在化妆品、保健品、药品中的用途。
9.根据权利要求8所述的用途，其特征在于，所述化妆品为化妆品精华油或者化妆品无水配方体系。
10.根据权利要求8所述的用途，其特征在于，所述抗糖化氨基酸衍生物具有皮肤屏障修复、组织愈合、抗氧化、抗糖化功效中的至少一种。
11.一种组合物，其包含作为活性成分的权利要求1～5任意一项所述的抗糖化氨基酸衍生物、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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CN115260091A (zh) * 2022-08-05 2022-11-01 深圳市迪克曼生物科技有限公司 含环状羧酸的神经酰胺类化合物及其制备方法和应用

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* Cited by examiner, † Cited by third party
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CN115260091A (zh) * 2022-08-05 2022-11-01 深圳市迪克曼生物科技有限公司 含环状羧酸的神经酰胺类化合物及其制备方法和应用

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