CN115260091A - 含环状羧酸的神经酰胺类化合物及其制备方法和应用 - Google Patents

含环状羧酸的神经酰胺类化合物及其制备方法和应用 Download PDF

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CN115260091A
CN115260091A CN202210939889.4A CN202210939889A CN115260091A CN 115260091 A CN115260091 A CN 115260091A CN 202210939889 A CN202210939889 A CN 202210939889A CN 115260091 A CN115260091 A CN 115260091A
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ceramide
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杨超文
叶柳
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Abstract

本发明属于生物医药技术领域，公开了一种如化学式I所示的神经酰胺类化合物：
Figure DDA0003785100090000011
其中，R1选自唾液酸、单水白屈氨酸、2,5‑呋喃二甲酸、奎尼酸、绿原酸、依克多因、烟酸、莽草酸、葡萄糖醛酸、水杨酸、鼠尾草酸、二氢燕麦酰基邻氨基苯甲酸、松香酸、熊果酸、氨甲环酸、丁香酸、龙胆酸、香草酸、5‑羟基异香草酸、乳清酸、5‑氨基乳清酸、3,5‑二羟基‑4‑甲基苯甲酸、甘草酸或没食子酸缩合后的残基，R2选自以下结构之一：‑C15H29、‑C15H31、‑C15H27、‑CHOHC14H27、‑CHOHC14H29。本发明还公开了神经酰胺类化合物的制备方法和应用。本发明将功效性羧酸具有生理活性的分子片段引入到神经酰胺中，将会提升该类分子的原有功效，也会改善神经酰胺化合物理化性质。

Description

含环状羧酸的神经酰胺类化合物及其制备方法和应用
技术领域
本发明属于生物医药技术领域，具体涉及含环状羧酸的神经酰胺类化合物及其制备方法和应用。
背景技术
神经酰胺是由鞘氨醇与长链脂肪酸通过酰胺键结合的化合物。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，所以神经酰胺是一类化合物而不是一种化合物。目前在皮肤中检测出有15种神经酰胺，大体可以分为三类，短链神经酰胺，长链神经酰胺，与角质细胞键合神经酰胺。获取神经酰胺的方式主要包括天然提取，微生物发酵和化学合成。提取法得到的神经酰胺纯度低，一般适合作食品使用，而且在神经酰胺的鞘氨醇部分、脂肪酸部分为均混合物，属于混合型的神经酰胺，其功能成分的比例不好调节；同时，动物组织中提取的神经酰胺还有可能受到病菌的污染，因此在化妆品等领域的应用受到限制。相较于前两种途径，化学合成具有所得产物成分单一，结构确定等特点，更为重要的是，化学合成方法能快速构建功能相似的神经酰胺衍生物，广泛地拓展了神经酰胺衍生物的应用范围。
神经酰胺具有保湿、信号转导、免疫调节等功能。不同的因素(如遗传，皮肤病，恶劣的外界环境，药物使用不当，过度护肤等)导致其含量的变化可能引发皮肤屏障功能受损，甚至一些皮肤疾病的发生，如特应性皮炎、银屑病等。因而近年来神经酰胺在日化品，医学研究和化妆品等领域成为了研究的热点。
由于市场上对于功能性神经酰胺的广泛需求，通过化学合成的方法快速构建神经酰胺衍生物，进一步改善神经酰胺的性质、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类结构新颖的神经酰胺类化合物，其含有环状羧酸，环状羧酸是指与羧基直接相连的是环状结构的碳原子的羧酸，环状结构可以是芳环(尤其是苯环)、杂环(尤其是尿嘧啶、四氢吡喃、吡啶、二氢吡啶、呋喃、四氢嘧啶)、皂苷、萜类(尤其是双萜、三环二萜、五环三萜)、环烷烃(如环己烷)、环烯烃(如环己烯)等，环烷烃、环烯烃可以带有一个或多个杂原子，芳环、杂环可以有一个或多个取代基。
本发明的另一目的是提供神经酰胺类化合物的合成方法。
本发明的另一目的是提供神经酰胺类化合物的用途。
为达到上述目的之一，本发明采用以下技术方案；
本发明的第一方面，一种神经酰胺类化合物，其具有通式I的结构或通式I的对映异构体、非对映异构体：
Figure BDA0003785100070000021
其中，R1选自唾液酸、单水白屈氨酸、2,5-呋喃二甲酸、奎尼酸、绿原酸、依克多因、烟酸、莽草酸、葡萄糖醛酸、水杨酸、鼠尾草酸、二氢燕麦酰基邻氨基苯甲酸、松香酸、熊果酸、氨甲环酸、丁香酸、龙胆酸、香草酸、5-羟基异香草酸、乳清酸、5-氨基乳清酸、3,5-二羟基-4-甲基苯甲酸、甘草酸或没食子酸缩合后的残基，
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羧酸RCOOH的羧基与鞘氨醇碱的氨基缩合形成肽键之后，残余的羧酸片段R，如烟酸缩合后的残基是
Figure BDA0003785100070000022
莽草酸缩合后的残基是
Figure BDA0003785100070000023
其中，依克多因能提升皮肤细胞的免疫防护能力，具有较好的抗过敏、抗炎效果；增加细胞修复能力，使皮肤能有效对抗微生物及过敏原的入侵，对皮肤有很好的保护及修复功效；在对抗紫外线方面，依克多因能修复紫外线导致的细胞DNA损伤，能有效减少晒伤细胞的生成，防止细胞膜结构受到伤害。
莽草酸不仅具有抗炎、镇痛作用，还可作为抗病毒和抗癌药物中间体。
进一步地，所述R2选自以下结构之一：
Figure BDA0003785100070000031
进一步地，所述R2选自以下结构之一：
Figure BDA0003785100070000032
分别对应鞘氨醇、二氢鞘氨醇、植物鞘氨醇。
进一步地，所述R1选自依克多因、烟酸、莽草酸、2,5-呋喃二甲酸、没食子酸或水杨酸缩合后的残基。
进一步地，所述R1选自依克多因、烟酸、莽草酸、2,5-呋喃二甲酸或没食子酸缩合后的残基。
进一步地，所述R1选自依克多因缩合后的残基。
进一步地，所述R1选自烟酸缩合后的残基。
进一步地，所述R1选自莽草酸缩合后的残基。
进一步地，所述R1选自2,5-呋喃二甲酸缩合后的残基。
进一步地，所述R1选自没食子酸缩合后的残基。
进一步地，所述R1选自水杨酸缩合后的残基。
神经酰胺类化合物选自以下化合物之一：
Figure BDA0003785100070000041
本发明的第二方面，一种制备神经酰胺类化合物的方法，包括以下步骤：
Figure BDA0003785100070000051
化合物S1和N-羟基琥珀酰亚胺、缩合剂反应得到化合物S2；
化合物S2和鞘氨醇碱反应得到化合物I。
进一步地，所述化合物S1、N-羟基琥珀酰亚胺、缩合剂、鞘氨醇碱的摩尔比为1：(1～2)：(1～2)：(0.8～1)。
进一步地，所述缩合剂为DCC。
进一步地，所述反应的溶剂为THF。
一种制备神经酰胺类化合物的方法，包括以下步骤：
Figure BDA0003785100070000052
化合物S1和鞘氨醇碱、缩合剂反应得到化合物I。
进一步地，所述缩合剂包括EDCI和HOBT。
进一步地，所述化合物S1、EDCI、HOBT、鞘氨醇碱的摩尔比为1：(1～2)：(1～2)：(0.8～1)。
进一步地，所述反应的溶剂为DCM。
本发明的第三方面，神经酰胺类化合物作为抗氧化剂的应用，尤其是在化妆品、保健品、药品中的应用。
本发明具有以下有益效果：
本发明将功效性羧酸与鞘氨醇碱反应，得到一类结构新颖的神经酰胺类化合物，功效性羧酸具有生理活性的分子片段引入到神经酰胺中，将会提升该类分子的原有功效，也会改善神经酰胺化合物理化性质，比如，提升神经酰胺化合物的抗氧化性。
说明书附图
图1为实施例10神经酰胺化合物的抗氧化性的测试结果。
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。
DCC指N,N'-二环己基碳二亚胺，THF指四氢呋喃，DCM指二氯甲烷，EDCI指1-(3-二甲胺基丙基)-3-乙基碳二亚胺，HOBT指1-羟基苯并三唑。
神经酰胺类化合物的通用合成方法
方法A
Figure BDA0003785100070000061
步骤1：将化合物S1(50mmol)，N-羟基琥珀酰亚胺(60～75mmol，优选60mmol)，DCC(60～75mmol，优选60mmol)置于250mL加入圆底烧瓶中，加入100mL四氢呋喃，随后在室温条件下搅拌4～24小时，通过TLC检测，直至化合物S1完全消失。后处理：过滤反应体系，收集滤液直接用于下一步反应。
步骤2：将鞘氨醇碱(40～50mmol，优选45mmol)加入到上一步的滤液中，随后在室温条件下搅拌24～72小时，通过TLC检测，直至鞘氨醇碱完全消失。后处理：加入饱和碳酸氢钠水溶液淬灭。分离有机层，干燥，过滤并真空浓缩。由此获得的残余物通过硅胶柱纯化，得到产物(50～70％收率)。
方法B
Figure BDA0003785100070000062
将化合物S1(50mmol)，EDCI(60～75mmol，优选60mmol)，HOBT(60～75mmol，优选60mmol)置于250mL加入圆底烧瓶中，加入100mL二氯甲烷，随后在室温条件下搅拌1小时，随后将鞘氨醇碱(40～50mmol，优选45mmol)加入到反应体系中，在室温条件下搅拌24～72小时，直至鞘氨醇碱完全消失。后处理：加入水淬灭。分离有机层，干燥，过滤并真空浓缩。由此获得的残余物通过硅胶柱纯化，得到产物(50～65％收率)。
实施例1
烟酸与植物鞘氨醇通过方法A缩合的产物。
Figure BDA0003785100070000071
1H NMR(400MHz,DMSO-d6)δ9.02(d,J＝2.2Hz,1H),8.68(dd,J＝4.9,1.7Hz,1H),8.36(d,J＝8.7Hz,1H),8.21(dt,J＝8.0,2.0Hz,1H),7.49(dd,J＝7.9,4.8Hz,1H),4.17(dtd,J＝10.1,6.5,4.3Hz,1H),3.70(dd,J＝11.1,4.2Hz,1H),3.60(dd,J＝11.1,7.0Hz,1H),3.53(t,J＝5.8Hz,2H),1.60–1.48(m,1H),1.41(d,J＝9.7Hz,1H),1.34–1.11(m,24H),0.90–0.78(m,3H)。
实施例2
莽草酸与植物鞘氨醇通过方法A缩合的产物。
Figure BDA0003785100070000072
1H NMR(400MHz,Methanol-d4)δ6.53–6.46(m,1H),4.42(dd,J＝5.1,3.3Hz,1H),4.25(q,J＝5.3Hz,1H),4.06(dt,J＝7.8,5.6Hz,1H),3.84(qd,J＝12.4,11.8,5.6Hz,2H),3.71(dd,J＝7.8,4.2Hz,1H),3.66(t,J＝5.8Hz,1H),3.59(ddd,J＝9.1,6.2,2.5Hz,1H),2.81(dd,J＝17.7,5.0Hz,1H),2.27(dd,J＝17.7,6.2Hz,1H),1.64–1.59(m,1H),1.36(d,J＝7.4Hz,25H),1.01–0.91(m,3H)。
实施例3
莽草酸与鞘氨醇通过方法A缩合的产物。
Figure BDA0003785100070000073
1H NMR(400MHz,Methanol-d4)δ6.37(dt,J＝3.8,1.8Hz,1H),5.77–5.64(m,1H),5.47(ddt,J＝15.3,7.2,1.4Hz,1H),4.33(t,J＝4.2Hz,1H),4.12(t,J＝7.1Hz,1H),4.02–3.84(m,2H),3.73(d,J＝5.1Hz,2H),3.61(dd,J＝8.0,4.2Hz,1H),2.70(ddt,J＝17.6,5.2,1.6Hz,1H),2.18(ddt,J＝17.7,6.5,1.8Hz,1H),2.02(q,J＝6.6Hz,2H),1.28(s,22H),0.96–0.79(m,3H)。
实施例4
依克多因与植物鞘氨醇通过方法A缩合的产物。
Figure BDA0003785100070000081
1H NMR(400MHz,Methanol-d4)δ4.18(dt,J＝6.6,4.5Hz,1H),3.82(dd,J＝11.3,4.2Hz,1H),3.71(dd,J＝11.3,6.6Hz,1H),3.60–3.44(m,3H),1.95(s,4H),1.79(dt,J＝14.0,6.9Hz,1H),1.68(t,J＝10.6Hz,1H),1.54(d,J＝11.7Hz,1H),1.29(d,J＝8.8Hz,26H),0.89(t,J＝6.8Hz,3H)。
实施例5
2,5-呋喃二甲酸与植物鞘氨醇通过方法A缩合的产物。
Figure BDA0003785100070000082
1H NMR(400MHz,Methanol-d4)δ7.68(d,J＝2.0Hz,1H),7.52(d,J＝2.0Hz,1H),4.17(dtd,J＝10.1,6.5,4.3Hz,1H),3.70(dd,J＝11.1,4.2Hz,1H),3.60(dd,J＝11.1,7.0Hz,1H),3.53(t,J＝5.8Hz,2H),1.60–1.48(m,1H),1.41(d,J＝9.7Hz,1H),1.34–1.11(m,24H),0.90–0.78(m,3H)。
实施例6
没食子酸与鞘氨醇通过方法B缩合的产物。
Figure BDA0003785100070000083
1H NMR(400MHz,Methanol-d4)δ6.73(s,2H),5.70(dt,J＝15.4,6.8Hz,1H),5.51(ddt,J＝15.4,7.4,1.4Hz,1H),4.20(t,J＝7.4Hz,1H),4.12(ddd,J＝7.4,5.5,4.1Hz,1H),3.86(dd,J＝11.3,5.5Hz,1H),3.79(dd,J＝11.3,4.2Hz,1H),2.98(s,1H),2.85(s,1H),1.99(dq,J＝15.0,7.6,7.1Hz,2H),1.40–1.03(m,24H),0.96–0.80(m,3H)。
实施例7
没食子酸与植物鞘氨醇通过方法B缩合的产物。
Figure BDA0003785100070000091
1H NMR(400MHz,Methanol-d4)δ6.73(s,2H),4.23(q,J＝5.3Hz,1H),3.80(qd,J＝11.2,5.0Hz,2H),3.64(t,J＝5.8Hz,1H),3.56(ddd,J＝8.9,5.9,2.5Hz,1H),1.71–1.65(m,1H),1.53(d,J＝8.4Hz,1H),1.46–1.38(m,1H),1.36–1.16(m,23H),0.89(t,J＝6.7Hz,3H)。
实施例8
水杨酸与鞘氨醇通过方法A缩合的产物。
Figure BDA0003785100070000092
1H NMR(400MHz,Methanol-d4)δ7.82(dd,J＝8.2,1.7Hz,1H),7.43–7.25(m,1H),6.93–6.81(m,2H),5.70(dt,J＝15.4,6.8Hz,1H),5.51(ddt,J＝15.4,7.4,1.4Hz,1H),4.20(t,J＝7.4Hz,1H),4.12(ddd,J＝7.4,5.5,4.1Hz,1H),3.86(dd,J＝11.3,5.5Hz,1H),3.79(dd,J＝11.3,4.2Hz,1H),1.99(dq,J＝15.0,7.6,7.1Hz,2H),1.40–1.03(m,22H),0.96–0.80(m,3H)。
实施例9
水杨酸与二氢鞘氨醇通过方法B缩合的产物。
Figure BDA0003785100070000093
1H NMR(400MHz,Methanol-d4)δ7.87(dd,J＝8.3,1.7Hz,1H),7.38(td,J＝7.8,1.7Hz,1H),6.96–6.87(m,2H),4.12(td,J＝6.1,4.1Hz,1H),3.91–3.81(m,2H),3.82–3.76(m,1H),1.68–1.44(m,3H),1.30(dd,J＝7.4,4.7Hz,25H),0.96–0.86(m,3H)。
实施例10
用抗氧化-ABTS法测试实施例1、4、8、9制备的神经酰胺化合物的抗氧化性
实验原理：采用ABTS(2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonicacid)diammonium salt)评价样品抗氧化能力最初由Miller等(1993)提出，现采用的一般是后来Re等(1999)改进后的方法。该方法利用ABTS可被过硫酸钾、过氧化氢、二氧化锰等一系列化合物氧化，生成蓝绿色的ABTS+阳离子自由基，在734nm处有最大吸收峰。在抗氧化剂的作用下，ABTS+还原成无色的ABTS。通过测定734nm处的吸光值，即可判定反应物的抗氧化能力。
ABTS自由基清除检测抗氧化性能：3mL ABTS水溶液(12mmol/L)与3mL过硫酸钾溶液(2.45mmol/L)，均匀混合，于室温下避光稳定12～16h。以DMSO作为稀释介质，选取合适的稀释比例，调整过硫酸钾溶液于734nm波长处的吸光度为0.700±0.025。加入不同浓度样品摇匀，避光放置10min，于734nm处测吸光值。
结果如图1所示，对照1为神经酰胺3，对照2为神经酰胺3B。
可见，本发明的化合物相比现有的神经酰胺化合物具有更好的抗氧化效果，对自由基的清除率普遍高出40～80％。
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)

1.一种神经酰胺类化合物，其具有通式I的结构或通式I的对映异构体、非对映异构体：
Figure FDA0003785100060000011
其中，R1选自唾液酸、单水白屈氨酸、2,5-呋喃二甲酸、奎尼酸、绿原酸、依克多因、烟酸、莽草酸、葡萄糖醛酸、水杨酸、鼠尾草酸、二氢燕麦酰基邻氨基苯甲酸、松香酸、熊果酸、氨甲环酸、丁香酸、龙胆酸、香草酸、5-羟基异香草酸、乳清酸、5-氨基乳清酸、3,5-二羟基-4-甲基苯甲酸、甘草酸或没食子酸缩合后的残基，
R2选自以下结构之一：-C15H29、-C15H31、-C15H27、-CHOHC14H27、-CHOHC14H29。
2.根据权利要求1所述的神经酰胺类化合物，其特征在于，所述R2选自以下结构之一：
Figure FDA0003785100060000012
3.根据权利要求2所述的神经酰胺类化合物，其特征在于，所述R2选自以下结构之一：
Figure FDA0003785100060000021
4.根据权利要求1所述的神经酰胺类化合物，其特征在于，所述R1选自依克多因、烟酸、莽草酸、2,5-呋喃二甲酸、没食子酸或水杨酸缩合后的残基。
5.根据权利要求1所述的神经酰胺类化合物，其特征在于，选自以下化合物之一：
Figure FDA0003785100060000022
Figure FDA0003785100060000031
6.一种制备权利要求1～5任意一项所述的神经酰胺类化合物的方法，其特征在于，包括以下步骤：
Figure FDA0003785100060000032
化合物S1和N-羟基琥珀酰亚胺、缩合剂反应得到化合物S2；
化合物S2和鞘氨醇碱反应得到化合物I；
R1、R2如权利要求1～5所定义。
7.根据权利要求6所述的方法，其特征在于，所述化合物S1、N-羟基琥珀酰亚胺、缩合剂、鞘氨醇碱的摩尔比为1：(1～2)：(1～2)：(0.8～1)；所述缩合剂为DCC；所述反应的溶剂为THF。
8.一种制备权利要求1～5任意一项所述的神经酰胺类化合物的方法，其特征在于，包括以下步骤：
Figure FDA0003785100060000033
化合物S1和鞘氨醇碱、缩合剂反应得到化合物I；
R1、R2如权利要求1～5所定义。
9.根据权利要求8所述的方法，其特征在于，所述缩合剂包括EDCI和HOBT，所述化合物S1、EDCI、HOBT、鞘氨醇碱的摩尔比为1：(1～2)：(1～2)：(0.8～1)；所述反应的溶剂为DCM。
10.权利要求1～5任意一项所述的神经酰胺类化合物作为抗氧化剂的应用。
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