CN107417532B - 一种白藜芦醇丙烯酸酚酯类衍生物及其制备方法和用途 - Google Patents

一种白藜芦醇丙烯酸酚酯类衍生物及其制备方法和用途 Download PDF

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CN107417532B
CN107417532B CN201710285377.XA CN201710285377A CN107417532B CN 107417532 B CN107417532 B CN 107417532B CN 201710285377 A CN201710285377 A CN 201710285377A CN 107417532 B CN107417532 B CN 107417532B
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阮班锋
林梦雪
李遥
李青山
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Abstract

本发明公开了一种白藜芦醇丙烯酸酚酯类衍生物及其制备方法和用途，其中白藜芦醇丙烯酸酚酯类衍生物的结构由如下：
Figure DDA0001280551230000011
生物活性测试结果表明本发明白藜芦醇丙烯酸酚酯类衍生物能够抑制LPS刺激的RAW264.7释放NO，并且在有效的抗炎浓度范围内没有细胞毒性。

Description

一种白藜芦醇丙烯酸酚酯类衍生物及其制备方法和用途
技术领域
本发明涉及一种白藜芦醇类衍生物，具体地说是一种白藜芦醇丙烯酸酚酯类衍生物及其制备方法和用途。
背景技术
白藜芦醇，又称3,4',5-三羟基二苯乙烯，是一种含有芪类结构的非类黄酮多酚，天然存在的白藜芦醇具有反式和顺式两种异构体，反式异构体比顺式异构体更稳定。
白藜芦醇是具有生物学多效性的多酚类物质之一。除了作为植物抗毒素，用于植物自我保护之外，白藜芦醇还具有抗菌、抗癌、抗炎、抗过敏、降血脂、抗氧化等多种药理活性。在这些药理活性中，白藜芦醇的抗炎作用引起了人们的广泛兴趣。研究表明，白藜芦醇对急性、慢性炎症均有良好的治疗作用，其抗炎机制可能与抑制炎症信号转导通路，减少炎症细胞因子生成，干扰花生四烯酸代谢相关。
近些年随着白藜芦醇衍生物的不断出现，研究者们发现其中一些二苯乙烯类化合物同样具有许多与白藜芦醇相似的药理活性。将白藜芦醇的羟基全部甲基化可得到(E)-1,3-二甲氧基-5-(4-甲氧基苯乙烯基)苯，即白藜芦醇三甲醚。Deng等的研究表明，白藜芦醇三甲醚可能具有比白藜芦醇更强的抗炎能力(Phytotherapy Research,2011,25(3):451-457)。在抗对碘乙酸钠致大鼠骨关节炎的实验中，白藜芦醇三甲醚表现了更好的疗效(中国药学杂志,2014,49(3):199-203)。
发明内容
本发明旨在提供一种白藜芦醇丙烯酸酚酯类衍生物及其制备方法和用途。本发明依据药物的拼合原理和基于结构的药物分子设计理念，在白藜芦醇所具有的二苯乙烯分子骨架上引入丙烯酸酚酯结构，设计和合成出了一系列新型白藜芦醇丙烯酸酚酯类衍生物。生物活性测试结果表明此系列化合物能够抑制LPS刺激的RAW264.7释放NO。
本发明白藜芦醇丙烯酸酚酯类衍生物，其结构由如下通式(1)表示：
Figure BDA0001280551210000011
其中R选自
Figure BDA0001280551210000021
Figure BDA0001280551210000022
本发明白藜芦醇丙烯酸酚酯类衍生物的制备方法，包括如下步骤：
步骤1：向N,N-二甲基甲酰胺中加入白藜芦醇三甲醚(A)，然后于冰水浴中缓慢滴加三氯氧磷，滴完后升温至室温反应1h，反应结束后将反应液滴加至冰水与乙酸乙酯的混合溶液中，再分次加入碳酸钠固体直至无气泡产生，搅拌8-12h后析出淡黄色固体，抽滤、干燥，最后柱层析(洗脱液为二氯甲烷：石油醚＝1:2，v/v)分离得到中间体B—(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯甲醛；
步骤1中，白藜芦醇三甲醚与三氯氧磷的摩尔比为1:1。
步骤1中，冰水与乙酸乙酯的混合溶液中冰水与乙酸乙酯的体积比为5:1。
步骤1中，N,N-二甲基甲酰胺的用量为每毫摩尔白藜芦醇三甲醚加0.5mL。
本步骤的反应过程如下：
Figure BDA0001280551210000023
步骤2：向圆底烧瓶中加入中间体B和丙二酸，再加入吡啶和六氢吡啶，95℃下回流反应，TLC检测至原料反应完全，反应4h；反应结束后，将反应液滴加至加有冰块的盐酸溶液中(保证低温下反应体系的淬灭，有利于结晶的生成)，室温下搅拌2h后，析出黄色固体，抽滤，干燥，柱层析分离(洗脱液为乙酸乙酯：石油醚＝1:20，v/v)，得到中间体C—(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯丙烯酸；
步骤2中，中间体B和丙二酸的摩尔比为1:3。
步骤2中，六氢吡啶的用量为每毫摩尔中间体B加0.1mL，吡啶的用量为每毫摩尔中间体B加1.5mL。
步骤2中，盐酸溶液的用量为每毫摩尔中间体B加25mL盐酸溶液(盐酸溶液的质量浓度为8.5％)。
本步骤的反应过程如下：
Figure BDA0001280551210000031
步骤3：向圆底烧瓶中加入中间体C，用二氯甲烷溶解，再加入取代芳香酚、DCC(二环己基碳二亚胺)以及DMAP(二甲氨基吡啶)，室温下反应2h，反应结束后加水洗涤，萃取，有机相旋蒸，柱层析分离(洗脱液为石油醚/乙酸乙酯＝20/1，v/v)，最终得目标产物D1-23。
步骤3中，二氯甲烷的用量为每毫摩尔中间体C加10mL。
步骤3中，中间体C、取代芳香酚、DCC和DMAP的摩尔比为10:11:12:1。
本步骤的反应过程如下：
Figure BDA0001280551210000032
本发明白藜芦醇丙烯酸酚酯类衍生物的用途，是在制备抗炎药物中的应用，用于抑制LPS刺激的RAW264.7释放NO。
生物活性测试结果表明本发明白藜芦醇丙烯酸酚酯类衍生物能够抑制LPS刺激的RAW264.7释放NO，并且在有效的抗炎浓度范围内没有细胞毒性。
附图说明
图1是本发明白藜芦醇丙烯酸酯衍生物(D1-D23)对LPS刺激的RAW264.7释放NO的影响，其中化合物D15表现最为出色，可将其作为有效化合物，可进行进一步抗炎活性研究。
图2是MTT法细胞毒性测定实验结果。
图3是不同浓度化合物D15对RAW264.7释放NO的影响，结果表明D15一定范围内浓度依赖性抑制NO生成。
具体实施方式
通过以下实施例进一步详细说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
实施例1：(E)-苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D1)
Figure BDA0001280551210000041
步骤1：取100mL圆底烧瓶，在冰水浴下加入N,N-二甲基甲酰胺(30mL)，另外称取白藜芦醇三甲醚(13.5g，0.075mol)，用10mL N,N-二甲基甲酰胺溶解，然后将其加入圆底烧瓶中，再缓慢滴加三氯氧磷(7mL，0.075mol)，滴加完毕后恢复至室温反应，搅拌反应1h；反应结束后取一个1000mL烧杯，加500mL冰水和100mL乙酸乙酯，然后将反应液逐滴加入其中，搅拌下分次加入碳酸钠固体直至无气泡产生，过夜析出淡黄色固体，抽滤、干燥，柱层析分离(洗脱液为二氯甲烷：石油醚＝1:2，v/v)得到中间体B—(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯甲醛，产物为淡黄色固体粉末，收率93％，熔点108-109℃。
1H NMR(600MHz,DMSO):δ3.78(s,3H),3.90(s,3H),3.92(s,3H),6.63(s,1H),6.91(s,1H),6.97(d,2H,J＝7.9Hz),7.21(d,1H,J＝16.2Hz),7.50(d,2H,J＝7.9Hz),7.95(d,1H,J＝16.2Hz),10.41(s,1H).MS(EI):299.3(C18H18O4,[M+H]+)。
步骤2：取一个50mL圆底烧瓶，加入中间体B(2980mg,10mmol)、丙二酸(3120mg,30mmol)，15mL吡啶作溶剂，1mL六氢吡啶作催化剂，95℃下回流反应，TLC检测该反应，反应4h后原料基本反应完全；反应结束后，取50mL浓盐酸加入200mL水稀释，加入2块冰块，在盐酸的搅拌过程中逐滴加入反应液，室温下搅拌2h，析出黄色固体，抽滤，得黄色滤饼，干燥后柱层析分离(洗脱液为石油醚：乙酸乙酯＝1:20，v/v)得到中间体C—(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯丙烯酸，产物为白色固体粉末，收率92％，熔点：150-152℃。 1H NMR(600MHz,CDCl3):δ8.13(d,J＝16.0Hz,1H),7.46(d,J＝7.8Hz,2H),7.26(s,1H),6.95-6.89(m,3H),6.70(s,1H),6.52(d,J＝15.9Hz,1H),6.42(s,1H),3.88(s,6H),3.84(d,J＝0.7Hz,3H).13C NMR(151MHz,CDCl3):δ172.97(s),161.65(s),160.74(s),159.62(s),141.67(s),140.75(s),132.13(s),129.76(s),128.07(s),124.86(s),119.60(s),114.91(s),114.20(s),103.57(s),97.54(s),55.61(s),55.44(s),55.32(s).MS(EI):341.4(C20H20O5,[M+H]+).Anal.Calcd for C20H20O5:C,70.57；H,5.92％；Found:C,75.42；H,5.94％。
步骤3：取一个50mL单口瓶，加入中间体C(340mg,1mmol)，用二氯甲烷溶解(10mL)，再加入苯酚(95mg,1.1mmol)、DCC(二环己基碳二亚胺,206mg,1.2mmol)和DMAP(二甲氨基吡啶,12mg,0.1mmol)，室温下反应2h，反应结束后加水洗涤，萃取，有机相旋蒸，最后柱层析分离得到目标产物—(E)-苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D1)。产物为淡黄色固体粉末，收率82％，熔点：95-97℃。
1H NMR(600MHz,CDCl3):δ8.21(d,J＝16.0Hz,1H),7.47(d,J＝8.5Hz,2H),7.39(t,J＝7.9Hz,2H),7.32(d,J＝16.0Hz,1H),7.23(t,J＝7.4Hz,1H),7.18(d,J＝8.4Hz,2H),6.94(d,J＝16.0Hz,1H),6.90(d,J＝8.6Hz,2H),6.71(d,J＝16.0Hz,2H),6.45(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H).13C NMR(151MHz,CDCl3):δ166.60(s),161.70(s),160.80(s),159.67(s),151.10(s),141.79(s),140.39(s),132.26(s),129.78(s),129.29(s),128.09(s),125.47(s),124.85(s),121.76(s),119.44(s),114.98(s),114.21(s),103.66(s),97.63(s),55.65(s),55.46(s),55.33(s).MS(EI):417.2(C26H24O5,[M+H]+).Anal.Calcd for C26H24O5:C,74.98；H,5.81；O,19.21％.Found:C,75.00；H,5.82；O,19.18％.
实施例2：(E)-对甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D2)
Figure BDA0001280551210000051
本实施例的制备方法同实施例1，不同的是步骤3中以4-甲基苯酚代替苯酚，得到目标产物D2—(E)-对甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率80％，淡黄色固体，熔点：78-81℃。
1H NMR(600MHz,CDCl3):δ8.20(d,J＝16.0Hz,1H),7.47(d,J＝8.6Hz,2H),7.32(d,J＝16.0Hz,1H),7.19(d,J＝8.1Hz,2H),7.06(d,J＝8.3Hz,2H),6.94(d,J＝16.0Hz,1H),6.90(d,J＝8.6Hz,2H),6.73(d,J＝2.0Hz,1H),6.71(d,J＝16.0Hz,1H),6.45(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),2.36(s,3H).13C NMR(151MHz,CDCl3):δ166.77(s),161.63(s),160.75(s),159.64(s),148.82(s),141.70(s),140.20(s),135.03(s),132.18(s),129.79(s),128.07(s),124.86(s),121.40(s),119.57(s),115.00(s),114.19(s),103.62(s),97.60(s),55.61(s),55.42(s),55.30(s),20.85(s).MS(EI):431.1(C27H26O5,[M+H]+).Anal.Calcd for C27H26O5:C,75.33；H,6.09；O,18.58％.Found:C,75.41；H,6.06；O,18.53％.
实施例3：(E)-2,3-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D3)
Figure BDA0001280551210000061
本实施例的制备方法同实施例1，不同的是步骤3中以2,3-二甲基苯酚代替苯酚，得到目标产物D3—(E)-2,3-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率78％，淡黄色固体，熔点：98-100℃。
1H NMR(600MHz,CDCl3):δ8.24(d,J＝16.0Hz,1H),7.47(d,J＝8.6Hz,2H),7.33(d,J＝16.0Hz,1H),7.12(t,J＝7.8Hz,1H),7.04(d,J＝7.5Hz,1H),6.95(s,2H),6.90(d,J＝8.6Hz,2H),6.76(d,J＝16.0Hz,1H),6.73(d,J＝1.9Hz,1H),6.45(d,J＝1.8Hz,1H),3.92(s,3H),3.90(s,3H),3.83(s,3H),2.31(s,3H),2.13(s,3H).13C NMR(150MHz,CDCl3):δ166.57(s),161.67(s),160.83(s),159.65(s),149.52(s),141.77(s),140.26(s),138.32(s),132.20(s),129.78(s),128.91(s),128.04(s),127.16(s),125.92(s),124.87(s),119.63(s),119.31(s),114.98(s),114.19(s),103.64(s),97.62(s),55.63(s),55.44(s),55.32(s),20.06(s),12.48(s).MS(EI):445.2.(C28H28O5,[M+H]+).Anal.Calcd forC28H28O5:C,75.65；H,6.35；O,18.00％.Found:C,75.63；H,6.32；O,18.05％.
实施例4：(E)-2,4-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D4)
Figure BDA0001280551210000062
本实施例的制备方法同实施例1，不同的是步骤3中以2,4-二甲基苯酚代替苯酚，得到目标产物D4—(E)-2,4-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率79％，淡黄色固体，熔点：97-99℃。
1H NMR(600MHz,CDCl3):δ8.23(d,J＝16.0Hz,1H),7.47(d,J＝8.6Hz,2H),7.33(d,J＝16.0Hz,1H),7.05(s,1H),7.02(d,J＝8.2Hz,1H),6.98(d,J＝8.1Hz,1H),6.93(d,J＝16.0Hz,1H),6.90(d,J＝8.7Hz,2H),6.74(d,J＝16.1Hz,2H),6.45(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),2.32(s,3H),2.19(s,3H).13C NMR(151MHz,CDCl3):δ166.51(s),161.64(s),160.80(s),159.64(s),147.38(s),141.73(s),140.18(s),135.18(s),132.17(s),131.60(s),129.84(s),129.78(s),128.03(s),127.30(s),124.88(s),121.71(s),119.35(s),114.98(s),114.18(s),103.63(s),97.60(s), 55.61(s),55.43(s),55.30(s),20.80(s),16.17(s).MS(EI):445.2.(C28H28O5,[M+H]+).Anal.Calcd for C28H28O5:C,75.65；H,6.35；O,18.00％.Found:C,75.61；H,6.34；O,18.05％.
实施例5：(E)-2,5-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D5)
Figure BDA0001280551210000071
本实施例的制备方法同实施例1，不同的是步骤3中以2,5-二甲基苯酚代替苯酚，得到目标产物D5—(E)-2,5-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率75％，淡黄色固体，熔点：116-119℃。
1H NMR(600Hz,CDCl3):δ8.24(d,J＝16.0Hz,1H),7.47(d,J＝8.1Hz,2H),7.33(d,J＝16.0Hz,1H),7.13(d,J＝7.6Hz,1H),6.99-6.92(m,3H),6.90(d,J＝8.0Hz,2H),6.79-6.70(m,2H),6.45(s,1H),3.92(s,3H),3.90(s,3H),3.83(s,3H),2.33(s,3H),2.19(s,3H).13C NMR(151MHz,CDCl3):δ166.42(s),161.66(s),160.81(s),159.64(s),149.44(s),141.75(s),140.24(s),136.66(s),132.19(s),130.66(s),129.76(s),128.03(s),127.00(s),126.46(s),124.85(s),122.57(s),119.28(s),114.95(s),114.18(s),103.63(s),97.60(s),55.61(s),55.42(s),55.29(s),20.87(s),15.81(s).MS(EI):445.2.(C28H28O5,[M+H]+).Anal.Calcd for C28H28O5:C,5.65；H,.35；O,18.00％.Found:C,75.59；H,6.37；O,8.05％.
实施例6：(E)-3,4-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D6)
Figure BDA0001280551210000072
本实施例的制备方法同实施例1，不同的是步骤3中以3,4-二甲基苯酚代替苯酚，得到目标产物D6—(E)-3,4-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率74％，白色固体，熔点：102-105℃。
1H NMR(600MHz,CDCl3):δ8.20(d,J＝16.0Hz,1H),7.47(d,J＝8.6Hz,2H),7.32(d,J＝16.0Hz,1H),7.14(d,J＝8.1Hz,1H),6.98-6.92(m,2H),6.90(d,J＝8.6Hz,3H),6.72(s,1H),6.70(d, J＝16.0Hz,1H),6.44(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),2.27(s,3H),2.25(s,3H).13C NMR(151MHz,CDCl3):δ166.89(s),161.61(s),160.74(s),159.63(s),148.98(s),141.67(s),140.11(s),137.69(s),133.73(s),132.16(s),130.21(s),129.80(s),128.08(s),124.88(s),122.66(s),119.68(s),118.76(s),115.04(s),114.19(s),103.60(s),97.60(s),55.62(s),55.43(s),55.31(s),19.85(s),19.17(s).MS(EI):445.2.(C28H28O5,[M+H]+).Anal.Calcd for C28H28O5:C,5.65；H,.35；O,18.00％.Found:C,75.61；H,6.37；O,8.02％.
实施例7：(E)-3,5-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D7)
Figure BDA0001280551210000081
本实施例的制备方法同实施例1，不同的是步骤3中以3,5-二甲基苯酚代替苯酚，得到目标产物D7—(E)-3,5-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率74％，黄色油状物。
1H NMR(600Hz,CDCl3):δ8.19(d,J＝16.0Hz,1H),7.47(d,J＝8.6Hz,2H),7.31(d,J＝16.0Hz,1H),6.94(d,J＝16.0Hz,1H),6.90(d,J＝8.6Hz,2H),6.86(s,1H),6.80(s,2H),6.72(d,J＝1.9Hz,1H),6.69(d,J＝16.0Hz,1H),6.44(d,J＝1.7Hz,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),2.33(s,6H).13C NMR(151MHz,CDCl3):δ166.80(s),161.63(s),160.76(s),159.65(s),150.98(s),141.70(s),140.17(s),139.08(s),132.19(s),129.80(s),128.09(s),127.24(s),124.87(s),119.65(s),119.33(s),115.04(s),114.19(s),103.61(s),97.61(s),55.62(s),55.44(s),55.32(s),1.23(s).MS(EI):445.2.(C28H28O5,[M+H]+).Anal.Calcd for C28H28O5:C,75.65；H,6.35；O,18.00％.Found:C,75.73；H,6.33；O,17.96％.
实施例8：(E)-2,3,5-三甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D8)
Figure BDA0001280551210000082
本实施例的制备方法同实施例1，不同的是步骤3中以2,3,5-三甲基苯酚代替苯酚，得到目标产物D8—(E)-2,3,5-三甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率77％，白色固体，熔点：127-129℃。
1H NMR(600Hz,CDCl3):δ8.24(d,J＝16.0Hz,1H),7.47(d,J＝8.5Hz,2H),7.34(d,J＝16.0Hz,1H),6.94(d,J＝16.0Hz,1H),6.90(d,J＝8.6Hz,2H),6.88(s,1H),6.78(s,1H),6.76(d,J＝16.0Hz,1H),6.73(s,1H),6.45(s,1H),3.92(s,3H),3.90(s,3H),3.83(s,3H),2.30(s,3H),2.27(s,3H),2.09(s,3H).13C NMR(151MHz,CDCl3):δ166.66(s),161.63(s),160.80(s),159.63(s),149.35(s),141.72(s),140.16(s),137.91(s),135.68(s),132.15(s),129.77(s),128.14(s),128.03(s),125.57(s),124.86(s),120.07(s),119.39(s),114.98(s),114.17(s),103.60(s),97.59(s),55.60(s),55.41(s),55.29(s),20.81(s),19.98(s),12.13(s).MS(EI):459.2.(C29H30O5,[M+H]+).Anal.Calcd for C29H30O5:C,75.96；H,6.59；O,17.45％.Found:C,76.03；H,6.57；O,17.40％.
实施例9：(E)-4-氯苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D9)
Figure BDA0001280551210000091
本实施例的制备方法同实施例1，不同的是步骤3中以4-氯苯酚代替苯酚，得到目标产物D9—(E)-4-氯苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率81％，淡黄色固体，熔点：105-107℃。
1H NMR(600MHz,CDCl3):δ8.20(d,J＝16.0Hz,1H),7.69(d,J＝8.6Hz,2H),7.46(d,J＝8.4Hz,2H),7.29(d,J＝16.0Hz,1H),7.00-6.86(m,5H),6.72(s,1H),6.68(d,J＝16.0Hz,1H),6.44(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H).13C NMR(151MHz,CDCl3):δ168.88(s),164.50(s),163.54(s),162.37(s),153.63(s),144.61(s),143.53(s),140.98(s),135.08(s),132.38(s),130.75(s),127.42(s),126.65(s),121.49(s),117.49(s),116.88(s),106.43(s),100.29(s),92.05(s),58.31(s),58.13(s),58.00(s).MS(EI):451.1(C26H23ClO5,[M+H]+).Anal.Calcd for C26H23ClO5:C,69.25；H,5.14；Cl,7.86；O,17.74％.Found:C,69.31；H,5.12；Cl,7.84；O,17.70％.
实施例10：(E)-4-碘苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D10)
Figure BDA0001280551210000101
本实施例的制备方法同实施例1，不同的是步骤3中以4-碘苯酚代替苯酚，得到目标产物D10—(E)-4-碘苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率80％，淡黄色固体，熔点94-97℃。
1H NMR(600MHz,CDCl3):δ8.21(d,J＝16.0Hz,1H),7.47(d,J＝8.5Hz,2H),7.35(d,J＝8.7Hz,2H),7.30(d,J＝16.0Hz,1H),7.12(d,J＝8.7Hz,2H),6.93(d,J＝16.2Hz,1H),6.90(d,J＝8.5Hz,2H),6.72(s,1H),6.69(d,J＝16.0Hz,1H),6.44(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H).13C NMR(151MHz,CDCl3):δ166.36(s),161.83(s),160.87(s),159.71(s),149.58(s),141.94(s),140.83(s),132.40(s),130.77(s),129.73(s),129.32(s),128.09(s),124.77(s),123.13(s),118.84(s),114.83(s),114.22(s),103.76(s),97.63(s),55.65(s),55.46(s),55.33(s).MS(EI):543.1(C26H23IO5,[M+H]+).Anal.Calcdfor C26H23IO5:C,57.58；H,4.27；I,23.40；O,14.75％.Found:C,57.58；H,4.26；I,23.33；O,17.73％.
实施例11：(E)-4-氯-3,5-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D11)
Figure BDA0001280551210000102
本实施例的制备方法同实施例1，不同的是步骤3中以4-氯-3,5-二甲基苯酚代替苯酚，得到目标产物D11—(E)-4-氯-3,5-二甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率81％，淡黄色固体，熔点：93-95℃。
1H NMR(600MHz,CDCl3):δ8.19(d,J＝16.0Hz,1H),7.47(d,J＝8.6Hz,2H),7.30(d,J＝16.0Hz,1H),6.93(d,J＝16.5Hz,3H),6.90(d,J＝8.6Hz,2H),6.72(d,J＝1.9Hz,1H),6.68(d,J＝16.0Hz,1H),6.44(d,J＝1.8Hz,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),2.38(s,6H).13C NMR(151MHz,CDCl3):δ166.65(s),161.75(s),160.83(s),159.68(s),148.68(s),141.84(s),140.57(s),137.26(s),132.32(s),131.33(s),129.75(s),128.09(s),124.80(s),121.55(s),119.12(s),114.90(s),114.20(s),103.70(s),97.61(s),55.63(s),55.44(s),55.32(s),20.80(s).MS(EI):479.1 (C28H27ClO5,[M+H]+).Anal.Calcdfor C28H27ClO5:C,70.21；H,5.68；Cl,7.40；O,16.70％.Found:C,70.23；H,5.69；Cl,7.39；O,16.68％.
实施例12：(E)-3-(二甲基氨基)苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D12)
Figure BDA0001280551210000111
本实施例的制备方法同实施例1，不同的是步骤3中以3-(二甲基氨基)苯酚代替苯酚，得到目标产物D12—(E)-3-(二甲基氨基)苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率72％，紫色油状物。
1H NMR(600MHz,CDCl3):δ8.20(d,J＝16.0Hz,1H),7.47(d,J＝8.5Hz,2H),7.32(d,J＝16.0Hz,1H),7.23(t,J＝8.1Hz,1H),6.94(d,J＝16.0Hz,1H),6.90(d,J＝8.5Hz,2H),6.71(d,J＝16.3Hz,2H),6.59(d,J＝7.1Hz,1H),6.54(d,J＝7.7Hz,1H),6.51(s,1H),6.44(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),2.95(s,6H).13C NMR(151MHz,CDCl3):δ166.72(s),161.59(s),160.74(s),159.63(s),152.15(s),141.67(s),140.03(s),132.16(s),129.80(s),129.52(s),128.09(s),124.90(s),119.84(s),115.07(s),114.19(s),109.75(s),109.56(s),105.80(s),103.59(s),97.61(s),55.62(s),55.43(s),55.31(s),40.50(s).MS(EI):460.2(C28H29NO5,[M+H]+).Anal.Calcd for C28H29NO5:C,73.18；H,6.36；N,3.05；O,17.41％.Found:C,73.20；H,6.38；Cl,3.04；O,17.38％.
实施例13：(E)-3,5-二甲氧基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D13)
Figure BDA0001280551210000112
本实施例的制备方法同实施例1，不同的是步骤3中以3,5-二甲氧基苯酚代替苯酚，得到目标产物D13—(E)-3,5-二甲氧基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率78％，黄色油状物。
1H NMR(600MHz,CDCl3):δ8.19(d,J＝16.0Hz,1H),7.47(d,J＝8.5Hz,2H),7.31(d,J＝15.9Hz,1H),6.93(d,J＝16.1Hz,1H),6.90(d,J＝8.5Hz,2H),6.72(s,1H),6.69(d,J＝16.0Hz,1H), 6.44(s,1H),6.35(s,3H),3.91(s,3H),3.90(s,3H),3.83(s,3H),3.78(s,6H),.13C NMR(151MHz,CDCl3):δ166.47(s),161.70(s),161.02(s),160.80(s),152.63(s),140.49(s),132.29(s),128.10(s),124.81(s),119.26(s),114.18(s),103.61(s),100.30(s),99.90(s),98.18(s),97.60(s),55.64(s),55.46(s),55.34(s),55.26(s).MS(EI):477.2(C28H28O7,[M+H]+).Anal.Calcd for C28H28O7:C,70.57；H,5.92；O,23.50％.Found:C,70.61；H,5.93；O,23.46％.
实施例14：(E)-4-烯丙基-2-甲氧基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D14)
Figure BDA0001280551210000121
本实施例的制备方法同实施例1，不同的是步骤3中以4-烯丙基-2-甲氧基苯酚代替苯酚，得到目标产物D14—(E)-4-烯丙基-2-甲氧基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率81％，黄色油状物。
1H NMR(600MHz,CDCl3):δ8.22(d,J＝16.0Hz,1H),7.46(d,J＝8.5Hz,2H),7.34(d,J＝16.0Hz,1H),7.03(d,J＝7.9Hz,1H),6.92(d,J＝16.1Hz,1H),6.89(s,1H),6.88(s,1H),6.80(dd,J＝15.9,5.7Hz,3H),6.72(s,1H),6.44(s,1H),5.98(d,J＝6.9Hz,1H),5.11(t,J＝13.7Hz,2H),3.90(s,3H),3.89(s,3H),3.82(s,6H),3.39(d,J＝6.6Hz,1H).13C NMR(151MHz,CDCl3):δ166.50(s),161.58(s),160.91(s),159.57(s),151.11(s),141.85(s),140.23(s),138.61(s),138.26(s),137.16(s),132.18(s),129.79(s),128.08(s),124.85(s),122.78(s),120.62(s),118.93(s),116.02(s),114.93(s),114.12(s),112.70(s),103.51(s),97.56(s),55.88(s),55.57(s),55.43(s),55.30(s),40.09(s).MS(EI):487.2(C30H30O6,[M+H]+).Anal.Calcd for C30H30O6:C,74.06；H,6.21；O,19.73％.Found:C,73.99；H,6.23；O,19.78％.
实施例15：(E)-苯并[d][1,3]二氧戊环-5-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D15)
Figure BDA0001280551210000131
本实施例的制备方法同实施例1，不同的是步骤3中以苯并[d][1,3]二氧戊环-5-醇代替苯酚，得到目标产D15—(E)-苯并[d][1,3]二氧戊环-5-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率75％，黄色油状物。
1H NMR(600MHz,CDCl3):δ8.19(d,J＝16.0Hz,1H),7.47(d,J＝8.5Hz,2H),7.30(d,J＝16.0Hz,1H),6.92(dd,J＝17.0,12.4Hz,3H),6.79(d,J＝8.3Hz,1H),6.72(s,1H),6.70(s,1H),6.68(d,J＝16.0Hz,1H),6.61(dd,J＝8.3,1.9Hz,1H),6.44(s,1H),5.98(s,2H),3.91(s,3H),3.90(s,3H),3.83(s,3H).13C NMR(151MHz,CDCl3):δ166.91(s),161.67(s),160.76(s),159.62(s),147.86(s),145.36(s),145.07(s),141.77(s),140.44(s),132.24(s),129.71(s),128.07(s),124.78(s),119.16(s),114.86(s),114.17(s),114.31(s),107.88(s),103.97(s),103.59(s),101.58(s),97.57(s),55.62(s),55.44(s),55.31(s).MS(EI):461.2(C27H24O7,[M+H]+).Anal.Calcd for C27H24O7:C,70.43；H,5.25；O,24.32％.Found:C,70.38；H,5.24；O,24.38％.
实施例16：(E)-4-环己基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D16)
Figure BDA0001280551210000132
本实施例的制备方法同实施例1，不同的是步骤3中以4-环己基苯酚代替苯酚，得到目标产物D16—(E)-4-环己基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率81％，淡黄色固体。熔点：109-111℃。
1H NMR(600MHz,CDCl3):δ8.20(d,J＝16.0Hz,1H),7.47(d,J＝8.2Hz,2H),7.32(d,J＝16.0Hz,1H),7.22(d,J＝7.9Hz,2H),7.08(d,J＝8.1Hz,2H),6.93(d,J＝16.0Hz,1H),6.90(d,J＝8.0Hz,2H),6.72(m,2H),6.44(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),2.51(m,1H),1.92-1.80(m,4H),1.40(s,4H),1.26(s,2H).13C NMR(151MHz,CDCl3):δ166.82(s),161.60(s),160.74(s),159.60(s),148.93(s),145.22(s),141.69(s),140.18(s),132.16(s),129.74(s),128.07(s),127.57(s),124.81(s),121.33(s),119.56(s),114.96(s),114.16(s),103.53(s),97.57(s),77.21(s),77.00 (s),76.79(s),55.62(s),55.44(s),55.31(s),44.00(s),34.50(s),26.86(s),26.11(s).MS(EI):499.3(C32H34O5,[M+H]+).Anal.Calcd for C32H34O5:C,77.08；H,6.87；O,16.04％.Found:C,70.07；H,6.85；O,16.08％.
实施例17：(E)-萘-1-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D17)
Figure BDA0001280551210000141
本实施例的制备方法同实施例1，不同的是步骤3中以萘酚代替苯酚，得到目标产物D17—(E)-萘-1-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率72％，黄色油状物。
1H NMR(600MHz,CDCl3):δ8.36(d,J＝16.0Hz,1H),7.99(d,J＝7.8Hz,1H),7.88(d,J＝7.9Hz,1H),7.75(d,J＝8.2Hz,1H),7.50(s,5H),7.38(d,J＝12.8Hz,1H),7.36(d,J＝4.2Hz,1H),6.97(d,J＝16.0Hz,1H),6.92(d,J＝18.6Hz,3H),6.76(s,1H),6.48(s,1H),3.95(s,3H),3.91(s,3H),3.81(s,3H).13C NMR(151MHz,CDCl3):δ166.66(s),161.80(s),160.94(s),159.66(s),146.98(s),141.95(s),140.79(s),134.62(s),132.36(s),129.74(s),128.06(s),127.90(s),127.10(s),126.27(s),126.25(s),125.62(s),125.43(s),124.80(s),121.48(s),118.94(s),118.15(s),114.89(s),114.19(s),103.72(s),97.62(s),55.64(s),55.44(s),55.28(s).MS(EI):467.2(C30H26O5,[M+H]+).Anal.Calcd forC30H26O5:C,77.24；H,5.62；O,17.15％.Found:C,77.23；H,5.60；O,17.17％.
实施例18：(E)-萘-2-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D18)
Figure BDA0001280551210000142
本实施例的制备方法同实施例1，不同的是步骤3中以2-萘酚代替苯酚，得到目标产物D18—(E)-萘-2-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率70％，淡黄色固体，熔点：120-122℃。
1H NMR(600MHz,CDCl3):δ8.27(d,J＝16.0Hz,1H),7.86(t,J＝8.9Hz,2H),7.82(d,J＝7.9Hz,1H),7.66(s,1H),7.48(m,4H),7.35(d,J＝5.9Hz,1H),7.33(s,1H),6.95(d,J＝16.0Hz,1H),6.91(d,J＝8.3Hz,2H),6.78(d,J＝16.0Hz,1H),6.74(s,1H),6.46(s,1H),3.93(s,3H),3.91(s,3H),3.82(s,3H).13C NMR(151MHz,CDCl3):δ166.77(s),161.73(s),160.84(s),159.67(s),148.77 (s),141.84(s),140.54(s),133.82(s),132.30(s),131.34(s),129.76(s),129.18(s),128.09(s),127.71(s),127.63(s),126.37(s),125.46(s),124.83(s),121.48(s),119.35(s),118.58(s),114.97(s),114.21(s),103.70(s),97.62(s),55.64(s),55.44(s),55.30(s).MS(EI):467.2(C30H26O5,[M+H]+).Anal.Calcd forC30H26O5:C,77.24；H,5.62；O,17.15％.Found:C,77.21；H,5.61；O,17.18％.
实施例19：(E)-[1,1'-联苯]-2-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D19)
Figure BDA0001280551210000151
本实施例的制备方法同实施例1，不同的是步骤3中以2-苯基苯酚代替苯酚，得到目标产物D19—(E)-[1,1'-联苯]-2-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率68％，黄色固体，熔点：50-52℃。
1H NMR(600MHz,CDCl3):δ8.07(d,J＝16.0Hz,1H),7.47(d,J＝7.4Hz,2H),7.44(d,J＝7.5Hz,2H),7.40(d,J＝8.8Hz,3H),7.35(t,J＝7.6Hz,2H),7.32(d,J＝7.4Hz,1H),7.29(s,1H),7.24(d,J＝7.9Hz,1H),7.19(d,J＝16.0Hz,1H),6.93-6.86(m,3H),6.69(d,J＝1.8Hz,1H),6.53(d,J＝16.0Hz,1H),6.41(d,J＝1.8Hz,1H),3.89(s,3H),3.87(s,3H),3.83(s,3H).13C NMR(151MHz,CDCl3):δ169.14(s),162.29(s),144.30(s),142.96(s),140.34(s),137.47(s),134.72(s),133.47(s),131.64(s),131.01(s),130.82(s),130.70(s),129.92(s),128.67(s),127.50(s),125.87(s),121.98(s),117.68(s),116.85(s),106.26(s),100.25(s),58.27(s),58.10(s),57.99(s).MS(EI):493.2(C32H28O5,[M+H]+).Anal.Calcd for C32H28O5:C,78.03；H,5.73；O,16.24％.Found:C,77.99；H,5.75；O,16.26％.
实施例20：(E)-[1,1'-联苯]-3-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D20)
Figure BDA0001280551210000152
本实施例的制备方法同实施例1，不同的是步骤3中以3-苯基苯酚代替苯酚，得到目标产物D20—(E)-[1,1'-联苯]-3-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率76％，黄色固体，熔点：50-52℃。
1H NMR(600MHz,CDCl3):δ8.25(d,J＝16.0Hz,1H),7.60(d,J＝7.7Hz,2H),7.47(s,7H),7.36(d,J＝7.1Hz,2H),7.33(d,J＝15.9Hz,1H),7.18(d,J＝3.5Hz,1H),6.95(d,J＝16.0Hz,1H),6.91(d,J＝8.5Hz,2H),6.75(d,J＝16.0Hz,2H),6.45(s,1H),3.92(s,3H),3.90(s,3H),3.82(s,3H).13C NMR(151MHz,CDCl3):δ166.61(s),161.72(s),160.82(s),159.67(s),151.48(s),142.66(s),141.82(s),140.51(s),140.31(s),132.31(s),129.76(s),129.55(s),128.72(s),128.09(s),127.52(s),127.17(s),124.83(s),124.24(s),120.55(s),120.53(s),119.34(s),114.95(s),114.21(s),103.70(s),97.62(s),55.64(s),55.44(s),55.31(s).MS(EI):493.2(C32H28O5,[M+H]+).Anal.Calcd for C32H28O5:C,78.03；H,5.73；O,16.24％.Found:C,78.00；H,5.75；O,16.25％.
实施例21：(E)-[1,1'-联苯]-4-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D21)
Figure BDA0001280551210000161
本实施例的制备方法同实施例1，不同的是步骤3中以4-苯基苯酚代替苯酚，得到目标产物D21—(E)-[1,1'-联苯]-4-基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率68％，白色固体，熔点：99-102℃。
1H NMR(600MHz,CDCl3):δ8.25(d,J＝16.0Hz,1H),7.61(d,J＝8.5Hz,2H),7.59(d,J＝8.2Hz,2H),7.48(d,J＝8.5Hz,2H),7.45(t,J＝7.3Hz,2H),7.34(dd,J＝15.0,10.4Hz,2H),7.26(d,J＝7.3Hz,2H),6.95(d,J＝16.0Hz,1H),6.91(d,J＝8.5Hz,2H),6.75(d,J＝14.7Hz,2H),6.46(s,1H),3.92(s,3H),3.91(s,3H),3.83(s,3H).13C NMR(151MHz,CDCl3):δ166.65(s),161.73(s),160.83(s),159.67(s),150.53(s),141.82(s),140.53(s),138.59(s),132.29(s),129.76(s),128.73(s),128.08(s),128.02(s),127.20(s),127.08(s),124.82(s),122.01(s),119.29(s),114.94(s),114.21(s),103.69(s),97.61(s),77.21(s),77.00(s),76.79(s),55.64(s),55.44(s),55.31(s).MS(EI):493.2(C32H28O5,[M+H]+).Anal.Calcd for C32H28O5:C,78.03；H,5.73；O,16.24％.Found:C,78.06；H,5.73；O,16.21％.
实施例22：(E)-2-苯甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D22)
Figure BDA0001280551210000171
本实施例的制备方法同实施例1，不同的是步骤3中以2-苄基苯酚代替苯酚，得到目标产物D22—(E)-2-苯甲基苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率73％，黄色油状物。
1H NMR(600MHz,CDCl3):δ8.20(d,J＝16.0Hz,1H),7.45(d,J＝8.5Hz,2H),7.30(d,J＝16.0Hz,1H),7.24(d,J＝7.4Hz,3H),7.19(d,J＝7.2Hz,6H),6.94(d,J＝16.0Hz,1H),6.87(d,J＝8.5Hz,2H),6.73(s,2H),6.45(s,1H),3.95(s,2H),3.91(d,J＝3.8Hz,6H),3.82(s,3H).13C NMR(151MHz,CDCl3):δ166.36(s),161.68(s),160.79(s),159.60(s),149.17(s),141.76(s),140.45(s),139.91(s),133.33(s),132.22(s),130.59(s),129.69(s),129.04(s),128.35(s),128.04(s),127.27(s),126.05(s),125.81(s),124.79(s),122.55(s),119.15(s),114.88(s),114.16(s),103.58(s),97.57(s),55.61(s),55.44(s),55.30(s),36.17(s).MS(EI):507.2(C33H30O5,[M+H]+).Anal.Calcd for C33H30O5:C,78.24；H,5.97；O,15.79％.Found:C,78.23；H,5.96；O,15.81％.
实施例23：(E)-4-(2-苯丙烷-2-基)苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯(D23)
Figure BDA0001280551210000172
本实施例的制备方法同实施例1，不同的是步骤3中以4-(2-苯丙烷-2-基)苯酚代替苯酚，得到目标产物D23—(E)-4-(2-苯丙烷-2-基)苯基-3-(2,4-二甲氧基-6-((E)-4-苯乙烯基)苯基)丙烯酸酯，产率64％，黄色油状物。
1H NMR(600MHz,CDCl3):δ8.20(d,J＝16.0Hz,1H),7.47(d,J＝8.4Hz,2H),7.32(d,J＝16.0Hz,1H),7.29(d,J＝7.9Hz,1H),7.26(dd,J＝9.3,8.0Hz,5H),7.18(dd,J＝9.7,4.2Hz,1H),7.08(d,J＝8.5Hz,2H),6.94(d,J＝16.0Hz,1H),6.91(d,J＝8.4Hz,2H),6.73(s,1H),6.71(d,J＝16.0Hz,1H),6.45(s,1H),3.91(s,3H),3.90(s,3H),3.83(s,3H),1.70(s,6H).13C NMR(151MHz, CDCl3):δ166.68(s),161.66(s),160.77(s),159.64(s),150.43(s),148.86(s),147.79(s),141.73(s),140.26(s),132.20(s),129.77(s),128.06(s),127.99(s),127.69(s),126.77(s),125.64(s),124.82(s),121.02(s),119.50(s),114.97(s),114.19(s),103.62(s),97.60(s),55.62(s),55.42(s),55.31(s),42.68(s),30.83(s).MS(EI):535.3(C35H34O5,[M+H]+).Anal.Calcd for C35H34O5:C,78.63；H,6.41；O,14.96％.Found:C,78.70；H,6.39；O,14.91％.
实施例24：白藜芦醇丙烯酸酚酯类衍生物对LPS刺激的RAW264.7释放NO的影响
以LPS刺激小鼠RAW 264.7细胞为炎症细胞模型，采用Griess法测定细胞上清液中NO含量，检测了白藜芦醇丙烯酸酚酯类衍生物对LPS刺激的RAW264.7释放NO的影响。
取对数生长期的细胞以7×104个/孔接种于24孔板中，培养24h。实验共分3分组，弃去原先培养基。空白对照组用500μL新培养基培养细胞，LPS刺激组同样加入500μL新培养基，给药组加入含有40μM化合物的培养基500μL。1h后，LPS刺激组和给药组均给予0.5μLLPS刺激，空白对照组不加LPS。干预24h后,收集各孔细胞上清液，用Griess法检测并计算NO细胞浓度
如图2所示，给予1μg/mL LPS刺激后细胞释放的NO的量剧增(与control相比，###p<0.001)。40μM浓度下，除化合物D7、D11、D19和D22外，大多数白藜芦醇丙烯酸酚酯衍生物均能够不同程度抑制NO的释放(与LPS相比，*P<0.05，**P<0.01，***P<0.001)。对所合成的白藜芦醇丙烯酸酚酯衍生物初步进行构效关系讨论，结果如下：比较化合物D1-11、D13，在苯环邻、间、对位分别引入甲基等疏水性基团，在对位引入有利于抑制NO释放，相反，在间位引入不利于抑制NO释放。观察化合物D12，在间位引入N,N-二甲基使得抑制NO释放能力有所提升。比较化合物D4、D14，实验结果表明，在对位引入不饱和脂肪链也能抑制NO释放。化合物D15引入氧杂环结构，能够极显著抑制NO释放。比较化合物D16-23，实验证实，引入萘环以及联苯等大基团使得抑制NO释放能力有所降低，化合物D17、D18、D23仍对NO释放有着较高的抑制活性。然而，与LPS组相比，化合物D19、D22实验组中NO含量几乎无差异。
实施例25：化合物D15细胞毒性测定
培养细胞至对数期，收集细胞，稀释至8×104个/mL，每孔加入100μL(8000个细胞)接种在96孔板上，每个样品设5×3孔，同时设置空白孔和阴性对照孔，边缘孔用等量PBS溶液填充。置37℃、5％CO2培养箱培养过夜。第二天加入含有药物的新鲜培养基100μL，待测样品浓度依次为100、50、25、12.5μM。1h后，加入LPS，使得每孔LPS浓度为1μg/mL。24h后，观察化合物作用情况，加入20μL MTT溶液(5mg/mL)，37℃、5％CO2继续培养4h。弃去上清，每孔加入150μL DMSO，摇床快速摇匀10min，在酶标仪492nm处测量各孔的吸光度值。结果如图3所示
不同浓度化合物D15与LPS共同作用24h后，与对照组相比，存活率无显著差异。实验证明，在有效的抗炎浓度范围内化合物D15没有细胞毒性。
实施例26：不同浓度化合物D15对LPS刺激的RAW264.7释放NO的影响
选取D15为有效化合物，进一步考察不同浓度(10μM、20μM、40μM)对细胞释放NO的影响，结果如图3所示。化合物D15对LPS诱导RAW 264.7细胞产生NO都具有很好的抑制作用(与LPS相比，*P<0.05，**P<0.01，***P<0.001)，且一定范围内，随着药物浓度的升高其抑制NO释放的程度越高。

Claims (5)

1.一种白藜芦醇丙烯酸酚酯类衍生物，其特征在于其结构由如下通式(1)表示：
Figure FDA0002440149890000011
其中R选自
Figure FDA0002440149890000012
Figure FDA0002440149890000013
2.一种权利要求1所述的白藜芦醇丙烯酸酚酯类衍生物的制备方法，其特征在于包括如下步骤：
步骤1：向N,N-二甲基甲酰胺中加入白藜芦醇三甲醚(A)，然后于冰水浴中缓慢滴加三氯氧磷，滴完后升温至室温反应1h，反应结束后将反应液滴加至冰水与乙酸乙酯的混合溶液中，再分次加入碳酸钠固体直至无气泡产生，搅拌8-12h后析出淡黄色固体，抽滤、干燥，最后柱层析分离得到中间体B—(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯甲醛；白藜芦醇三甲醚与三氯氧磷的摩尔比为1:1；
步骤2：向圆底烧瓶中加入中间体B和丙二酸，再加入吡啶和六氢吡啶，95℃下回流反应，TLC检测至原料反应完全，反应4h；反应结束后，将反应液滴加至加有冰块的盐酸溶液中，室温下搅拌2h，析出黄色固体，抽滤，干燥，柱层析分离，得到中间体C—(E)-2,4-二甲氧基-6-(4-甲氧基苯乙烯)苯丙烯酸；中间体B和丙二酸的摩尔比为1:3；
步骤3：向圆底烧瓶中加入中间体C，用二氯甲烷溶解，再加入取代芳香酚、二环己基碳二亚胺以及二甲氨基吡啶，室温下反应2h，反应结束后加水洗涤，萃取，有机相旋蒸，柱层析分离，得目标产物D1-23；中间体C、取代芳香酚、二环己基碳二亚胺和二甲氨基吡啶的摩尔比为10:11:12:1。
3.根据权利要求2所述的制备方法，其特征在于：
步骤1中，冰水与乙酸乙酯的混合溶液中冰水与乙酸乙酯的体积比为5:1。
4.根据权利要求2所述的制备方法，其特征在于：
步骤2中，六氢吡啶的用量为每毫摩尔中间体B加0.1mL，吡啶的用量为每毫摩尔中间体B加1.5mL。
5.一种权利要求1所述的白藜芦醇丙烯酸酚酯类衍生物的用途，其特征在于：
所述白藜芦醇丙烯酸酚酯类衍生物在制备抗炎药物中的应用；所述抗炎药物用于抑制LPS刺激的RAW264.7释放NO。
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