CN103936754A - 一种苯并吡喃类化合物及其制备方法与应用 - Google Patents
一种苯并吡喃类化合物及其制备方法与应用 Download PDFInfo
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- CN103936754A CN103936754A CN201410130657.XA CN201410130657A CN103936754A CN 103936754 A CN103936754 A CN 103936754A CN 201410130657 A CN201410130657 A CN 201410130657A CN 103936754 A CN103936754 A CN 103936754A
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- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- Chemical & Material Sciences (AREA)
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Abstract
本发明公开一种苯并吡喃类化合物及其制备方法与应用。所述苯并吡喃类化合物具有不同程度的氧化应激损伤保护作用，可以有效减少H2O2诱导人脐静脉内皮细胞损伤引起的膜电位降低幅度，是一类潜在的保护心脑血管药物。同时本发明设计合理，操作简便，为心脑血管疾病药物提供了新的活性成分。
Description
技术领域
本发明属于天然产物合成与改性领域，具体涉及一种苯并吡喃类化合物及其制备方法与应用。
背景技术
心脑血管疾病是一种严重威胁人类，特别是50岁以上中老年人健康的常见病。具有“发病率高、致残率高、死亡率高、复发率高、并发症多”等特点。2012年，中国心脑血管病死亡已占总死亡构成的41%，每年有2000万人死亡与心脑血管疾病有关。心脑血管疾病已成为人类死亡病因最高的头号杀手，让人胆战心惊！因此，寻找活性好、无毒或毒性低、高耐受性的心脑血管药物成为新药研究的一项重要课题。
Xyloketals类化合物是林永成研究小组于2001年从南海海洋真菌Xylaria sp. (#2508)分离出来的一系列结构珍奇的缩酮类化合物，具有珍奇结构的苯并吡喃并呋喃结构片段，于当年发表在著名杂志J. Org. Chem.上。活性研究表明，这一类苯并吡喃类化合物显示较强的L-钙离子通道抑制活性（0.2 μg/ml，抑制率60 %），以及良好的乙酰胆碱酯酶抑制活性。特别是近年来研究发现，拥有此类结构的代表化合物Xyloketal B具有很强的抗氧化应激作用，同时具有显著的AngⅡ、H2O--2和oxo-LDL诱发的血管内皮细胞（HUVECs）损伤保护作用、抗炎及促NO生成特性，且显示出极低的毒性。因此此类具有特异的苯并吡喃类化合物作为一种低毒、高效、多靶点活性额新型结构药物，对进一步深入研究其构效关系和筛选更适用于临床的衍生物将具有重要意义。
目前，虽然苯并吡喃类化合物具有一定的体内抗氧化活性，但是它有多个手型中心，其的合成路线长、收率低，不能满足各种测试实验的需求。
发明内容
本发明的目的在于公开一种苯并吡喃类化合物。
本发明的另一目的，在于公开一种苯并吡喃类化合物的制备方法。
本发明还有一个目的，在于公开一种苯并吡喃类化合物的应用。
本发明的上述目的通过如下技术方案予以实现：
一种苯并吡喃类化合物，具有以下结构式：
。
优选地，所述苯并吡喃类化合物的结构式为：
。
本发明所述苯并吡喃类化合物的制备方法，具体如下：
所述化合物1~11的制备方法为：Xyloketal B羧酸与相应胺类化合物或氨基酸甲酯盐酸盐，以及苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、N,N-二异丙基乙胺反应制得目标化合物。
。
以化合物1为例，本发明化合物1的制备方法具体为：
Xyloketal B羧酸与对乙胺基苯酚Bop、DIEA反应制得目标化合物1。更具体的步骤为Xyloketal B羧酸与对乙胺基苯酚溶于DMF中，加入Bop和DIEA反应过夜，在冰水浴条件下加入氯化铵饱和溶液终止反应，乙酸乙酯萃取，洗涤，干燥，减压浓缩，硅胶柱层析得目标化合物1。
所述化合物12~27的制备方法为：Xyloketal B与相应胺类化合物、甲醛反应制得目标化合物。
或。
以化合物12为例，本发明化合物12的制备方法具体为：
Xyloketal B与甲胺、甲醛反应制得目标化合物12。更具体的步骤为Xyloketal B溶于THF中，加入甲胺、甲醛反应，TLC跟踪反应，加入水终止反应，乙酸乙酯萃取，洗涤，干燥，减压浓缩，硅胶柱层析得目标化合物12。
本发明所述Xyloketal B或Xyloketal B羧酸可以参照文献的方法制备，如Zhongliang Xu, Yiying Li, Qi Xiang, Zhong Pei, Xilin Liu, Ling Chen, Guanlei Wang, Bingtai Lu, Jiyan Pang, and Yongcheng Lin, Design and Synthesis of Novel Xyloketal Derivatives and Their Vasorelaxing Activities in Rat Thoracic Aorta and Vascular Proliferation Activities in Zebrafish Angiogenesis Screen, J. Med. Chem., 2010, Online, DOI: 10.1021/jm1001502 (IF: 4.9). (第二章，第四章)。
一种药物组合物，以本发明所述苯并吡喃类化合物为活性成分，含有一种或多种药学上可接受的载体。
通过实验测试可知，本发明所述苯并吡喃类化合物对H2O2诱导人脐静脉内皮细胞（HUVECs）氧化应激损伤显示不同程度的保护活性，其活性与化合物的结构有关；JC-1膜电位检测表明，可以有效减少H2O2诱导人脐静脉内皮细胞（HUVECs）氧化应激损伤引起的膜电位降低幅度，因而其在制备治疗或预防H2O2诱导人脐静脉内皮细胞损伤药物中有很大的应用前景。
测试结果还显示出本发明所述苯并吡喃类化合物是一类潜在的心脑血管药物，具有很好的应用前景。
与现有技术相比，本发明具有如下有益效果：
（1）本发明设计合成了一系列的全新化合物，对苯并吡喃类化合物进行了初步的构效关系研究，寻找出了活性必要的结构片段，从中优选出一组有发展前景的化合物，
（2）本发明设计合理，操作简便，收率较高。
（3）本发明对苯并吡喃类化合物进行抗氧化保护活性研究：对H2O2诱导人脐静脉内皮细胞（HUVECs）损伤的保护活性与化合物的构效关系进行讨论，结果显示，目标化合物具有不同程度的氧化应激损伤保护作用；JC-1膜电位检测表明，筛选出比先导化合物更好的氧化应激损伤保护作用的化合物，可以有效减少H2O2诱导人脐静脉内皮细胞（HUVECs）损伤引起的膜电位降低幅度，具有很好的应用前景。
附图说明
图1 为苯并吡喃类化合物22~23对HUVECs细胞线粒体膜电位测试结果示意图。
具体实施方式
下面结合具体实施例对本发明作进一步的解释说明，但具体实施例并不对本发明作任何限定。除非特别说明，实施例中所涉及的试剂、方法均为本领域常用的试剂和方法。
本发明实施例所述Xyloketal B或Xyloketal B羧酸参照以下文献的方法制备：
Zhongliang Xu, Yiying Li, Qi Xiang, Zhong Pei, Xilin Liu, Ling Chen, Guanlei Wang, Bingtai Lu, Jiyan Pang, and Yongcheng Lin, Design and Synthesis of Novel Xyloketal Derivatives and Their Vasorelaxing Activities in Rat Thoracic Aorta and Vascular Proliferation Activities in Zebrafish Angiogenesis Screen, J. Med. Chem., 2010, Online, DOI: 10.1021/jm1001502 (IF: 4.9) (第二章，第四章)。
具体步骤如下：
（1）2, 4-二甲基-3-三氯乙酰基-4, 5-二氢呋喃的合成
称取3.0 g (0.031 mol) 2, 4-二甲基-4, 5-二氢呋喃，溶于10 mL二氯甲烷，将4.9 g (0.062 mol)吡啶加入到上述溶液中，在170℃下搅拌回流，然后将10.2 g (0.056 mol)三氯乙酰氯溶10 mL二氯甲烷，170℃下缓慢滴加进体系，约10~20 min滴加完毕，再反应40 min停止反应。用水溶解所生成的盐，200 mL乙酸乙酯萃取，再依次用饱和碳酸氢钠溶液、水和饱和氯化钠溶液洗涤有机层一次，每次15 mL，无水Na2SO4干燥。过滤浓缩，硅胶柱层析 (石油醚) 得到淡黄色透明液体3.4 g，产率45.3%。1HNMR (300 MHz, CDCl3) δ 1.295 (d, J = 6.6Hz, 3H), 2.299 (s, 3H), 3.582 (m, 1H), 4.192 (d, J = 9.0 Hz 1H), 4.472 (d, J = 8.7 Hz, 1H)。
（2）2,4-二甲基-4,5-二氢呋喃-3-甲酸甲酯的合成
称取 2, 4-二甲基-3-三氯乙酰基-4, 5-二氢呋喃1.0 g (4.16 mmol）溶于25 mL甲醇，再加入0.13 g (1.58 mmol）碳酸氢钠，加热回流3 h。反应完毕后，减压除去甲醇，加入20 mL乙醚溶解，再依次用水和饱和氯化钠溶液洗一次，每次5 mL，无水MgSO4 干燥。过滤浓缩得淡黄色透明液体0.63 g，产率97%。1HNMR(300 MHz, CDCl3) δ 1.81 (d, J = 6.0Hz, 3H), 2.183 (s, 3H), 3.220 (m, 1H), 3.711 (s,3H), 3.990 (m, 1H), 4.444 (t, J = 9.0 Hz, 1H)。
（3）2, 4-二甲基-3-羟甲基-4, 5-二氢呋喃的合成
称取 115 mg (3 mmol) LiAlH4 加入到6 mL无水乙醚中，置于0 ℃下搅拌。称取149 mg (0.96 mmol) 2, 4-二甲基-4, 5-二氢呋喃-3-甲酸甲酯溶于6 mL 乙醚，滴加到上述溶液中，15 min后移置室温下反应5 h。反应停止后，冰浴冷却，向体系中缓慢滴加冰水至无气体产生，以除去过量的LiAlH4。再加入3滴2 mol·L-1 NaOH 溶液，过滤，用20 mL 乙醚分几次洗涤滤渣，合并滤液，分别用水和饱和氯化钠溶液洗一次，每次各5 mL，无水MgSO4 干燥。过滤浓缩得淡黄色透明液体0.118 mg，产率 96 %。由于该化合物及其不稳定，未经处理直接用于下一步。
（4）Xyloketal B的合成：
称取215 mg (1.68 mmol) 2,4-二甲基-3-羟甲基-4,5-二氢呋喃溶于4 mL 乙醚，置于0 ℃下搅拌。加入140 mg 无水MgSO4 和70 mg (0.56 mmol)间苯三酚于上述体系中，加入BF3·Et2O 106.4 mg (0.56 mmol)，反应30 min。过滤，用10 mL乙醚洗涤滤渣，滤液用水洗涤三次，每次5 mL，无水MgSO4 干燥。过滤浓缩，硅胶柱层析得到白色固体270 mg，产率93%。1HNMR(CDCl3, 400 MHz) δ 6.210 (s, 1H), 4.203 (t, J =8.0 Hz, 1H), 4.152 (t, J =8.0 Hz, 1H), 3.546 (t, J = 8.0 Hz, 1H), 3.484 (t, J = 8.0 Hz, 1H), 2.881 (dt, J=1.2, 5.6 Hz, 1H), 2.838 (dt, J=1.2, 5.6 Hz, 1H), 2.722 (m, 1H), 2.602 (dt, J = 5.6, 17.2 Hz, 1H), 2.151 (m, 2H), 1.922 (m, 2H), 1.541 (s, 3H), 1.519 (s, 3H), 1.072 (d, J=6.8 Hz, 3H), 1.027 (d, J = 6.8 Hz, 3H). 13CNMR (CDCl3) δ 153.49, 151.99, 151.62, 107.93, 107.67, 98.61, 98.58, 96.08, 73.97, 73.87, 47.98, 47.55, 35.50, 35.37, 23.45, 23.07, 18.69, 16.09, 15.78. HREIMS m/z 346.1776 (calculated for C20H26O5, 346.1775)。
（5）Xyloketal B甲酸的合成
称取215 mg (1.68 mmol) 2,4-二甲基-3-羟甲基-4,5-二氢呋喃溶于4 mL乙醚，置于0 ℃下搅拌。称取140 mg无水MgSO4 加入到上述溶液中，将95.2 mg (0.56 mmol) 2,4,6-三羟基苯甲酸的乙醚溶液滴入上述体系中，加入BF3·Et2O 106.4 mg (0.56 mmol)，反应30 min。过滤，用10 mL乙醚洗涤滤渣，滤液用水洗涤三次，每次5 mL，无水MgSO4干燥。过滤浓缩，硅胶柱层析得到白色固体187.7 mg，产率84.2 %。mp 159-160oC. 1HNMR (CDCl3, 400 MHz) δ 11.462 (s, 1H), 4.124(m,2H), 3.511 (t, J = 8.5 Hz, 2H), 2.827 (m, 2H), 2.600 (m, 2H), 2.028(m, 2H), 1.922(m,2H), 1.533 (s, 3H), 1.470 (s, 3H), 1.025(s, 6H); 13C NMR (CDCl3): 171.08, 161.37,156.59, 151.19, 111.40, 108.66, 99.68, 98.09, 93.92, 74.54, 74.07, 47.41, 46.89,35.08, 34.95, 22.81, 22.50, 18.14, 17.96, 15.62, 15.51; HREIMS m/z 390.1672(calculated for C21H26O7, 390.1673)。
实施例1：Xyloketal B酰胺类衍生物的制备（化合物1~8）：
称取Xyloketal B羧酸50 mg（0.13 mmol）和相应胺类化合物0.2 mmol于50ml圆底瓶中，然后加入DMF 10 ml，搅拌溶解，加入Bop 80mg（0.2 mmol）和DIEA 0.40 ml(2.0 mmol)，室温下搅拌，反应过夜。在冰水浴下加入氯化铵的饱和溶液10 ml，终止反应。用乙酸乙酯萃取三次，每次25 ml。合并有机层，依次用10 ml饱和NH4Cl，饱和NaCl溶液10 ml洗涤各一次，加入无水MgSO4干燥，减压浓缩，硅胶柱层析得相应目标产物。
化合物1：胺类化合物原料为对乙胺基苯酚，产率72％，浅黄色固体。1HNMR (400 MHz,CDCl3 ) δ 8.56 (s, 1H), 7.08 (d, J = 8.4 Hz,2H), 6.76 (d, J = 8.5 Hz,2H), 6.19 (s,1H), 4.20 – 4.04 (m,2H), 3.69 – 3.58 (m,2H), 3.56 – 3.45 (m,2H), 2.93 – 2.77 (m,4H), 2.72 – 2.50 (m,2H), 2.10 – 2.01 (m,2H), 1.96 – 1.84 (m,2H), 1.50 (s,3H), 1.44 (s,3H), 1.06 (d, J = 6.6 Hz,3H), 1.03 (d, J = 6.5 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 170.61, 161.50, 154.68, 154.62, 151.34, 130.72, 129.83, 115.48, 109.76, 109.55, 108.44, 108.32, 99.55, 97.90, 96.72, 74.31, 74.23, 47.62, 47.37, 40.87, 35.46, 35.29, 34.55, 23.02, 22.83, 18.53, 18.35, 15.98, 15.86. HREIMS m/z 509.2404 (calculated for C29H35NO7 509.2414)。
化合物2：胺类化合物原料为对氟苯胺，产率75％，白色固体。1HNMR (400 MHz,CDCl3 ) δ 10.59 (s,1H), 7.57 (d, J = 8.8 Hz,2H), 7.03 (d, J = 8.6 Hz,2H), 4.23 – 4.11 (m,2H), 3.56 (dd, J = 14.4, 8.3 Hz,2H), 3.00 – 2.83 (m,2H), 2.76 – 2.55 (m,2H), 2.20 – 2.06 (m,2H), 2.02 – 1.88 (m,2H), 1.61 (s,3H), 1.53 (s,3H), 1.09 (d, J = 5.9 Hz,3H), 1.07 (d, J = 6.5 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 168.78, 161.96, 160.64, 158.22, 155.31, 150.93, 134.00, 122.44, 115.52, 110.57, 110.31, 108.43, 99.96, 98.40, 96.85, 74.63, 74.25, 47.84, 47.29, 35.68, 35.27, 23.51, 23.02, 18.61, 18.31, 15.89, 15.87. HREIMS m/z 483.2057 (calculated for C27H30FNO6 483.2057)。
化合物3：胺类化合物原料为对甲氧基苯胺，产率73％，白色固体。1HNMR (400 MHz,CDCl3 ) δ 10.49 (s,1H), 7.51 (d, J = 8.9 Hz,2H), 6.90 (d, J = 9.0 Hz,2H), 4.18 (dd, J = 14.5, 8.4 Hz,2H), 3.81 (s,3H), 3.56 (t, J = 8.4 Hz,2H), 2.99 – 2.82 (m,2H), 2.74 – 2.58 (m,2H), 2.16 – 2.05 (m,2H), 2.02 – 1.93 (m,2H), 1.60 (s,3H), 1.53 (s,3H), 1.08 (d, J = 6.2 Hz,3H), 1.07 (d, J = 6.6 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 168.62, 161.91, 156.51, 155.08, 151.00, 131.05, 122.56, 114.24, 110.42, 110.17, 108.50, 108.36, 99.89, 98.53, 97.03, 74.55, 74.24, 55.54,47.77, 47.32, 35.77, 35.28, 23.14, 22.79, 18.75, 18.34, 16.05, 15.91. HREIMS m/z 495.2251 (calculated for C28H33NO7 495.2257)。
化合物4：胺类化合物原料为半胱胺，产率73％，白色固体。1HNMR (400 MHz,CDCl3 ) δ 8.84 (s，1H), 4.21 – 4.13 (m,2H), 3.82 – 3.68 (m,2H), 3.57 – 3.48 (m,2H), 2.96 – 2.80 (m,4H), 2.70 – 2.56 (m,2H), 2.13 – 2.03 (m,2H), 1.97 – 1.90 (m,2H), 1.67 (s,1H), 1.55 (s,3H), 1.51 (s,3H), 1.07 (d, J = 6.3 Hz,3H), 1.04 (d, J = 6.3 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 170.72, 161.59, 154.98, 151.45, 109.66, 108.27, 99.47, 97.80, 96.64, 74.42, 74.22, 47.65, 47.33, 38.06, 37.76, 35.62, 35.25, 23.22, 22.93, 18.60, 18.31, 16.04, 15.90. HREIMS m/z 449.1869 (calculated for C23H31NO6S 449.1872)。
化合物5：胺类化合物原料为N,N-二甲基乙二胺，产率70％，白色固体。1HNMR (400 MHz,CDCl3 ) δ 8.94 (s,1H), 4.17 (t, J = 8.2 Hz,2H), 3.75 – 3.65 (m,2H), 3.52 (dd, J = 18.1, 9.3 Hz,2H), 3.27 (t, J = 5.4 Hz,2H), 2.91 (s,6H), 2.82 (dd, J = 17.3, 8.8 Hz,2H), 2.60 – 2.49 (m,2H), 2.10 – 2.01 (m,2H), 1.96 – 1.88 (m,2H), 1.53 (s,3H), 1.50 (s,3H), 1.06 (d, J = 6.9 Hz,3H), 1.02 (d, J = 6.1 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 172.26, 161.34, 155.71, 151.49, 110.03, 108.58, 99.59, 98.46, 95.89, 74.37, 74.18, 59.20, 47.46, 47.18, 44.18, 36.69, 36.01, 35.40, 23.04, 22.75, 18.36, 18.25, 15.95, 15.81, 15.68. HREIMS m/z 460.2563 (calculated for C25H36N2O6 460.2573)。
化合物6：胺类化合物原料为噻吩乙胺，产率76％，白色固体。1HNMR (400 MHz,CDCl3 ) δ 8.66 (s，1H), 7.14 (d, J = 5.1 Hz,1H), 6.95 – 6.88 (m,2H), 4.25 – 3.98 (m,2H), 3.85 – 3.63 (m,2H), 3.63 – 3.42 (m,2H), 3.13 (t, J = 6.7 Hz,2H), 2.96 – 2.76 (m,2H), 2.71 – 2.53 (m,2H), 2.12 – 2.01 (m,2H), 1.97 – 1.86 (m,2H), 1.51 (s,3H), 1.42 (s,3H), 1.07 (d, J = 6.7 Hz,3H), 1.03 (d, J = 6.4 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 170.67, 161.65, 154.67, 151.35, 141.59, 126.94, 125.34, 123.73, 109.46, 108.37, 99.45, 97.56, 96.64, 74.34, 74.21, 47.56, 47.34, 40.70, 35.53, 35.26, 29.80, 22.97, 22.68, 18.67, 18.38, 16.06, 15.91. HREIMS m/z 499.2025 (calculated for C27H33NO6S 499.2029)。
化合物7：胺类化合物原料为对氯苯甲胺，产率71％，浅黄色固体。1HNMR (400 MHz,CDCl3 ) δ 8.93 (s,1H), 7.28 (d, J = 3.2 Hz,4H), 4.59 (d, J = 5.7 Hz,2H), 4.20 – 4.04 (m,2H), 3.59 – 3.43 (m,2H), 2.95 – 2.80 (m,2H), 2.74 – 2.54 (m,2H), 2.08 (dd, J = 13.9, 7.2 Hz,2H), 1.96 – 1.90 (m,2H), 1.51 (s,3H), 1.50 (s,3H), 1.07 (d, J = 4.4 Hz,3H), 1.05 (d, J = 4.2 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 170.58, 161.60, 155.01, 154.83, 151.40, 137.06, 132.93, 128.71, 128.54, 110.05, 109.83, 108.47, 99.70, 98.34, 96.68, 74.41, 74.20, 47.78, 47.37, 42.32, 35.72, 35.29, 23.07, 22.78, 18.69, 18.33, 16.04, 15.89；HREIMS m/z 513.1907 (calculated for C28H32ClNO6 513.1918)。
化合物8：胺类化合物原料为间氨基苯甲酰胺，产率78％，白色固体。1HNMR (400 MHz,CDCl3 ) δ 10.75 (s，1H), 8.19 (s,1H), 7.66 (d, J = 30.9 Hz,2H), 7.45 (dd, J = 26.4, 18.5 Hz,1H), 4.19 (dd, J = 19.6, 8.3 Hz,2H), 3.61 – 3.51 (m,2H), 2.97 – 2.84 (m,2H), 2.73 – 2.60 (m,2H), 2.18 – 2.08 (m,2H), 2.03 – 1.96 (m,2H), 1.62 (s,3H), 1.53 (s,3H), 1.09 (d, J = 6.1 Hz,3H), 1.07 (d, J = 7.1 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 169.10, 169.05, 162.01, 155.52, 150.98, 138.32, 134.37, 129.29, 124.14, 123.39, 119.47, 110.47, 108.49, 100.00, 98.57, 96.83, 74.67, 74.26, 47.86, 47.29, 35.76, 35.26, 23.23, 23.03, 18.71, 18.37, 16.04, 15.97.HREIMS m/z 508.2201 (calculated for C28H32N2O7 508.2210)。
实施例2：Xyloketal B氨基酸甲酯的制备：
称取Xyloketal B羧酸50 mg（0.13 mmol）和相应氨基酸甲酯盐酸盐0.2 mmol于50 ml圆底瓶中，然后加入DMF 10 ml，搅拌溶解，加入Bop 80mg（0.2 mmol）和DIEA 0.40 ml(2.0 mmol)，室温下搅拌，反应过夜。在冰水浴下加入氯化铵的饱和溶液10 ml，终止反应。用乙酸乙酯萃取三次，每次25 ml。合并有机层，依次用10 ml饱和NH4Cl，饱和NaCl溶液10 ml洗涤各一次，加入无水MgSO4干燥，减压浓缩，硅胶柱层析得相应目标产物。
化合物9：氨基酸甲酯盐酸盐原料为酪氨酸甲酯盐酸盐，产率75％，浅黄色固体。1HNMR (400 MHz,CDCl3 ) δ 9.01（s，1H）7.04 (d, J = 8.0 Hz,2H), 6.71 (d, J = 7.8 Hz,2H), 4.95 – 4.87 (m,1H), 4.22 – 3.97 (m,2H), 3.72 (s,3H), 3.61 – 3.44 (m,2H), 3.26 – 3.14 (m,1H), 3.04 (dd, J = 14.1, 7.0 Hz,1H), 2.95 – 2.77 (m,2H), 2.72 – 2.51 (m,2H), 2.17 – 2.02 (m,2H), 1.99 – 1.85 (m,2H), 1.51 (s,3H), 1.39 (s,3H), 1.06 (d, J = 6.6 Hz,3H), 0.98 (d, J = 6.7 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 171.99, 170.10, 161.58, 154.98, 154.82, 151.63, 130.48, 128.23, 115.46, 109.82, 109.59, 108.44, 108.33, 99.34, 97.83, 96.40, 74.25, 74.09, 54.13, 52.29, 47.56, 47.29, 37.24, 35.23, 23.04, 22.79, 19.16, 18.72, 18.30, 16.16, 15.99； HREIMS m/z 567.2465(calculated for C31H37NO9 567.2468)。
化合物10：氨基酸甲酯盐酸盐原料为甘氨酸甲酯盐酸盐，产率78％，浅黄色固体。1HNMR (400 MHz,CDCl3 ) δ 9.03（s，1H） 4.28 – 4.17 (m,2H), 4.17 – 4.11 (m,2H), 3.78 (s,3H), 3.52 (dd, J = 20.2, 8.4 Hz,2H), 2.85 (dd, J = 25.0, 15.8 Hz,2H), 2.61 (dd, J = 28.4, 13.5 Hz,2H), 2.17 – 2.02 (m,2H), 2.00 – 1.88 (m,2H), 1.60 (s,3H), 1.50 (s,3H), 1.06 (d, J = 6.4 Hz,3H), 1.04 (d, J = 6.6 Hz,3H). 13CNMR (101 MHz, CDCl3 ) δ 170.57, 170.12, 161.48, 154.93, 151.52, 109.75, 108.40, 99.66, 98.28, 96.51, 74.41, 74.17, 52.28, 47.76, 47.27, 41.31, 35.70, 35.22, 22.96, 22.75, 18.60, 18.30, 16.04, 15.85; HREIMS m/z 461.2043(calculated for C24H31NO8 461.2050)。
化合物11：氨基酸甲酯盐酸盐原料为缬氨酸甲酯盐酸盐，产率76％，白色固体。1HNMR (400 MHz,CDCl3 ) δ 9.17（s，1H），4.65 (t, J = 12.5 Hz，1H), 4.25 – 4.08 (m，2H), 3.77 (s，3H), 3.57 (t, J = 11.0 Hz，2H), 2.90 (dd, J = 17.3, 12.9 Hz，2H), 2.74 – 2.57 (m，2H), 2.39 – 2.25 (m，1H), 2.22 – 2.07 (m，2H), 2.05 – 1.91 (m，2H), 1.62 (s,3H), 1.54 (s, 3H), 1.09 (d, J = 6.5 Hz，6H), 1.04 (d, J = 2.4 Hz，6H). 13CNMR (101 MHz, CDCl3 ) δ 172.19, 170.47, 161.57, 154.90, 151.53, 109.73, 108.42, 99.49, 98.22, 96.62, 77.02, 74.37, 74.26, 57.23, 52.04, 47.53, 47.33, 35.27, 30.92, 23.20，23.01, 22.76, 19.22, 18.66, 18.36, 17.54, 16.23, 15.88；HREIMS m/z 503.2515(calculated for C27H37NO8 503.2519)。
实施例3：Xyloketal B衍生物的合成（化合物12~24）
称取Xyloketal B 50 mg（0.144 mmol），溶于10 mL的四氢呋喃（THF）中，加入相应胺类化合物0.288 mmol，搅拌均匀后滴加甲醛溶液2滴，室温下继续搅拌，TLC跟踪反应，1 h后反应完全。加入水终止反应，200 mL乙酸乙酯萃取，有机层以20 mL饱和盐水洗涤一次，无水硫酸镁干燥，过滤浓缩，硅胶柱层析得到相应目标物。
化合物12：胺类化合物原料为甲胺，产率89.3 %，浅黄色固体，m.p. 109-110 ℃。1HNMR (400 MHz,CDCl3 ) δ 4.664 (s, 2H), 4.137 (m, 2H), 3.758 (s, 2H), 3.497 (t, J = 8.4 Hz, 2H), 2.794 (dt, J = 17.2 5.2 Hz, 2H), 2.609 (d, J = 17.2 Hz, 2H), 2.533 (s, 3H), 2.084 (m, 2H), 1.858 (m, 2H), 1.471 (s, 6H), 1.036 (d, J = 6.4 Hz, 6H); 13CNMR (125 MHz, CDCl3): 150.135, 149.505, 148.875, 107.257, 107.145, 100.010, 98.731, 98.127, 83.580, 73.851, 47.338, 47.474, 40.035, 35.425, 35.326, 22.981, 22.723, 18.731, 18.390, 16.079, 15.991; HREIMS m/z 401.2196 (calculated for C23H31O5N1, 401.2197)。
化合物13：胺类化合物原料为丁胺，产率92.8 %，黄色固体，m.p. 106-107 ℃。1HNMR (400 MHz,CDCl3 ) δ 4.768 (s, 2H), 4.164 (apparent t, J = 8.4 Hz, 2H), 3.824 (s, 2H), 3.522 (apparent t, J = 8.4 Hz, 2H), 2.805 (m, 2H), 2.690 (t, J = 17.2 Hz, 2H), 2.636 (m, 2H), 2.128 (m, 2H), 1.882 (m, 2H), 1.549 (m, 2H), 1.492 (s, 3H), 1.482 (s, 3H), 1.368 (m, 2H), 1.062 (d, J = 6.4 Hz, 6H), 0.925 (t, J = 7.6 Hz, 3H); 13CNMR (125 MHz, CDCl3): 150.756, 149.409, 148.953, 107.337, 107.248, 100.499, 98.723, 98.259, 82.681, 73.963, 51.642, 47.597, 47.519, 45.917, 35.552, 35.447, 30.293, 23.062, 22.798, 20.488, 18.854, 18.506, 16.081, 16.005, 14.051; HREIMS m/z 443.2665 (calculated for C26H37O5N1, 443.2666)。
化合物14：胺类化合物原料为二甘醇胺，产率72.2 %，白色固体，m.p.128-129 ℃。1HNMR (400 MHz,CDCl3 ) δ 4.824 (s, 2H), 4.147 (m, 2H), 3.899 (s, 2H), 3.733 (t, J = 5.2 Hz, 2H), 3.689 (t, J = 5.2 Hz, 2H), 3.611 (t, J = 5.2 Hz, 2H), 3.528 (m, 2H), 2.958 (m, 2H), 2.805 (m, 2H), 2.623 (apparent t, J = 17.2 Hz, 2H), 2.119 (m, 2H), 1.888 (m, 2H), 1.501 (s, 3H), 1.479 (s, 3H), 1.066 (d, J = 6.4 Hz, 6H); 13CNMR (125 MHz, CDCl3) : 150.552, 149.685, 148.982, 107.393, 107.220, 99.932, 99.018, 98.313, 82.663, 73.916, 72.396, 69.212, 61.700, 51.590, 47.584, 47.421, 46.053, 35.519, 35.370, 23.028, 22.758, 18.761, 18.377, 16.014, 15.919; HREIMS m/z 475.2563 (calculated for C26H37O7N1, 475.2565)。
化合物15：胺类化合物原料为对氟苯胺，产率87.2%，黄色固体，m.p. 136-137 ℃。1HNMR (400 MHz,CDCl3 ) δ 7.077 (d, J = 9.2 Hz, 2H), 6.955 (d, J = 9.2 Hz, 1H), 6.931 (d, J = 9.2 Hz, 1H), 5.247 (s, 2H), 4.423 (s, 2H), 4.151 (apparent t, J = 8.0 Hz, 2H), 3.497 (t, J = 8.0 Hz, 2H), 2.798 (t, J = 17.2 Hz, 2H), 2.682 (m, 2H), 2.096 (m, 2H), 1.870 (m, 2H), 1.486 (s, 6H), 1.056 (d, J = 6.8 Hz, 3H), 1.029 (d, J = 6.8 Hz, 3H); 13CNMR (125 MHz, CDCl3): 159.242, 156.059, 150.850, 149.896, 148.282, 144.965, 144.817, 119.782, 119.556, 115.624, 115.349, 107.464, 107.286, 100.848, 99.143, 98.643, 79.526, 73.949, 70.389, 47.551, 46.990, 35.502, 35.393, 23.047, 22.771, 18.762, 18.419, 16.028; HREIMS m/z 481.2259 (calculated for C28H32O5N1F1, 481.2259)。
化合物16：胺类化合物原料为对氯苯胺，产率78.8 %，淡黄色固体，m.p. 122-123 ℃。1HNMR (400 MHz,CDCl3 ) δ 7.202 (d, J = 8.4 Hz, 2H), 7.030 (d, J = 8.4 Hz, 2H), 5.267 (s, 2H), 4.439 (s, 2H), 4.153 (apparent t, J = 8.4 Hz, 2H), 3.520 (t, J = 8.4 Hz, 2H), 2.799 (t, J = 17.2 Hz, 2H), 2.625 (m, 2H), 2.076 (m, 2H), 1.873 (m, 2H), 1.486 (s, 6H), 1.473 (s, 3H), 1.054 (d, J = 6.8 Hz, 3H), 1.028 (d, J = 6.8 Hz, 3H); 13CNMR (125 MHz, CDCl3) : 150.840, 149.969, 149.812, 148.347, 147.089, 128.908, 125.558, 118.851, 107.520, 107.326, 100..822, 99.241, 98.677, 78.730, 73.984, 47.562, 47.409, 46.542, 35.404, 23.050, 22.784, 18.707, 18.431, 16.046; HREIMS m/z 497.1965 (calculated for C28H32O5N1Cl1, 497.1964)。
化合物17：胺类化合物原料为对溴苯胺，产率87.8 %，淡黄色固体，m.p. 113-114 ℃。1HNMR (400 MHz,CDCl3 ) δ 7.340 (d, J = 9.2 Hz, 2H), 6.980 (d, J = 9.2 Hz, 2H), 5.266 (s, 2H), 4.437 (s, 2H), 4.153 (apparent t, J = 8.0 Hz, 2H), 3.516 (t, J = 8.0 Hz, 2H), 2.795 (t, J = 17.2 Hz, 2H), 2.624 (m, 2H), 2.090 (m, 2H), 1.873 (m, 2H), 1.480 (s, 6H), 1.053 (d, J = 6.8 Hz, 3H), 1.027 (d, J = 6.8 Hz, 3H); 13CNMR (125 MHz, CDCl3) : 150.820, 149.967, 149.809, 148.330, 147.513, 131.816, 119.210, 112.890, 107.516, 107.319, 100.794, 99.246, 98.669, 78.563, 73.973, 47.558, 47.400, 46.449, 35.507, 35.394, 23.048, 22.794, 18.701, 18.461, 16.043, 15.939; HREIMS m/z 541.1455 (calculated for C28H32O5N1Br1, 541.1458)。
化合物18：胺类化合物原料为对碘苯胺，产率85.7 %，黄色固体，m.p. 109-110 ℃。1HNMR (400 MHz,CDCl3 ) δ 7.503 (d, J = 8.8 Hz, 2H), 6.855 (d, J = 8.8 Hz, 2H), 5.247 (s, 2H), 4.416 (s, 2H), 4.134 (apparent t, J = 8.4 Hz, 2H), 3.501 (t, J = 8.4 Hz, 2H), 2.774 (t, J = 17.2 Hz, 2H), 2.603 (m, 2H), 2.054 (m, 2H), 1.852 (m, 2H), 1.460 (s, 6H), 1.034 (d, J = 6.8 Hz, 3H), 1.010 (d, J = 6.8 Hz, 3H); 13CNMR (125 MHz, CDCl3) : 150.825, 149.979, 149.824, 148.340, 148.144, 137.760, 119.620, 107.527, 107.322, 100.825, 99.255, 98.672, 82.753, 78.364, 73.993, 47.553, 47.393, 46.322, 35.397, 23.062, 22.777, 18.694, 18.423, 16.058, 15.945; HREIMS m/z 589.1312 (calculated for C28H32O5N1I1, 589.1320)。
化合物19：胺类化合物原料为苯胺，产率93.1 %，黄色固体，m.p. 105-106 ℃。1HNMR (400 MHz,CDCl3 ) δ 7.251 (t, J = 8.8 Hz, 2H), 7.104 (d, J = 8.8 Hz, 1H), 6.888 (t, J = 8.0 Hz, 1H), 5.303 (s, 2H), 4.468 (s, 2H), 4.140 (apparent q, J = 8.0 Hz, 2H), 3.494 (apparent q, J = 8.0 Hz, 2H), 2.799 (t, J = 17.2 Hz, 2H), 2.616 (m, 2H), 2.089 (m, 2H), 1.860 (m, 2H), 1.480 (s, 3H), 1.462 (s, 3H), 1.042 (d, J = 6.4 Hz, 3H), 1.018 (d, J = 6.4 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 151.056, 149.865, 148.385, 148.385, 129.033, 120.593, 117.513, 107.465, 107.293, 101.232, 99.053, 96.661, 78.840, 73.993, 47.590, 47.463, 46.348, 35.411, 23.048, 22.755, 18.810, 18.734, 18.507, 16.061, 15.978; HREIMS m/z 463.2352 (calculated for C28H33O5N1, 463.2353)。
化合物20：胺类化合物原料为对羟基苯胺，产率85.2 %，黄色固体，m.p. 112-113 ℃。1HNMR (400 MHz,CDCl3 ) δ 6.999 (d, J = 8.8 Hz, 2H), 6.748 (d, J = 8.8 Hz, 2H), 5.205 (s, 2H), 4.371 (s, 2H), 4.148 (apparent t, J = 8.0 Hz, 2H), 3.511 (t, J = 8.0 Hz, 2H), 2.794 (t, J = 17.2 Hz, 2H), 2.627 (m, 2H), 2.108 (m, 2H), 1.879 (m, 2H), 1.478 (s, 6H), 1.046 (d, J = 6.4 Hz, 3H), 1.018 (d, J = 6.4 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 150.917, 150.788, 149.739, 148.240, 142.184, 120.166, 115.770, 109.649, 107.536, 107.362, 101.204, 99.007, 98.764, 80.239, 73.987, 47.539, 47.471, 47.074, 35.394, 23.086, 22.845, 18.693, 18.425, 16.294, 15.987; HREIMS m/z 479.2308 (calculated for C28H33O6N1, 479.2309)。
化合物21：胺类化合物原料为对甲氧基苯胺，产率89.3 %，淡黄色固体，m.p. 129-130 ℃。1HNMR (400 MHz,CDCl3 ) δ 7.015 (d, J = 9.2 Hz, 2H), 6.785 (d, J = 9.2 Hz, 2H), 5.213 (s, 2H), 4.380 (s, 2H), 4.130 (apparent t, J = 8.0 Hz, 2H), 3.734 (s, 3H), 3.494 (t, J = 8.0 Hz, 2H), 2.787 (t, J = 17.2 Hz, 2H), 2.612 (m, 2H), 2.077 (m, 2H), 1.843 (m, 2H), 1.519 (s, 3H), 1.460 (s, 3H), 1.033 (d, J = 6.8 Hz, 3H), 1.006 (d, J = 6.8 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 154.332, 150.960, 149.836, 148.385, 142.552, 119.871, 114.351, 107.432, 107.283, 101.140, 98.992, 98.627, 80.109, 73.997, 55.536, 47.597, 47.496, 47.036, 35.432, 23.068, 22.797, 18.748, 18.471, 16.084, 15.984; HREIMS m/z 493.2458 (calculated for C29H35O6N1, 493.2459)。
化合物22：胺类化合物原料为对硝基苯胺，产率82.6 %，白色固体，m.p. 172-173 ℃。1HNMR (400 MHz,CDCl3 ) δ 8.146 (d, J = 9.2 Hz, 2H), 7.060 (d, J = 9.2 Hz, 2H), 5.375 (s, 2H), 4.560 (s, 2H), 4.170 (apparent t, J = 8.0 Hz, 2H), 3.522 (m, 2H), 2.820 (t, J = 17.2 Hz, 2H), 2.652 (m, 2H), 2.083 (m, 2H), 1.906 (m, 2H), 1.517 (s, 3H), 1.491 (s, 3H), 1.063 (d, J = 6.8 Hz, 3H), 1.042 (d, J = 6.8 Hz, 3H); 13CNMR (CDCl3 , 125 MHz): 153.002, 150.904, 150.471, 150.311, 148.563, 139.932, 125.742, 114.467, 107.816, 107.640, 100.472, 99.986, 99.855, 98.998, 76.576, 73.975, 47.570, 47.378, 45.492, 35.463, 35.344, 23.028, 22.780, 18.638, 18.340, 15.992, 15.868; HREIMS m/z 508.2205 (calculated for C28H32O7N2, 508.2204)。
化合物23：胺类化合物原料为对氨基苯甲酸，产率88.4 %，淡黄色固体，m.p. 132-133 ℃。1HNMR (400 MHz,CDCl3 ) δ 8.013 (d, J = 8.8 Hz, 2H), 7.089 (d, J = 8.8 Hz, 2H), 5.371 (s, 2H), 4.544 (s, 2H), 4.162 (apparent t, J = 8.0 Hz, 2H), 3.519 (t, J = 8.0 Hz, 2H), 2.812 (t, J = 17.2 Hz, 2H), 2.638 (m, 2H), 2.091 (m, 2H), 1.890 (m, 2H), 1.515 (s, 3H), 1.482 (s, 3H), 1.058 (d, J = 6.8 Hz, 3H), 1.036 (d, J = 6.8 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 171.513, 152.214, 150.864, 149.972, 148.259, 131..829, 120.052, 114.941, 107.546, 107.408, 100.826, 99.383, 98.682, 73.971, 47.391, 47.218, 45.533, 35.299, 22.968, 22.712, 18.715, 18.394, 16.016, 15.953; HREIMS m/z 507.2253 (calculated for C29H33O7N1, 507.2252)。
化合物24：胺类化合物原料为乙醇胺，产率78.6 %，淡黄色固体，m.p. 114-115 ℃。1HNMR (400 MHz,CDCl3 ) δ 4.805 (s, 2H), 4.160 (apparent t, J = 8.4 Hz, 2H), 3.860 (s, 2H), 3.689 (t, J = 5.2 Hz, 2H), 3.507 (m, 2H), 2.913 (t, J = 5.2 Hz, 2H), 2.828 (m, 2H), 2.629 (apparent t, J = 17.2 Hz, 2H), 2.123 (m, 2H), 1.882 (m, 2H), 1.494 (s, 3H), 1.478 (s, 3H), 1.066 (d, J = 6.4 Hz, 3H), 1.038 (d, J = 6.4 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 150.556, 149.642, 148.835, 107.279, 99.913, 98.827, 98.212, 82.793, 73.906, 59.023, 53.779, 47.369, 47.267, 45.397, 35.311, 22.930, 22.676, 18.636, 18.381, 15.956; HREIMS m/z 431.2301 (calculated for C24H33O6N1, 431.2302)。
实施例4：Xyloketal B衍生物的合成（化合物25~27）
称取Xyloketal B 50 mg（0.144 mmol），溶于10 mL的四氢呋喃（THF）中，加入相应胺类化合物0.288 mmol，搅拌均匀后滴加甲醛溶液2滴，室温下继续搅拌，TLC跟踪反应，1 h后反应完全。加入水终止反应，200 mL乙酸乙酯萃取，有机层以20 mL饱和盐水洗涤一次，无水硫酸镁干燥，过滤浓缩，硅胶柱层析得到相应目标物。
化合物25：胺类化合物原料为六氢吡啶，产率84.7 %，淡黄色固体，m.p. 120-121 ℃。1HNMR (CDCl3 , 400 MHz) δ 4.120 (m, 2H), 3.709 (s, 2H), 3.458 (apparent q, J = 8.8 Hz, 2H), 2.808 (t, J = 17.2 Hz, 2H), 2.640 (m, 2H), 2.579 (m, 4H), 2.075 (m, 2H), 1.862 (m, 2H), 1.619 (m, 6H), 1.483 (s, 3H), 1.435 (s, 3H), 1.065 (d, J = 8.4 Hz, 3H), 1.023 (d, J = 8.4 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 155.490, 150.357, 149.529, 107.581, 107.345, 100.427, 98.501, 97.789, 73.917, 54.715, 53.716, 47.933, 35.820, 35.496, 25.855, 24.043, 23.211, 22.857, 19.022, 18.752, 16.136; HREIMS m/z 443.2664 (calculated for C26H37O5N1, 443.2666)。
化合物26：胺类化合物原料为吗啡啉，产率80.6 %，白色固体，m.p. 126-127 ℃。1HNMR (400 MHz,CDCl3 ) δ 4.092 (m, 2H), 3.745 (m, 4H), 3.712 (s, 2H), 3.449 (apparent q, J = 8.8 Hz, 2H), 2.778 (t, J = 17.2 Hz, 2H), 2.638 (m, 2H), 2.549 (m, 4H), 2.092 (m, 2H), 1.840 (m, 2H), 1.471 (s, 3H), 1.433 (s, 3H), 1.033 (d, J = 8.4 Hz, 3H), 0.997 (d, J = 8.4 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 155.187, 150.843, 150.034, 108.004, 107.770, 100.046, 98.838, 98.595, 74.267, 67.169, 54.624, 53.110, 48.199, 47.978, 36.162, 35.822, 23.524, 23.162, 19.357, 19.034, 16.547, 16.448; HREIMS m/z 445.2458 (calculated for C25H35O6N1, 445.2459)。
化合物27：胺类化合物原料为二乙胺，产率80.6 %，产率80.5 %，白色固体，m.p. 126-127 ℃。1HNMR (400 MHz,CDCl3 ) δ 4.151 (m, 2H), 3.780 (s, 2H), 3.498 (m, 2H), 2.828 (m, 2H), 2.674 (m, 2H), 2.613 (m, 4H), 2.102 (m, 2H), 1.876 (m, 2H), 1.506 (s, 6H), 1.085 (d, J = 6.8 Hz, 3H), 1.040 (d, J = 6.8 Hz, 3H); 13CNMR (CDCl3, 125 MHz): 155.761, 150.294, 149.379, 107.456, 107.325, 100.765, 98.423, 97.501, 73.939, 49.368, 47.627, 46.313, 35.719, 35.468, 23.139, 22.836, 18.704, 16.077, 11.212; HREIMS m/z 431.2668 (calculated for C25H37O5N1, 431.2666)。
实施例5：对H
2
O
2
诱导人脐静脉内皮细胞（HUVECs）损伤的保护作用
实验材料：人脐静脉内皮细胞（HUVECs）株，胎牛血清（FBS），杭州四季青生物材料工程研究所；高糖DMEM培养基，Gibco；二甲基亚砜（DMSO）；过氧化氢（H2O2），广州化学试剂厂；噻唑蓝（MTT）；96孔板，Corning；全波长多功能酶标仪，Thermo。
实验方法：HUVECs细胞以高糖DMEM加10% FBS以及1%双抗与38℃恒温培养箱培养。取对数生长期细胞，以6×104/mL细胞浓度接种于96孔板中，每孔100 μL，被试细胞分为阴性对照组、加药组及模型组(H2O2)。加药组设置10 μM和1 μM两个浓度，每组3个复孔，首先用上述1~27号化合物孵育HUVECs细胞30 min，后加入含H2O2的培养基使H2O2终浓度为800 μM H2O2，继续孵育20 h。孵育结束后每孔加入10μL的MTT溶液（5 mg/mL），继续培养4 h，弃上清，每孔加入150 μL的DMSO，酶标仪使用双波长模式（570 nm, 630 nm）测量每孔的OD值并计算细胞的存活率。
实验结果：正常的人脐静脉内皮细胞（HUVECs）呈典型的“鹅卵石”铺路石形态，经过H2O2处理20 h，细胞活性显著降低，细胞发生皱缩、变圆以及形成细胞碎片，而实验发现上述的药物对于H2O2诱导的人脐静脉内皮细胞氧化应激损伤起到不同程度的保护作用，与双氧水组细胞的存活率比较，大部分的给药组的细胞的存活率有了不同程度的上升，其中，22、23、26、27号化合物有着很好的活性。
通过控制加入H2O2的终浓度控制模型组(H2O2)存活率为50%，空白组存活率为100%，给药组的细胞存活率以给药组的OD值与空白组的OD值相对百分比(%)来表示：
表1 苯并吡喃类化合物对H2O2诱导人脐静脉内皮细胞（HUVECs）损伤的保护作用
a. 给药浓度为10 μM和1 μM的细胞存活率以其OD值与空白组OD值进行比较所得的相对百分比(%)来表示，其中，模型组（H2O2）存活率控制为50%。
b. 每个活性试验重复三次并给出平均值。统计学处理由计算机运用SPSS 13.0 软件进行, 组间差异比较用方差分析, P < 0.05表示差异有统计学意义。
实施例6： JC-1线粒体膜电位检测试
实验材料：人脐静脉内皮细胞（HUVECs）株，线粒体膜电位检测试剂盒(JC-1)，碧云天；六孔板，Corning；胎牛血清（FBS），杭州四季青生物材料工程研究所；高糖DMEM培养基，Gibco；BD FACS Calibur流式细胞仪。
实验化合物：
通过上述MTT法挑选出以下化合物开展进一步细胞线粒体膜电位测定：
。
实验方法：取对数生长期细胞，以2.5×105/mL细胞浓度接种于6孔板中，每孔2mL，被试细胞分为阴性对照组组、加药组及模型组(H2O2)。加药组设置25和10μM两个浓度，，首先用上述化合物孵育HUVECs细胞30 min，后加入终浓度为700μM浓度H2O2的培养基，继续孵育20 h。孵育结束后用胰酶消化收集细胞，用PBS调整细胞浓度至5×105/mL，加入终浓度为10μg/mL的JC-1染色液，放置于细胞培养箱中37℃孵育20 min。孵育结束后，600 g 4℃离心3~4 min，再用JC-1染色缓冲液洗涤细胞，重悬。用FACS Calibur流式细胞仪，测定JC-1多聚体及单体的荧光发射强度，每个样本采集10000个细胞，数据用Flowjo软件进行分析，计算JC-1多聚体荧光/单体荧光强度。
实验结果：
细胞凋亡是细胞对所处环境中的某些特定信息的一种应答反应, 贯穿于全部细胞活动中。线粒体是促进能量转换, 参与细胞凋亡的重要细胞器。在细胞凋亡过程中，线粒体膜电位发生变化。实验结果表明，加入H2O2能有效使HUVECs细胞的线粒体膜电位降低，显示该细胞很可能处于细胞凋亡早起。而加入上述化合物预孵后，能有效减少细胞膜电位降低的幅度，说明以上2种化合物对H2O2引起的细胞损伤起到很好的保护作用。
每个活性试验重复三次并给出平均值。统计学处理由计算机运用SPSS 13.0 软件进行，组间差异比较用方差分析, P < 0.05表示差异有统计学意义。
测试结果如图1所示，从图中可以看出，所选的2个化合物均对H2O2诱导人脐静脉内皮细胞（HUVECs）损伤引起的细胞膜电位下降起到减少降低幅度的作用。
实施例5~6的结果有力地证明了，本发明所制得的苯并吡喃类化合物对H2O2诱导人脐静脉内皮细胞（HUVECs）氧化应激损伤有显著的保护活性，可以有效减少H2O2诱导人脐静脉内皮细胞（HUVECs）氧化应激损伤引起的膜电位降低幅度，在制备治疗或预防H2O2诱导人脐静脉内皮细胞损伤药物及制备心脑血管药物中具有很好的应用前景。
Claims (7)
1.一种苯并吡喃类化合物，其特征在于，具有以下结构式：
。
2. 根据权利要求1所述苯并吡喃类化合物，其特征在于，所述苯并吡喃类化合物的结构式为：
。
3. 权利要求1所述苯并吡喃类化合物的制备方法，其特征在于，所述化合物1~11的制备方法为：Xyloketal B羧酸与相应胺类化合物或氨基酸甲酯盐酸盐，以及苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、N,N-二异丙基乙胺反应制得目标化合物。
4. 权利要求1所述苯并吡喃类化合物的制备方法，其特征在于，所述化合物12~27的制备方法为：Xyloketal B与相应胺类化合物、甲醛反应制得目标化合物。
5. 一种药物组合物，其特征在于，以权利要求1或2所述的化合物为活性成分，含有一种或多种药学上可接受的载体。
6. 权利要求1或2所述苯并吡喃类化合物在制备治疗或预防H2O2诱导人脐静脉内皮细胞损伤药物中的应用。
7. 权利要求1或2所述苯并吡喃类化合物在制备心脑血管药物中的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945410A (zh) * | 2015-05-22 | 2015-09-30 | 济南新斯诺生物技术有限公司 | 一种不对称催化合成四氢呋喃[2,3-b]苯并吡喃或四氢吡喃[2,3-b]苯并吡喃的方法 |
| CN108434132A (zh) * | 2018-01-30 | 2018-08-24 | 中山大学 | 苯并吡喃并呋喃类化合物在制备调控热休克转录因子药物中的应用 |
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| CN101723960A (zh) * | 2009-12-18 | 2010-06-09 | 中山大学 | 苯并吡喃并呋喃化合物及其制备方法与应用 |
| CN102702221A (zh) * | 2012-06-04 | 2012-10-03 | 中山大学 | Xyloketal B 类似物及其制备方法和应用 |
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| CN101723960A (zh) * | 2009-12-18 | 2010-06-09 | 中山大学 | 苯并吡喃并呋喃化合物及其制备方法与应用 |
| CN102702221A (zh) * | 2012-06-04 | 2012-10-03 | 中山大学 | Xyloketal B 类似物及其制备方法和应用 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945410A (zh) * | 2015-05-22 | 2015-09-30 | 济南新斯诺生物技术有限公司 | 一种不对称催化合成四氢呋喃[2,3-b]苯并吡喃或四氢吡喃[2,3-b]苯并吡喃的方法 |
| CN104945410B (zh) * | 2015-05-22 | 2017-03-15 | 济南新斯诺生物技术有限公司 | 一种不对称催化合成四氢呋喃[2,3‑b]苯并吡喃或四氢吡喃[2,3‑b]苯并吡喃的方法 |
| CN108434132A (zh) * | 2018-01-30 | 2018-08-24 | 中山大学 | 苯并吡喃并呋喃类化合物在制备调控热休克转录因子药物中的应用 |
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