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CN111635389B - 一种用于成像和治疗的过氧化氢响应性化合物及其合成方法 - Google Patents

一种用于成像和治疗的过氧化氢响应性化合物及其合成方法 Download PDF

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CN111635389B
CN111635389B CN202010378023.1A CN202010378023A CN111635389B CN 111635389 B CN111635389 B CN 111635389B CN 202010378023 A CN202010378023 A CN 202010378023A CN 111635389 B CN111635389 B CN 111635389B
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张建祥
闫新豪
郭嘉伟
吴鹏
李兰兰
窦寅
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Army Medical University
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Abstract

本发明公开了一种用于成像和治疗的过氧化氢响应性化合物及其合成方法。该响应性化合物的化学结构如下图所示。本发明还提供了该类过氧化氢响应性化合物的合成方法：将单羟基化合物和草酰氯在含有缚酸剂的有机溶剂中反应，即得到过氧化氢响应性化合物。该类响应性化合物的合成方法简单，易于规模化合成；且可通过不同方法制备成纳米粒，其辅助化学发光特性具有过氧化氢响应性；当单羟基化合物为小分子药物时，可得到过氧化氢响应性前体药物，用于制备炎症和氧化应激损伤相关疾病及过氧化氢高表达肿瘤防治的纳米药物；该类过氧化氢响应性化合物具有良好的体内安全性。
Figure DDA0002480953080000011

Description

一种用于成像和治疗的过氧化氢响应性化合物及其合成方法
技术领域
本发明涉及过氧化氢响应性材料领域，具体是一种具有辅助化学发光成像和治疗功能的过氧化氢响应性化合物及其合成方法。
背景技术
当受到生长因子刺激或者免疫刺激时，细胞会产生内源性过氧化氢1。过氧化氢具有亲脂性，易于穿过细胞膜，实现细胞间的扩散，作为细胞中的第二化学信使，在调节细胞增殖、分化和迁移等生理反应中起着重要作用2-3。此外，过氧化氢还参与细胞氧化还原信号传导4，调节机体正常生理功能，同时与诸多疾病的发生发展密切相关，包括血管生成、氧化应激、衰老以及肿瘤等5。在疾病过程中，过氧化氢的表达和活性影响了疾病的病理生理变化，因此，借助过氧化氢响应性材料进行疾病的诊断和治疗的研究越来越受到关注6-11。
过氧草酸酯类化学发光系统是一类以二芳基草酸酯、过氧化氢、荧光剂、溶剂为主要组成的化学发光体系12。发光机理为反应生成的中间体将化学能传递给荧光团使之跃迁至激发态，激发态再跃迁到基态发射出一定波长的光13。该发光体系主要应用在两个方面：分析化学中的检测应用和化学冷光源的研制14。过氧草酸酯类化合物是过氧化氢敏感性的小分子物质，当其与过氧化氢反应时，草酸酯键会发生断裂，生成中间及原料分子，中间体能够激发染料发光成像15，利用该响应性可以制备过氧化氢响应性疾病成像诊断材料或过氧化氢响应性药物释放材料16-18，从而应用于炎症、氧化应激损伤和肿瘤相关疾病的治疗19-22。然而，目前可用的过氧草酸酯类化合物水解后产物的体内安全性严重限制了其在疾病成像和治疗中的应用；同时，已有的过氧草酸酯类化合物仅能用于辅助化学发光成像，不具备疾病治疗功能。
发明内容
针对上述现有技术的不足，本发明的第一目的在于提供一种过氧化氢响应性化合物，具有辅助化学发光成像和治疗的功能。本发明的另一目的是提供所述过氧化氢响应性化合物的合成方法。
为了实现上述第一目的，本发明采用的技术方案是：一种过氧化氢响应性化合物，其化学结构通式如下
Figure BDA0002480953060000021
其中：
Figure BDA0002480953060000022
为了实现上述第二目的，本发明采用的技术方案是：本发明提供一种过氧化氢响应性化合物的合成方法，包括以下步骤：将单羟基化合物与缚酸剂在有机溶剂中混合，氮气保护下，在冰浴条件下向溶液中缓慢滴加草酰氯，滴加完后移除冰浴，反应2-12h，待原料反应完全后加入甲醇或乙醇淬灭反应，得到过氧化氢响应性化合物粗产物。
为了将上述粗产物进一步纯化得到终产物，本发明的合成方法中还包括以下步骤：将所述粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去多余水分，抽滤，蒸发除去其中二氯甲烷浓缩得到粗产物，用硅胶色谱柱分离提纯，即得到终产物。
进一步，所述单羟基化合物选自生育酚，艾地苯醌，喜树碱，齐多夫定，4-羟甲基苯硼酸频哪醇酯，4-羟基-2,2,6,6-四甲基哌啶氮氧化物，3-甲氧基-4-羟基苯甲醛，4-羟基苯甲醛，4-甲氧甲基苯酚，4-乙氧甲基苯酚，水杨酸戊酯，(E)-3,5-二甲氧基-4'-羟基二苯乙烯或2,4-二硝基苯酚。
进一步，所述缚酸剂选自N,N-二异丙基乙胺或三乙胺。
进一步，所述有机溶剂为二氯甲烷。
进一步，所述单羟基化合物在有机溶剂中的浓度在0.1mmol/ml到0.4mmol/ml之间。
进一步，所述单羟基化合物与草酰氯的摩尔比在1:0.5至1:1之间，所述单羟基化合物与缚酸剂的摩尔比在1:2至1:5之间。
本发明的技术方案还包括，过氧化氢响应性化合物在制备预治炎症和/或氧化应激损伤相关疾病的药物和/或成像探针中的应用。
所述炎症包括变态反应性炎症、非特异性炎症以及感染性炎症；所述的非特异性炎症包括外伤或手术引起的红肿、疼痛；感染性炎症包括细菌、细菌产物或病毒造成的炎症；变态反应性炎症包括腹膜炎、炎性肠病、关节炎、哮喘、动脉粥样硬化、非酒精性脂肪肝等炎性疾病。
所述氧化应激损伤包括急性心脏损伤、急性肺损伤、急/慢性肝损伤、急/慢性肾损伤、急/慢性肠道损伤。
其中所述过氧化氢响应性化合物的给药方式包括口服、静脉注射、皮下注射、肌肉注射，以及以上方式的任意组合。
结合上述技术方案，本发明的有益技术效果在于：
(1)所述响应性化合物合成方法简便，选择的化合物为单羟基活性化合物时，反应位点单一，即一个当量的草酰氯结合两个当量单羟基活性化合物，室温反应得到目标化合物，条件温和，易于规模化合成。
(2)所述响应性化合物具有显著且敏感的过氧化氢依赖性水解特性。
(3)所述响应性化合物可以在生理水平的活性氧存在下水解为对应的原料化合物。
(4)所述响应性化合物可通过不同方法制备为过氧化氢响应性纳米粒，其可以有效负载荧光染料，方便得到具有不同自发光波长的发光成像用纳米探针。
(5)所述响应性化合物制备的纳米粒，可以有效负载疏水纳米药物，并实现其中负载药物的过氧化氢响应性释放。
(6)当选用含羟基药物合成所述响应性化合物时，可以方便地制备过氧化氢响应性前体药物，并采用不同方法制备为过氧化氢响应性前体药物纳米粒，实现对应药物的过氧化氢响应性激活和释放。
(7)所述响应性化合物制备的纳米粒具有良好的体内安全性。
(8)当所得的响应性化合物为固体时，纯化过程中可使用重结晶除去杂质，避免使用硅胶色谱柱分离提纯，该方法易于实现工业化生产。
附图说明
图1是生育酚与草酰氯反应得到的具有过氧化氢响应性生育酚化合物在氘代氯仿中的1H NMR图谱，根据谱图确证了其结构正确性。
图2是生育酚与草酰氯反应得到的具有过氧化氢响应性生育酚化合物的质谱数据。
图3是0.5mM过氧化氢响应性生育酚化合物和0.5mM磺基罗丹明101在不同浓度过氧化氢刺激下发光强度测试；由图可见，随着过氧化氢浓度增大，发光强度增大。
图4是0.5mM过氧化氢响应性生育酚化合物和0.5mM 1-氯-9,10-二苯乙炔基蒽在不同浓度过氧化氢刺激下发光强度测试，由图可见，随着过氧化氢浓度增大，发光强度增大，具有浓度依赖性。
图5是过氧化氢响应性生育酚化合物制备的纳米粒的样品照片、粒径分布图和透射电子显微镜图，其平均粒径为188nm。
图6是过氧化氢响应性生育酚化合物包载磺基罗丹明101纳米粒对不同类型活性氧刺激发光响应性测定，由图可见，该纳米粒对过氧化氢具有选择性响应。
图7是过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒对不同浓度过氧化氢发光响应性的孔板成像图，由图可见，纳米粒发光强度随着过氧化氢浓度增大而增大，具有浓度依赖性。
图8是过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒在小鼠腹腔中性粒细胞中的孔板成像图，随中性粒细胞数目的增加，纳米粒发光强度逐渐增强，纳米粒的成像具有中性粒细胞响应性。
图9是过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒在巯基醋酸盐诱导的小鼠腹膜炎中成像功能验证。
图10是过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒在酒精诱导的小鼠肝损伤中成像功能验证。
图11是过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒在皮下肿瘤中成像功能测试。
具体实施方式
下面结合具体实施方式对本发明的发明内容作进一步的详细描述。应理解，本发明的实施例只用于说明本发明而非限制本发明，在不脱离本发明技术思想的情况下，根据本领域普通技术知识和惯用手段，做出的各种替换和变更，均应包括在本发明的范围内。
实施例1
在氮气保护下，4mmol生育酚与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次(即100mL二氯甲烷溶解粗产物，转入250mL分液漏斗，加入15mL蒸馏水洗涤3次)，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/10)洗脱得到产物(M1)1.6克，产率为86％。
实施例2
在氮气保护下，4mmol生育酚与20mmol三乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加4mmol草酰氯，滴加完后移除冰浴，25℃反应12h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/10)洗脱得到产物(M1)1.2克，产率为66％。
实施例3
在氮气保护下，4mmol生育酚与20mmol N,N-二异丙基乙胺在40mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加3mmol草酰氯，滴加完后移除冰浴，25℃反应3h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/10)洗脱得到产物(M1)1.5克，产率为83％。
实施例4
在氮气保护下，4mmol生育酚与20mmol N,N-二异丙基乙胺在10mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入乙醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/10)洗脱得到产物(M1)1.5克，产率为83％。
上述实施例1-4所合成产物M1氢核磁共振1H NMR数据：1H NMR(600MHz，CDCl3)δ(ppm)2.64(t,J＝6.0Hz,4H,CH2),2.13(s,9H,CH3),2.08(s,9H,CH3),1.86-1.77(m,4H,CH2),1.62-1.49(m,8H,CH2),1.48-1.37(m,8H,CH2),1.34-1.17(m,24H),1.16-1.12(m,6H,CH2),1.11-1.05(m,6H,CH2),0.88(s,9H,CH3),0.86(s,9H,CH3),0.85(s,6H,CH3)；Ms(ESI)m/z:938.0[M+Na]+。
所制备的M1化学结构式为：
Figure BDA0002480953060000061
实施例5
在氮气保护下，1mmol艾地苯醌与2mmol N,N-二异丙基乙胺在5mL无水二氯甲烷中混合后冰浴条件下缓慢滴加0.5mmol草酰氯，滴加完后移除冰浴，25℃反应3h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/15)洗脱得到产物(M2)0.302克，产率为83％。氢核磁共振1H NMR数据：1H NMR(600MHz，CDCl3)δ(ppm)4.27(t,J＝6.0Hz,2H,CH2),3.97(s,3H,CH3),2.44(t,J＝6.0Hz,2H,CH2),1.99(s,3H,CH3),1.72-1.70(t,J＝6.0Hz,2H,CH2),1.37-1.25(m,12H,CH2)；Ms(ESI)m/z:753.4[M+Na]+。
所制备的M2化学结构式为：
Figure BDA0002480953060000062
实施例6
在氮气保护下，1mmol喜树碱与5mmol N,N-二异丙基乙胺在5mL无水二氯甲烷中混合后冰浴条件下缓慢滴加0.5mmol草酰氯，滴加完后移除冰浴，25℃反应4h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/15)洗脱得到产物(M3)0.296克，产率为79％。氢核磁共振1H NMR数据:1H NMR(600MHz，CDCl3)δ(ppm)8.66(s,1H,Ph),8.14(d,J＝12.0Hz,1H,Ph),8.10(d,J＝12.0Hz,1H,Ph),7.83(t,J＝6.0Hz,1H,Ph),7.69(t,J＝6.0Hz,1H,Ph),6.52(s,1H,Ph),5.39(s,2H,CH2),5.25(s,2H,CH2),1.87(m,2H,CH2),0.87(t,J＝6.0Hz,3H,CH3)；Ms(ESI)m/z:751.6[M+H]+。
所制备的M3化学结构式为：
Figure BDA0002480953060000071
实施例7
在氮气保护下，1mmol齐多夫定与4mmol N,N-二异丙基乙胺在5mL无水二氯甲烷中混合后冰浴条件下缓慢滴加0.5mmol草酰氯，滴加完后移除冰浴，40℃加热回流反应4h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/15)洗脱得到产物(M4)0.212克，产率为72％。氢核磁共振1H NMR数据:Ms(ESI)m/z:589.2[M+H]+。
所制备的M4化学结构式为：
Figure BDA0002480953060000081
实施例8
在氮气保护下，4mmol 4-羟甲基苯硼酸频哪醇酯与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/15)洗脱得到产物(M5)0.918克，产率为88％。氢核磁共振1H NMR数据:
1H NMR(600MHz，CDCl3)δ(ppm)7.92(d,J＝6.0Hz,2H,Ph),7.18(d,J＝6.0Hz,2H,Ph),4.66(s,2H,CH2),1.27(s,3H,CH3)；Ms(ESI)m/z:523.4[M+H]+。
所制备的M5化学结构式为：
Figure BDA0002480953060000082
实施例9
在氮气保护下，4mmol 4-羟基-2,2,6,6-四甲基哌啶氮氧化物与12mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。浓缩得到的粗产物，过硅胶色谱柱，用乙酸乙酯/正己烷(体积比1/15)洗脱得到产物(M6)0.740克，产率为93％。氢核磁共振1H NMR数据:1H NMR(600MHz，CDCl3)δ(ppm)3.82(m,1H,CH),2.23(m,2H,CH2),1.95(m,2H,CH2),1.50(s,12H,CH3)；Ms(ESI)m/z:422.4[M+Na]+。
所制备的M6化学结构式为：
Figure BDA0002480953060000091
实施例10
在氮气保护下，4mmol 3-甲氧基-4-羟基苯甲醛与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应12h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。
Figure BDA0002480953060000092
实施例11
在氮气保护下，4mmol 4-羟基苯甲醛与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。
Figure BDA0002480953060000093
实施例12
在氮气保护下，4mmol 4-甲氧甲基苯酚与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。
Figure BDA0002480953060000101
实施例13
在氮气保护下，4mmol 4-乙氧甲基苯酚与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。
Figure BDA0002480953060000102
实施例14
在氮气保护下，4mmol水杨酸戊酯与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。
Figure BDA0002480953060000103
实施例15
在氮气保护下，4mmol(E)-3,5-二甲氧基-4'-羟基二苯乙烯(紫檀茋)与20mmolN,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。
Figure BDA0002480953060000111
实施例16
在氮气保护下，4mmol 2,4-二硝基苯酚与20mmol N,N-二异丙基乙胺在20mL无水二氯甲烷中溶解混合后冰浴条件下缓慢滴加2mmol草酰氯，滴加完后移除冰浴，25℃反应2h，用薄层色谱板监测反应进程，原料反应完全后加入甲醇淬灭反应。所得的粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷中溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去样品中多余水分，抽滤得到有机相用旋转蒸发仪除去二氯甲烷浓缩得到粗产物。
Figure BDA0002480953060000112
基于过氧化氢响应性生育酚化合物纳米粒的制备：将10mg草酸酯生育酚与4mgDSPE-PEG2000溶于1.5mL二氯甲烷溶液，加入9mL三蒸水，利用超声探头间歇超声60s，功率70％，随后室温搅拌6h得到纳米粒，旋转蒸发仪蒸除二氯甲烷，测定DLS粒径，其样品照片、粒径分布图和透射电子显微镜图如图5，其平均粒径为188nm。
过氧化氢响应性生育酚化合物包载磺基罗丹明101纳米粒的制备：将10mg草酸酯生育酚，4mg DSPE-PEG2000和1mg磺基罗丹明101溶于1.5mL二氯甲烷溶液，加入9mL三蒸水，利用超声探头间歇超声60s，功率70％，随后室温搅拌6h得到负载磺基罗丹明101纳米粒。对不同类型活性氧刺激发光响应性测定，如图6可见，该纳米粒对过氧化氢具有选择性响应发光特性。
过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒的制备：将10mg草酸酯生育酚，4mg DSPE-PEG2000和1mg 1-氯-9,10-二苯乙炔基蒽溶于1.5mL二氯甲烷溶液，加入9mL三蒸水，利用超声探头间歇超声60s，功率70％，随后室温搅拌6h得到负载1-氯-9,10-二苯乙炔基蒽纳米粒。
过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒对不同浓度过氧化氢发光响应性的孔板成像图，由图7可见，纳米粒发光强度随着过氧化氢浓度增大而增大，具有浓度依赖性。
由图8可见，过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒在小鼠腹腔中性粒细胞中的孔板成像图，随中性粒细胞数目的增加，纳米粒发光强度逐渐增强，纳米粒的成像具有中性粒细胞响应性。
由图9可见，过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒可以用于小鼠腹膜炎的成像。其中，通过小鼠腹腔注射巯基乙酸盐，成功构建腹膜炎模型9。腹腔注射300μL纳米粒(1mg/mL)后在活体成像系统验证纳米粒成像性能。由于腹腔炎症产生大量ROS，激活过氧化氢响应性纳米粒，能量转移至荧光染料，实现化学发光成像。
由图10可见，过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒可用于小鼠肝损伤成像。其中，小鼠肝损伤根据文献方法用酒精诱导构建23；之后，酒精性肝损伤小鼠尾静脉注射100μL包载1-氯-9,10-二苯乙炔基蒽纳米粒(1mg/mL),活体成像系统验证纳米粒成像性能。由于氧化应激产生大量ROS，激活过氧化氢响应性纳米粒，能量转移至荧光染料，实现化学发光成像。
由图11可见，过氧化氢响应性生育酚化合物包载1-氯-9,10-二苯乙炔基蒽纳米粒可以用于小鼠中过氧化氢高表达4T1乳腺肿瘤的成像。由于4T1肿瘤微环境含大量ROS，激活过氧化氢响应性纳米粒，能量转移至荧光染料，实现过氧化氢高表达肿瘤的化学发光成像。
参考文献
1.D'Autréaux,B.；Toledano,M.B.,ROS as signalling molecules:mechanismsthat generate specificity in ROS homeostasis.Nature Reviews Molecular CellBiology 2007,8(10),813-824.
2.Giorgio,M.；Trinei,M.；Migliaccio,E.；Pelicci,P.G.,Hydrogen peroxide:ametabolic by-product or a common mediator of ageing signals？Nature ReviewsMolecular Cell Biology 2007,8(9),722-728.
3.Kim,J.S.；Huang,T.Y.；Bokoch,G.M.,Reactive oxygen species regulate aslingshot-cofilin activation pathway.Molecular biology of the cell 2009,20(11),2650-60.
4.Niethammer,P.；Grabher,C.；Look,A.T.；Mitchison,T.J.,A tissue-scalegradient of hydrogen peroxide mediates rapid wound detection inzebrafish.Nature 2009,459(7249),996-9.
5.Finkel,T.；Holbrook,N.J.,Oxidants,oxidative stress and the biologyof ageing.Nature 2000,408(6809),239-247.
6.Wang,D.；Peng,F.；Li,J.；Qiao,Y.；Li,Q.；Liu,X.,Butyrate-inserted Ni–Tilayered double hydroxide film for H2O2-mediated tumor and bacteriakilling.Materials Today 2017,20(5),238-257.
7.Cheng,J.；Zhang,R.；Li,C.；Tao,H.；Dou,Y.；Wang,Y.；Hu,H.；Zhang,J.,ATargeting Nanotherapy for Abdominal Aortic Aneurysms.Journal of the AmericanCollege of Cardiology 2018,72(21),2591-2605.
8.Guo,J.；Li,D.；Tao,H.；Li,G.；Liu,R.；Dou,Y.；Jin,T.；Li,L.；Huang,J.；Hu,H.；Zhang,J.,Cyclodextrin-Derived Intrinsically Bioactive Nanoparticles forTreatment of Acute and Chronic Inflammatory Diseases.Advanced Materials 2019,31(46),e1904607.
9.Guo,J.；Tao,H.；Dou,Y.；Li,L.；Xu,X.；Zhang,Q.；Cheng,J.；Han,S.；Huang,J.；Li,X.；Li,X.；Zhang,J.,A myeloperoxidase-responsive and biodegradableluminescent material for real-time imaging of inflammatory diseases.MaterialsToday 2017,20(9),493-500.
10.Li,L.；Guo,J.；Wang,Y.；Xiong,X.；Tao,H.；Li,J.；Jia,Y.；Hu,H.；Zhang,J.,ABroad-Spectrum ROS-Eliminating Material for Prevention of Inflammation andDrug-Induced Organ Toxicity.Advanced Science 2018,5(10),1800781.
11.Zhang,Q.；Zhang,F.；Chen,Y.；Dou,Y.；Tao,H.；Zhang,D.；Wang,R.；Li,X.；Zhang,J.,Structure–Property Correlations of Reactive Oxygen Species-Responsive and Hydrogen Peroxide-Eliminating Materials with Anti-Oxidant andAnti-Inflammatory Activities.Chemistry of Materials 2017,29(19),8221-8238.
12.Delafresnaye,L.；Bloesser,F.R.；Kockler,K.B.；Schmitt,C.W.；Irshadeen,I.M.；Barner-Kowollik,C.,All Eyes on Visible-Light PeroxyoxalateChemiluminescence Read-Out Systems.Chemistry–A European Journal 2019,26(1),114-127.
13.Kazemi,S.Y.；Abedirad,S.M.,Effect of glutathione on peroxyoxalatechemiluminescence of hypericin as the fluorophore.Spectrochimica Acta.Part A,Molecular and Biomolecular Spectroscopy 2014,118,782-6.
14.de Paula Oliveira,L.C.；Gaubeur,I.；Dantoni,P.,Hydrazone as a newfluorophore in the peroxyoxalate chemiluminescence reaction.Journal ofLuminescence 2017,183,418-423.
15.Kockler,K.B.；Frisch,H.；Barner-Kowollik,C.,Making and BreakingChemical Bonds by Chemiluminescence.Macromolecular Rapid Communications 2018,39(21),e1800516.
16.Wu,Y.；Zhou,D.；Qi,Y.；Xie,Z.；Chen,X.；Jing,X.；Huang,Y.,Novel multi-sensitive pseudo-poly(amino acid)for effective intracellular drugdelivery.RSC Advances 2015,5(40),31972-31983.
17.Liu,C.；Zhu,X.；Wang,X.；Miao,D.；Liang,X.；Wang,C.；Pang,L.；Sun,H.；Kong,D.；Yang,J.,Hydrogen peroxide-responsive micelles self-assembled from aperoxalate ester-containing triblock copolymer.Biomaterials Science 2016,4(2),255-7.
18.Li,J.；Li,Y.；Wang,Y.；Ke,W.；Chen,W.；Wang,W.；Ge,Z.,Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy.Nano Letters 2017,17(11),6983-6990.
19.Romanyuk,A.V.；Grozdova,I.D.；Ezhov,A.A.；Melik-Nubarov,N.S.,Peroxyoxalate Chemiluminescent Reaction as a Tool for Elimination of TumourCells Under Oxidative Stress.Scientific Reports 2017,7(1),3410.
20.Jung,E.；Noh,J.；Kang,C.；Yoo,D.；Song,C.；Lee,D.,Ultrasound imagingand on-demand therapy of peripheral arterial diseases using H2O2-Activatedbubble generating anti-inflammatory polymer particles.Biomaterials 2018,179,175-185.
21.Lee,D.；Khaja,S.；Velasquez-Castano,J.C.；Dasari,M.；Sun,C.；Petros,J.；Taylor,W.R.；Murthy,N.,In vivo imaging of hydrogen peroxide withchemiluminescent nanoparticles.Nature Materials 2007,6(10),765-769.
22.Kang,C.；Cho,W.；Park,M.；Kim,J.；Park,S.；Shin,D.；Song,C.；Lee,D.,H2O2-triggered bubble generating antioxidant polymeric nanoparticles as ischemia/reperfusion targeted nanotheranostics.Biomaterials 2016,85,195-203.
23.Ramaiah,S.K.；Jaeschke,H.,Hepatic Neutrophil Infiltration in thePathogenesis of Alcohol-Induced Liver Injury.Toxicology Mechanisms andMethods 2007,17(7),431-440.

Claims (8)

1.一种用于成像和治疗的过氧化氢响应性化合物，其特征在于：其化学结构式如下
Figure FDA0004179083090000011
2.一种权利要求1所述用于成像和治疗的过氧化氢响应性化合物的合成方法，其特征在于，包括以下步骤：将单羟基化合物与缚酸剂在有机溶剂中混合，氮气保护下，在冰浴条件下向溶液中缓慢滴加草酰氯，滴加完后移除冰浴，反应2-12h，待原料反应完全后加入甲醇或乙醇淬灭反应，得到过氧化氢响应性化合物粗产物，所述单羟基化合物为生育酚。
3.根据权利要求2所述一种用于成像和治疗的过氧化氢响应性化合物的合成方法，其特征在于：还包括将所述粗产物用二氯甲烷/水体系萃取3次，收集二氯甲烷溶液，再用饱和氯化钠水溶液萃取1次，有机相用无水硫酸镁干燥除去多余水分，抽滤，蒸发除去其中二氯甲烷浓缩得到粗产物，用硅胶色谱柱分离提纯，即得到终产物。
4.根据权利要求2或3所述一种用于成像和治疗的过氧化氢响应性化合物的合成方法，其特征在于：所述缚酸剂选自N,N-二异丙基乙胺或三乙胺。
5.根据权利要求2或3所述一种用于成像和治疗的过氧化氢响应性化合物的合成方法，其特征在于：所述有机溶剂为二氯甲烷。
6.根据权利要求2或3所述一种用于成像和治疗的过氧化氢响应性化合物的合成方法，其特征在于：所述单羟基化合物在有机溶剂中的浓度在0.1mmol/ml到0.4mmol/ml之间。
7.根据权利要求2或3所述一种用于成像和治疗的过氧化氢响应性化合物的合成方法，其特征在于：所述单羟基化合物与草酰氯的摩尔比在1:0.5至1:1之间，所述单羟基化合物与缚酸剂的摩尔比在1:2至1:5之间。
8.权利要求1所述过氧化氢响应性化合物在制备成像探针中的应用。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6233481B1 (en) * 1997-10-09 2001-05-15 Spectra Science Corporation Diagnostic application of sono-chemical excitation of fluorescent photosensitizers
CN101205462A (zh) * 2006-12-20 2008-06-25 天津天龙化学发光管有限公司 固态化学发光组合物
CN101240165A (zh) * 2007-02-07 2008-08-13 天津天龙化学发光管有限公司 一种优良的草酸酯化学发光体系
KR20110061432A (ko) * 2009-12-01 2011-06-09 한국과학기술연구원 수계 분산 화학 발광 나노 입자, 이의 제조 방법 및 용도
CN102775984A (zh) * 2011-05-13 2012-11-14 天津天龙化学发光管有限公司 一种低氧化性高稳定性的膏状化学发光组合物
JPWO2015068725A1 (ja) * 2013-11-07 2017-03-09 住友精化株式会社 光電気化学素子用電荷輸送材料
WO2019178247A1 (en) * 2018-03-15 2019-09-19 Biolum Sciences Llc Sensor devices and systems for monitoring markers in breath

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120016217A1 (en) * 2010-07-15 2012-01-19 Indian Institute Of Technology Bombay Biosensor for health monitoring and uses thereof
US20120039814A1 (en) * 2010-08-13 2012-02-16 Sample Jennifer L Topical Compositions and Methods of Detection and Treatment
KR101823490B1 (ko) * 2016-09-08 2018-01-30 한국과학기술연구원 옥사미드 나노겔, 이의 제조방법 및 용도

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6233481B1 (en) * 1997-10-09 2001-05-15 Spectra Science Corporation Diagnostic application of sono-chemical excitation of fluorescent photosensitizers
CN101205462A (zh) * 2006-12-20 2008-06-25 天津天龙化学发光管有限公司 固态化学发光组合物
CN101240165A (zh) * 2007-02-07 2008-08-13 天津天龙化学发光管有限公司 一种优良的草酸酯化学发光体系
KR20110061432A (ko) * 2009-12-01 2011-06-09 한국과학기술연구원 수계 분산 화학 발광 나노 입자, 이의 제조 방법 및 용도
CN102775984A (zh) * 2011-05-13 2012-11-14 天津天龙化学发光管有限公司 一种低氧化性高稳定性的膏状化学发光组合物
JPWO2015068725A1 (ja) * 2013-11-07 2017-03-09 住友精化株式会社 光電気化学素子用電荷輸送材料
WO2019178247A1 (en) * 2018-03-15 2019-09-19 Biolum Sciences Llc Sensor devices and systems for monitoring markers in breath

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Designing and Using a Safer, Greener Azole Oxamide for Chemiluminescence Demonstrations;Fabrizio Roncaglia;《J. Chem. Educ.》;20170711;第94卷(第9期);第1289页Figure 1 *
STN检索报告;Columbus, Ohio, US Registry[Online];《STN Registry》;20010119;第2页 *
吕玉光主编.分子发光光谱法.《仪器分析》.中国医药科技出版社,2016,(第1版),第183-184页. *
草酸二芳香酯类化合物的合成及其在药物超微量分析中的应用;胡文祥 等;《中 国 药 物 化 学 杂 志》;19930630;第3卷(第1期);第10-16页 *
过氧草酸酯类化合物的合成及其发光体系的应用;唐嘉;《化学工程与装备》;20100831(第8期);第51-52,57页 *
过氧草酸酯类化学发光体系的研究进展;支正良等;《化学世界》;19971231(第12期);第619-624页 *

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