CN111662278B - 一种光敏剂的合成及其应用 - Google Patents

一种光敏剂的合成及其应用 Download PDF

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CN111662278B
CN111662278B CN201910164192.2A CN201910164192A CN111662278B CN 111662278 B CN111662278 B CN 111662278B CN 201910164192 A CN201910164192 A CN 201910164192A CN 111662278 B CN111662278 B CN 111662278B
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张崇敬
杜恩明
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Abstract

本发明涉及有机合成和生物医药领域，具体是指一类具有聚集诱导发光性质的光敏剂的合成，以及将该类光敏剂负载于固相材料上，用于生物活性分子或者医药中间体的合成；同时该类光敏剂还可应用于光动力学治疗、免疫原性细胞死亡等医药领域。本发明的光敏剂在光照的条件下能够有效产生单线态氧，且与传统的光敏剂相比，不会发生聚集荧光淬灭和聚集单线态氧产生能力降低的现象；应用于生物活性分子或医药中间体的合成时，具有可重复利用和后处理简单方便等优点，这些特点是传统光敏剂所不具备的。

Description

一种光敏剂的合成及其应用
技术领域
本发明涉及有机合成和生物医药领域，具体是指一类具有聚集诱导发光性质的光敏剂发现与合成，以及将这类光敏剂负载于固相材料上，用于生物活性分子或医药中间体的合成；同时该光敏剂还可应用于光动力学治疗、免疫原性细胞死亡等医药领域。
背景技术
单线态氧(1O2)是一种氧分子的激发态，是一种重要的活性氧分子。由于其具有很高的活性，因此在物理、化学、环境以及生物医学许多领域都具有广阔的应用。在有机合成中，单线态氧能够与单烯烃反应，生成二氧杂环烷烃或烃过氧化物；也可与共轭π键发生Diels-Alder型加成反应生成内氧化物。利用单线态氧高反应活性，在有机反应中能够较为容易引入氧(CN1811430A)，早在1954年，Schenck等就报道了利用单线态氧在松油烯(α-terpinene)中引入过氧桥合成天然产物Ascaridole(Naturwissenschaften 1954,32,157)。工业上也实现了利用单线态氧合成青蒿素合成中的重要中间体(Org.ProcessRes.Dev.2014,18,417)。
制备单线态氧有多种方法，其中最常见的是在光照条件下，氧气由三线态转化为单线态。由于三线态和单线态二者之间转换时受自旋翻转的限制，在正常条件下很难发生，常需要借助光敏剂来实现三线态氧到单线态氧的激发。目前报道的传统光敏剂主要包括卟啉类化合物、酞菁类化合物、二氢卟吩类化合物(Adv.Mater.2018,1801350)、BODIPY化合物(Chem.Soc.Rev.2013,42,77)、钌多吡啶配合物(Chem.Rev.2013,113,5322)等，这些光敏剂具有很好的单线态氧产生能力，在污水处理、光氧化催化和光动力治疗中都有很好的应用。传统的光敏剂容易通过π-π堆积发生聚集，引起荧光淬灭，同时导致光敏剂的单线态氧产生效率降低，从而限制了光敏剂实际应用中的效果。2001年，唐本忠院士课题组发现硅杂环戊二烯在稀溶液时不发光，而在聚集态或固态时呈现很强的荧光发射，并将这一现象命名为聚集诱导发光(aggregation-induced emission,AIE)。聚集诱导发光的主要原因是由于聚集态下的分子内运动受限，即当分子之间相互聚集，彼此之间相互作用增强，限制了分子内运动，从而降低了其非辐射能量转移，使荧光发射得以增强。具有聚集诱导发光性质的四苯基乙烯及其衍生物，因其具有优良的发光性能、易合成、易修饰等特点，近年来越来越受到关注(Chem.Soc.Rev.2011,40,5361)。2017年，刘斌课题组报道了一种新颖的基于聚集诱导发光光敏剂，该光敏剂受到化学能激发后能够有效产生单线态氧，杀伤肿瘤细胞(Chem.,2017,3,991)。因此，基于聚集诱导发光光敏剂产生单线态氧的研究具有极大的应用前景。
发明内容
本发明的目的在于提供一类新型的具有聚集诱导发光性质的光敏剂，以及将该光敏剂负载于固相材料上用于生物活性分子或者医药中间体的合成；同时该光敏剂还可应用于光动力学治疗、免疫原性细胞死亡等医药领域。
为实现上述发明目的，本发明采用的技术方案如下：
一、本发明一方面提供一类具有聚集诱导发光性质的光敏剂，所述光敏剂的化学结构，其化学结构通式可以为如下：
Figure BDA0001985733300000021
其中，R选自炔基-C1-C6烷基、羧基-C1-C6烷基、氨基-C1-C6烷基或羟基-C1-C6烷基；炔基-C1-C6烷基优选乙炔基C1-C6烷基。
光敏剂的结构还可为通式式(II)所示化合物，
Figure BDA0001985733300000022
其中，R选自羧基-C1-C6烷基；
式(I)或(II)结构与固相载体以共价连接的方式组成式(III)的固相光敏剂，其结构如下：
Figure BDA0001985733300000023
其中，所述固相载体选自王树脂、2-氯三苯基氯树脂、氨甲基树脂、二氧化硅、聚乙烯酸、聚乙烯醇或聚N-乙烯基吡咯烷酮；
结构式(I)或(II)与靶向多肽以共价连接的方式组成具有靶向作用的光敏剂，其结构通式(IV)如下：
Figure BDA0001985733300000031
其中，Peptide选自具有靶向功能的Lys-Asp-Glu-Leu(KDEL)多肽、Arg-Gly-Asp(RGD)多肽、Tyr-Ile-Gly-Ser-Arg(YIGSR)多肽；
结构式(I)或(II)与马来酰亚胺基团以共价键的方式连接，所述的化合物为：
Figure BDA0001985733300000032
本发明还提供了上述光敏剂的制备方法，所述制备方法包括如下步骤：
Figure BDA0001985733300000041
具体步骤：
以芳基溴1和芳基硼酸酯2为原料，在钯催化下经Suzuki偶联得到化合物3；化合物3中氨基的保护基在酸性条件下脱去，然后与炔丙酸缩合得到化合物4；然后化合物4在丙二腈在四氯化钛、吡啶的作用下，引入丙二腈；化合物V-1与叠氮丙酸在硫酸铜、抗坏血酸钠作用下，经Click反应合成化合物V-2；进而再通过缩合反应连接到固相材料上得到化合物V-3；
Figure BDA0001985733300000042
化合物V-2通过缩合反应在分子中引入马来酰亚胺基团得到化合物V-4；然后化合物V-4分子中的马来酰亚胺基团与多肽分子中的巯基通过加成反应得到化合物V-5。
本发明合成的光敏剂V-3在光催化氧化反应的应用中，可经过滤回收重复利用。直接再次应用于下次光催化氧化反应，一方面简化反应的后处理过程，另一方面可重复利用，提高光敏剂利用率。
附图说明
图1为本发明实施例1中化合物V-2(20μM)或V-3(2.5mg/mL)在不同溶剂中经白光(8mW)照射后ABDA(100μM)吸收峰的变化(A：化合物V-2in H2O；B：化合物V-2in DMF；D：化合物V-3in H2O；E：化合物V-3in DMF；C：A和B组中ABDA在378nm处吸收值的变化；F：D和E组中ABDA在378nm处吸收值的变化)；
图2为本发明实施例2中化合物V-3在光催化氧化反应中重复使用的次数。
具体实施方式
本发明可对照以下具体实施例作进一步说明，但并不局限于以下实施例。
实施例1
Figure BDA0001985733300000051
(1)化合物3的合成
化合物1(500mg,0.83mmol)、化合物2(538mg,1.21mmol)、碳酸钾(2.5M in H2O,4mL)加入到四氢呋喃中，氮气保护下加入四三苯基膦钯(80mg)，60℃反应12小时，有机层经萃取、干燥、浓缩、硅胶柱层析得到化合物3(560mg,80.5％)。HRMS calcd.for C51H44N3O5S2[M+H]+842.2717,found 842.2730；1H NMR(500MHz,CDCl3)δ8.10(d,J＝8.0Hz,2H),8.01(d,J＝8.0Hz,2H),7.85-7.77(m,4H),7.60(d,J＝3.5Hz,1H),7.21(d,J＝8.0Hz,2H),7.17-7.08(m,5H),7.07-7.00(m,3H),6.97(d,J＝8.5Hz,2H),6.68(d,J＝8.5Hz,2H),6.65(d,J＝8.5Hz,2H),5.11(t,J＝6.0Hz,1H),4.55(d,J＝4.5Hz,2H),3.75(s,3H),3.74(s,3H),1.49(s,9H)；13C NMR(126MHz,CDCl3)δ187.4,158.2,158.1,155.5,153.9(2C),152.4,144.7,144.1,142.5,141.2,140.8,138.7,137.4,136.2,135.1,134.6,133.8,132.6(2C),131.7,131.6,131.5,129.4,129.2,128.8,128.7,127.8,127.7,126.2,125.9,113.1,113.0,80.1,55.1,40.0,28.3(3C).
(2)化合物4的合成
化合物3(130mg,0.15mmol)溶于二氯甲烷(2mL)中，冰浴条件下加入三氟乙酸(0.12mL,1.62mmol)，继续反应2小时后减压浓缩。所得粗产物、炔丙酸、HBTU溶于二氯甲烷，加入三乙胺(0.1mL,0.72mmol)，继续反应过夜。反应毕经萃取、干燥、浓缩、柱层析得到化合物4(108mg,85％)。HRMS calcd.for C51H40N3O4S2[M+H]+822.2455,found 822.2427；1H NMR(500MHz,CDCl3)δ8.10(d,J＝8.0Hz,2H),8.00(d,J＝8.0Hz,2H),7.85-7.76(m,4H),7.59(d,J＝4.0Hz,1H),7.20(d,J＝7.5Hz,2H),7.17-7.08(m,5H),7.06(d,J＝3.5Hz,1H),7.04(d,J＝8.5Hz,2H),6.97(d,J＝8.0Hz,2H),6.68(d,J＝8.5Hz,2H),6.65(d,J＝8.5Hz,2H),6.38(m,1H),4.70(d,J＝6.0Hz,2H),3.75(s,3H),3.74(s,3H),2.58(m,2H),2.49(t,J＝7.0Hz,2H),2.03(m,1H)；13C NMR(126MHz,CDCl3)δ187.5,171.1,158.2,158.1,153.9(2C),150.9,144.7,144.1,142.7,141.3,140.8,138.7,137.2,136.3,135.1,134.6,133.9,132.6(2C),131.7,131.5,129.5,129.2,128.7,128.4,127.8,127.7,126.6,126.2,113.2,113.0,82.7,69.7,55.1,38.8,35.1,14.8.
(3)化合物V-1的合成
化合物4(250mg,0.30mmol)和丙二腈(100mg,1.51mmol)溶于二氯甲烷(10mL)，然后缓慢滴加四氯化钛(0.2mL,1.83mmol)继续反应30分钟，然后缓慢滴加吡啶(0.15mL,1.86mmol)继续反应1.5小时。反应毕加水淬灭反应，有机层经萃取、干燥、浓缩、柱层析得到化合物V-1(135mg,51％)。HRMS calcd.for C54H40N5O3S2[M+H]+870.2567,found 870.2588；1H NMR(500MHz,CDCl3)δ8.15(d,J＝8.0Hz,2H),7.86(d,J＝7.5Hz,1H),7.81(d,J＝7.5Hz,3H),7.66(d,J＝2.5Hz,1H),7.61(d,J＝7.5Hz,2H),7.21(d,J＝5.5Hz,2H),7.18-7.07(m,6H),7.04(d,J＝7.5Hz,2H),6.97(d,J＝7.5Hz,2H),6.69(d,J＝8.0Hz,2H),6.65(d,J＝8.0Hz,2H),6.29(m,1H),4.68(d,J＝3.5Hz,2H),3.75(s,6H),2.54(m,2H),2.45(m,2H),2.02(s,1H)；13C NMR(126MHz,CDCl3)δ171.1,164.4,158.2,158.1,154.0,153.7,153.5,141.0,140.8,137.4(2C),136.3,135.3,132.6(2C),131.8,131.5,130.9,130.0,129.4,128.9,128.5,127.7,127.4,114.5,114.0,113.2,113.0,82.6,69.8,55.1,38.6,35.1,14.8.
(4)化合物V-2的合成
化合物V-1(100mg,0.115mmol)、3-叠氮丙酸(26.5mg,0.23mmol)溶于二甲基亚砜与水的混合物(10:1,2mL)，抗坏血酸钠(12mg,0.06mmol)、无水硫酸铜(9.5mg,0.06mmol)依次加入上述反应液，室温反应过夜。反应液经二氯甲烷萃取、干燥、浓缩、柱层析得到化合物V-2(92mg,81％)。HRMS calcd.for C57H45N8O5S2[M+H]+985.2949,found 985.2988；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.5Hz,2H),7.83(d,J＝7.5Hz,1H),7.78(d,J＝7.5Hz,3H),7.58(d,J＝8.0Hz,2H),7.55(m,2H),7.44(s,1H),7.20(d,J＝8.0Hz,2H),7.16-7.07(m,5H),7.03(d,J＝8.5Hz,2H),6.98(m,1H),6.97(d,J＝8.5Hz,2H),6.67(d,J＝8.5Hz,2H),6.65(d,J＝8.5Hz,2H),4.57(m,4H),3.75(s,3H),3.73(s,3H),3.03(m,2H),2.95(m,2H),2.68(m,2H)；13C NMR(126MHz,CDCl3)δ176.0,173.4,172.6,164.6,158.2,158.1,153.9(2C),153.7,145.7,144.8,144.1,141.0,140.8,138.6,137.7,137.2,136.3,135.3,134.4,134.0,132.6(2C),131.7,131.5,130.9,130.0,129.4,128.9,128.5,127.8,127.7,127.3,126.2,123.2,114.6,114.0,113.2,113.0,55.1,46.0,38.5,35.1,34.3,21.0.
(5)化合物V-3的合成
Rink amide AM树脂(100mg,0.05mmoL)在二氯甲烷中溶胀20分钟，哌啶(20％inDMF)脱去Fmoc保护基，然后与HBTU活化的化合物V-2(100mg,0.10mmoL)反应4小时，经N,N-二甲基甲酰胺、甲醇、二氯甲烷、乙醚洗后得深红色固体V-3(140mg,82％)。
实施例2
Figure BDA0001985733300000071
(1)化合物V-4的合成
化合物V-2(50mg,0.05mmoL)和HBTU(38mg,0.10mmoL)溶于5mL二氯甲烷，加入DIEA(36μL,0.20mmoL)室温搅拌10min，然后加入N-(2-氨基乙基)马来酰亚胺三氟乙酸盐(20mg,0.08mmoL)室温反应2h。反应液经二氯甲烷萃取、干燥、浓缩、柱层析得到化合物V-4(46mg,82％)。HRMS calcd.for C63H51N10O6S2[M+H]+1107.3435,found 1107.3456；1H NMR(500MHz,CDCl3)δ8.14(d,J＝7.5Hz,2H),7.86(d,J＝7.5Hz,1H),7.83-7.76(m,3H),7.68-7.55(m,4H),7.38(s,1H),7.20(d,J＝7.5Hz,2H),7.17-7.08(m,5H),7.06-7.00(m,3H),6.97(d,J＝8.0Hz,2H),6.73-6.62(m,6H),6.44(s,1H),4.70-4.58(m,4H),3.75(s,3H),3.75(s,3H),3.64(m,2H),3.41(m,2H),3.09(m,2H),2.79(m,4H).
(2)化合物V-5的合成
中间体V-4(20mg,0.018mmoL)溶于DMSO(0.5mL)，多肽(CFFKDEL-SH,20mg,0.021mmoL)、DIEA(4μL,0.022mmoL)和三苯基膦(5.5mg,0.021mmoL)依次加入上述溶液，室温下反应4h。反应毕通过液相制备得到化合物V-5(13mg,35％)。HRMS calcd.forC107H110N18O19S3[M-2H]2-1023.3757,found 1023.8642；1H NMR(500MHz,CDCl3)δ8.21(d,J＝8.0Hz,2H),7.95(d,J＝7.0Hz,1H),7.90-7.80(m,3H),7.73-7.60(m,4H),7.30-7.05(m,18H),7.01(d,J＝8.5Hz,2H),6.94(d,J＝8.5Hz,2H),6.71(d,J＝8.0Hz,2H),6.66(d,J＝8.0Hz,2H),4.65(t,J＝5.5Hz,1H),4.62-4.46(m,6H),4.46-4.35(m,2H),4.28(t,J＝6.0Hz,1H),3.94(m,1H),3.73(s,3H),3.71(s,3H),3.62-3.50(m,2H),3.42-3.35(m,1H),3.22-2.90(m,11H),2.90-2.77(m,3H),2.75-2.66(m,2H),2.59(t,J＝6.5Hz,2H),2.52-2.36(m,3H),2.24-2.12(m,2H),2.05-1.80(m,6H),1.78-1.55(m,7H),1.50-1.20(m,10H),1.00-0.85(m,6H).
实施例3
Figure BDA0001985733300000081
化合物V-3(15mg)、化合物5(100mg,0.61mmol)加入到乙腈(20mL)中，在反应液中通入氧气，光照3小时(300W,PerfectLight,China)，TLC监测反应结束后过滤，固体化合物V-3继续用于下次光催化氧化反应，反应液减压浓缩后得到化合物6，直接用于核磁测定。HRMS calcd.for C11H17O3[M+H]+197.1172,found 197.1157；1H NMR(300MHz,CDCl3)δ8.56(m,1H),6.76(s,1H),5.24(s,1H),5.08(s,1H),4.53(m,1H),2.90-1.83(m,5H),1.77(s,3H),1.40-1.20(m,3H)；13C NMR(75MHz,CDCl3)δ200.3,200.1,151.0,150.9,145.2,145.0,135.4,135.3,112.4,112.0,83.2,83.0,44.0,43.8,37.6,37.4,32.6,32.5,18.2,18.0,15.6.
实施例4
Figure BDA0001985733300000091
化合物V-3(12mg)、α-terpinene(100mg,0.74mmol)加入到乙腈(20mL)中，在反应液中通入氧气，光照6小时(300W,PerfectLight,China)，TLC监测反应结束后过滤，固体化合物V-3继续用于下次光催化氧化反应，反应液减压浓缩后柱层析得到ascaridole(40mg,32％)。HRMS calcd.for C10H17O2[M+H]+169.1229,found 169.1217；1H NMR(500MHz,CDCl3)δ6.50(d,J＝8.5Hz,1H),6.41(d,J＝8.5Hz,1H),2.08-1.98(m,2H),1.92(m,1H),1.55-1.48(m,1H),1.38(s,3H),1.00(s,3H),0.99(s,3H)；13C NMR(125MHz,CDCl3)δ136.4,133.0,79.8,74.4,32.1,29.5,25.6,21.4,17.2(2C).
以上结合附图对本发明的实施例进行了阐述，但是本发明并不局限于上述的具体实施例，凡在本发明的精神和原则之内所做的任何修改、等同替换和改进，均应包含在本发明的保护范围内。

Claims (4)

1.式(II)所示化合物，
Figure FDA0004095716310000011
其中，R选自羧基-C1-C6烷基。
2.式(III)所示化合物，
Figure FDA0004095716310000012
其中，所述固相载体选自王树脂、2-氯三苯基氯树脂、氨甲基树脂、二氧化硅、聚乙烯酸、聚乙烯醇或聚N-乙烯基吡咯烷酮。
3.如下化合物或其药学上可接受的盐，所述的化合物为：
Figure FDA0004095716310000013
4.权利要求1-3任一项所述化合物用于制备光敏剂。
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