CN111187299B - 一种基于噻吩并[3,4-b]噻吩的有机光敏剂及制备方法和应用 - Google Patents
一种基于噻吩并[3,4-b]噻吩的有机光敏剂及制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一类有机光敏剂，具体涉及一种基于噻吩并[3,4‑b]噻吩的有机光敏剂及制备方法和应用。这种有机光敏剂是以噻吩并[3,4‑b]噻吩为核心结构单元，具有红光吸收、近红外光发射、Stokes位移大、同时具有活性氧产生能力等特点的化合物。是一类应用在细胞成像和疾病治疗方面的有机光敏剂。
Description
技术领域
本发明涉及一类有机光敏剂，具体涉及一种基于噻吩并[3,4-b]噻吩的有机光敏剂及制备方法和应用。
背景技术
感染性疾病是目前全世界面临的重要公共卫生问题。病原菌感染，尤其是革兰氏阳性菌感染严重威胁人类健康。据世界卫生组织报道，由于缺乏新型抗生素，在未来每年因多重耐药菌而造成的病原菌感染将引起大约1000万人死亡。然而，开发新一代的抗生素技术难度大、资金投入多、回报低，迫使各大药企纷纷中止新型抗生素的研发与资金投入。因此，开发新型非抗生素抗菌材料是临床治疗的迫切需要。光动力治疗(PhotodynamicTherapy，PDT)是一种基于光化学反应的新型治疗技术。利用特定波长的光源照射病原菌感染部位，使聚集在病原菌部位的光敏剂敏化氧气产生活性氧来杀灭细菌的光动力治疗受到人们的广泛关注。光动力杀菌的机制不同于传统抗生素，因此在有效杀灭细菌的同时也可减少细菌耐药性的产生。光敏剂(Photosensitizer，PS)是光动力治疗的关键，因此发展新型高效的光敏剂一直是人们追求的目标。噻吩并[3,4-b]噻吩(TbT)是一类典型的醌式结构单元，其特殊的并环方式使得其外围的噻吩亚单元具有阶梯式芳香性，从而表现出不同于芳香性分子的独特光电物理性质。因此以噻吩并[3,4-b]噻吩为核心结构单元，发展具有近红外光发射及活性氧产生能力的光敏剂是本发明的核心内容。
发明内容
本发明的目的在于提供一种有机光敏剂，以噻吩并[3,4-b]噻吩为核心结构单元，具有红光吸收、近红外光发射、活性氧产生能力等特点的化合物。
为了达到上述目的，本发明采用了下列技术方案：
一种基于噻吩并[3,4-b]噻吩的有机光敏剂的结构式为：
一种基于噻吩并[3,4-b]噻吩的有机光敏剂的制备方法，包括以下步骤：
步骤1，将4-甲氧基-N-(4-甲氧基苯)-N-(4-(4,4,5,5,-四甲基-1,3,2-二氧杂硼喃)苯基)苯胺与4-溴-6-醛基噻吩并[3,4-b]噻吩-2-乙基甲酸酯溶于干燥的1，4-二氧六环，在惰性气体保护条件下依次加入Cs2CO3，双(三苯基膦)二氯化钯，加热回流反应，冷却至室温，萃取，干燥有机相，减压除去有机溶剂，粗产品柱层析得到化合物3；
步骤2，将(3-溴甲基)三苯基溴化膦与4-甲基吡啶溶于甲醇中，室温反应，减压除去有机溶剂，粗产品柱层析得到化合物6；
步骤3，将化合物3与化合物6溶于乙醇中，滴入三乙胺，在氮气保护下，加热回流反应，冷却至室温，萃取，水洗，干燥有机相，减压除去有机溶剂，粗产品柱层析得到基于噻吩并[3,4-b]噻吩的有机光敏剂(化合物7)。
一种基于噻吩并[3,4-b]噻吩的有机光敏剂的应用，应用在细胞成像和疾病治疗方面。
本发明提供的含有噻吩并[3,4-b]噻吩的有机光敏剂，具有以下光物理性质：
在水溶液中的最大紫外吸收峰和荧光发射峰分别位于560nm和726nm，Stokes位移为4083cm-1，化合物7的吸收带边位于691nm，其光学带隙为1.80eV；本发明有机光敏剂可以有效的杀伤大肠杆菌，在化合物7浓度为5μmol/L时，暗处下对大肠杆菌的杀菌率能达到33.69％，光照下杀菌率达到97.91％；光照有很好的杀菌效果。
与现有技术相比本发明具有以下优点：
本发明的光敏剂具有红光吸收，且具有近红外光发射，Stokes位移大，同时具有优异的活性氧产生能力，及靶向线粒体性质，是一类潜在的应用于病原菌杀伤、肿瘤细胞诊疗一体化的有机光敏试剂。本发明的有机光敏剂所采用的制备方法操作简单，条件温和，具有工业化生产的潜质。
附图说明
图1本发明光敏剂在水溶液中的紫外-可见吸收光谱和荧光发射光谱图；
图2本发明光敏剂的热重分析(TGA)曲线；
图3本发明光敏剂在黑暗和光照条件下对大肠杆菌的杀伤效果。
具体实施方式
下面给出相应的实施例对本发明进行详细的描述。但本领域技术人员理解，下述实施例不是对本发明保护范围的限制，任何在本发明基础上做出的改进和变化都在本发明的保护范围之内。
在下面的实施例中所描述的实验方法，如无特殊说明，均为常规方法；所述材料和试剂，如无特殊说明，均可从商业途径获得。
实施例1
将4-甲氧基-N-(4-甲氧基苯)-N-(4-(4,4,5,5,-四甲基-1,3,2-二氧杂硼喃)苯基)苯胺(517.2mg,1.2mmol)与4-溴-6-醛基噻吩并[3,4-b]噻吩-2-乙基甲酸酯(318mg,1.0mmol)溶于干燥的1，4-二氧六环(4mL)，在惰性气体保护条件下依次加入Cs2CO3(977.5mg,3mmol)，双(三苯基膦)二氯化钯(36.5mg,0.05mmol)，90℃加热回流反应12h。冷却至室温，二氯甲烷萃取，硫酸镁干燥有机相，减压除去有机溶剂，粗产品柱层析得到化合物3，橙色固体，产率50％。1H NMR(400MHz,CDCl3)δ9.85(s,1H),8.00(s,1H),7.55(d,J＝8.8Hz,2H),7.14(d,J＝8.9Hz,5H),6.96(d,J＝8.8Hz,3H),6.90(d,J＝8.9Hz,4H),4.40(d,J＝7.1Hz,2H),3.83(s,7H),1.40(t,J＝7.2Hz,4H)。
将(3-溴甲基)三苯基溴化膦(693mg,1.5mmol)与4-甲基吡啶(93mg,1mmol)溶解于甲醇中，室温反应72h，减压除去有机溶剂，粗产品柱层析得到化合物6，白色固体，产率为88％。1H NMR(400MHz,MeOD)δ8.92(d,J＝6.7Hz,2H),7.95-7.80(m,11H),7.79-7.74(m,6H),4.93-4.86(m,2H),3.77-3.64(m,2H),2.66(s,3H),2.46-2.33(m,2H)。
将化合物3(108.6mg,0.2mmol)与化合物6(158.9mg,0.4mmol)溶解于乙醇中，滴入1～2滴三乙胺，氮气保护，加热回流反应过夜，冷却至室温，三氯甲烷萃取，水洗，硫酸镁干燥有机相，减压除去有机溶剂，粗产品柱层析得到化合物7，黑色固体，产率为42％。1H NMR(600MHz,CDCl3)δ9.84(s,2H),7.99(s,1H),7.94(m,6H),7.81(m,4H),7.75(m,8H),7.65(d,J＝15.1Hz,1H),7.50(d,J＝8.3Hz,2H),7.14(d,J＝8.4Hz,4H),6.96(d,J＝8.2Hz,2H),6.91(d,J＝8.4Hz,4H),6.66(d,J＝14.1Hz,1H),5.44(s,2H),4.43(q,J＝6.9Hz,2H),3.84(s,6H),3.69(s,2H),2.64(s,2H),1.44(t,J＝6.9Hz,3H)；HRMS(ESI)calcdforC57H51Br2N2O4PS2[M]2+,461.1508；found,461.15109。
实施例2：
准确称取1.1mg化合物7，将其溶解于100mL二次水配置成浓度为1.0×10-5mol/L的溶液。利用移液枪准确移取2.0mL于比色皿中，置于日立UH5300型紫外可见分光光度计进行测定。荧光光谱测试仪器为日立HITACHI F-4600，激发波长为560nm，激发狭缝和发射狭缝都设定为5nm。测试结果如图1所示，化合物7的最大吸收峰为560nm，荧光发射峰为726nm。
实施例3：
在氮气保护条件下，利用PerkineElmer Pryisl TGA进行热重分析(TGA)测试，升温速率为5℃/min，如图2所示，化合物7的分解温度为229℃(5％重量损失)。
实施例4：
对大肠杆菌的杀菌率测试：
将大肠杆菌在LB液体培养基中培养6～8小时，在超净台中吸取2mL菌液进行离心(7100rpm,2min)沉淀，弃去上清液，将沉淀的大肠杆菌用1×PBS洗涤后再离心沉淀，重复两次后，弃去上清液，将细菌重新悬浮于1×PBS中，调节OD600为1。在1.5mL的离心管中，加入100μL(OD600＝1)的菌液，然后加入一系列体积的化合物7溶液，使化合物7与菌的孵育浓度分别为1.25μmol/L、2.5μmol/L、3.75μmol/L、5μmol/L，相同条件的菌和PBS的混合物液作为对照组。每组浓度作用下的细菌再分为光照组和黑暗组两组。光照组在25mW.cm-2的白光下照射15min后放入培养箱中然后孵育20min。黑暗组不进行光照处理，放置相同时间后放入培养箱中然后孵育相同时间。培养箱的培养温度为37℃。孵育结束后，将所有的菌液稀释1×104倍，吸取100μL稀释的菌液均匀涂布于LB固体培养基(直径大小为90mm，含50μg/mL-1的氨苄西林钠)上。然后放入培养箱培养，18h后对菌落进行计数测试结果如图3，在化合物7浓度为5μmol/L时，暗处大肠杆菌的存活率为66.31％，光照下的存活率率为2.09％，说明在光照下，化合物7对大肠杆菌有有很好的杀伤效果。
Claims (7)
1.一种基于噻吩并[3,4-b]噻吩的有机光敏剂，其特征在于，所述基于噻吩并[3,4-b]噻吩的有机光敏剂的结构式为：
2.一种基于噻吩并[3,4-b]噻吩的有机光敏剂的制备方法，其特征在于，包括以下步骤：
步骤1，将4-甲氧基-N-(4-甲氧基苯)-N-(4-(4,4,5,5,-四甲基-1,3,2-二氧杂硼喃)苯基)苯胺与4-溴-6-醛基噻吩并[3,4-b]噻吩-2-乙基甲酸酯溶于干燥的1，4-二氧六环，在惰性气体保护条件下依次加入Cs2CO3，双(三苯基膦)二氯化钯，加热回流反应，冷却至室温，萃取，干燥有机相，减压除去有机溶剂，粗产品柱层析得到化合物3，即4-(4-(二(4-甲氧基苯基)氨基)苯基))-6-醛基噻吩[3,4-b]噻吩-2-甲酸乙酯；
步骤2，将(3-溴甲基)三苯基溴化膦与4-甲基吡啶溶于甲醇中，室温反应，减压除去有机溶剂，粗产品柱层析得到化合物6，即4-甲基-1-(3-(三苯基溴化膦)丙基)-1-溴化吡啶鎓；
步骤3，将化合物3与化合物6溶于乙醇中，滴入三乙胺，在氮气保护下，加热回流反应，冷却至室温，萃取，水洗，干燥有机相，减压除去有机溶剂，粗产品柱层析得到基于噻吩并[3,4-b]噻吩的有机光敏剂。
3.根据权利要求2所述的一种基于噻吩并[3,4-b]噻吩的有机光敏剂的制备方法，其特征在于，所述步骤1中4-甲氧基-N-(4-甲氧基苯)-N-(4-(4,4,5,5,-四甲基-1,3,2-二氧杂硼喃)苯基)苯胺、4-溴-6-醛基噻吩并[3,4-b]噻吩-2-乙基甲酸酯、Cs2CO3、双(三苯基膦)二氯化钯的摩尔比为1.2:1.0:2.0～10.0:0.01～0.1。
4.根据权利要求2所述的一种基于噻吩并[3,4-b]噻吩的有机光敏剂的制备方法，其特征在于，所述步骤1中加热回流反应的温度为90～110℃，加热回流反应的时间为10～24h，萃取用二氯甲烷，干燥有机相用硫酸镁。
5.根据权利要求2所述的一种基于噻吩并[3,4-b]噻吩的有机光敏剂的制备方法，其特征在于，所述步骤2中(3-溴甲基)三苯基溴化膦与4-甲基吡啶的摩尔比为1:2～10，室温反应的时间为60～84h。
6.根据权利要求2所述的一种基于噻吩并[3,4-b]噻吩的有机光敏剂的制备方法，其特征在于，所述步骤3中三乙胺为1～2滴，加热回流反应的温度为70～85℃，加热回流反应的时间为10～24h，萃取用三氯甲烷，干燥有机相用硫酸镁。
7.一种基于噻吩并[3,4-b]噻吩的有机光敏剂的应用，其特征在于，在制备细胞成像和疾病治疗药物中的应用。
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