CN110408233B - 一种对磺酸苯氧菁染料及其制备方法与用途 - Google Patents
一种对磺酸苯氧菁染料及其制备方法与用途 Download PDFInfo
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Abstract
本发明公布了一种对磺酸苯氧菁染料及其制备方法与用途。所述对磺酸苯氧菁染料含有对磺酸苯氧基取代基，具有很好的水溶性以及很大的摩尔吸光系数，且稳定好、毒性低、光稳定性良好，可用于分子荧光成像以及肿瘤的光动力、声动力治疗。此外，所述对磺酸苯氧菁染料的合成路线短、反应条件温和、产率高、易于操作，特别适用于工业化生产。
Description
技术领域
本发明属于生物医用材料领域，具体涉及一类对磺酸苯氧菁染料及其制备方法，以及该对磺酸苯氧菁染料作为荧光分子探针、光敏剂、声敏剂等生物医药试剂的用途。
背景技术
分子影像技术可以用于对肿瘤细胞进行细胞分子水平的病理监控、诊断，还可以用于对肿瘤组织的微创治疗。该项技术的关键在于分子探针，分子探针性能的高低直接决定分子影像技术的成败。菁染料类分子探针由于具有吸收波长范围广(500～850nm)，生物相容性高，较强的细胞膜穿透性能等优点，被广泛用于分子影像技术中。
一般的菁染料，比如FDA批准的吲哚菁绿(ICG)，水溶性较差，比较容易聚集，且不能修饰连接靶向基团，难以使分子影像技术较好地推广。
发明内容
为了克服现有荧光探针水溶性差、无法修饰的缺点，本发明的目的是提供一种适合作为荧光分子探针的对磺酸苯氧菁染料及其制备方法。
本发明制备的对磺酸苯氧菁染料类衍生物含有对磺酸苯氧基取代基，具有很好的水溶性以及很大的摩尔吸光系数。此外，本发明制备得到的对磺酸苯氧菁染料既可以用于恶性肿瘤的荧光成像，也可以作为恶性肿瘤光动力、声动力诊断和治疗的药物。
本发明提供的对磺酸苯氧菁染料的结构如式I所示：
式I中，R1、R2相同或不同，各自独立为烷基、磺酸基(-SO3H)、磺酸基烷基(-RSO3H，其中R代表亚烷基)、磷酸基(-PO(OH)2)、磷酸基烷基(-RPO(OH)2，其中R代表亚烷基)、羧基(-COOH)或羧基烷基(-RCOOH，其中R代表亚烷基)。当R1、R2位置上含有羧基时，还可以连接N-羟基琥珀酰亚胺或2-氨基马来酰亚胺，再连接叶酸、精氨酸-甘氨酸-天冬氨酸(RGD)等靶向基团。
优选的，上述烷基为C1～C20的烷基，更优选为C1～C12的烷基，最优选为C1～C6的烷基，例如甲基、乙基、丙基、丁基等。
所述R优选为C1～C20的亚烷基，更优选为C1～C12的亚烷基，最优选为C1～C6的亚烷基，例如亚甲基、亚乙基等。
本发明的对磺酸苯氧菁染料的合成方法具体描述如下：
第一步，对羟基苯磺酸与对硝基氟苯(一倍量)在碱的作用下反应，得到对(4-硝基苯氧基)苯磺酸(化合物A)。其中，在溶剂方面，可以使用甲醇、乙醇等质子极性溶剂，也可以使用DMF、乙腈等非质子极性溶剂，优选DMF。在碱方面，可以使用三乙胺、吡啶等有机碱，也可以使用碳酸钾、碳酸钠、碳酸氢钠等无机碱，优选碳酸钾。碱的用量为对硝基氟苯的2～3倍。反应温度为0～80℃，反应时间为6～48小时。
第二步，对(4-硝基苯氧基)苯磺酸(化合物A)在Pd/C(5％～10％用量)催化作用下，使用氢气还原硝基，得到对(4-氨基苯氧基)苯磺酸(化合物B)。在溶剂方面，选用甲醇、乙醇等质子极性溶剂。反应温度为0～80℃，反应时间为6～48小时。
第三步，对(4-氨基苯氧基)苯磺酸(化合物B)与亚硝酸钠(1～1.2倍量)在盐酸(1～5倍量)的作用下进行重氮化反应，再使用二氯化锡等还原剂(1～5倍量)还原得到苯肼衍生物(化合物C)。反应温度为0～25℃，反应时间为0.5～48小时。
第四步，苯肼衍生物(化合物C)与3-甲基丁酮(1～5倍量)反应得到对磺酸苯氧基吲哚衍生物(化合物D)。在溶剂方面，使用乙酸、乙醇等质子性溶剂。反应温度为0～140℃，反应时间为6～48小时。
第五步，对磺酸苯氧基吲哚衍生物(化合物D)与烷基化试剂反应得到季铵盐吲哚衍生物(化合物E1或E2)，反应溶剂使用甲醇、乙醇、乙腈或反应物烷基化试剂本身，反应温度为0～140℃，反应时间为6～48小时。所述烷基化试剂可以表示为R1Y或R2Y，其中R1、R2如前所述，Y代表氯、溴、碘等卤素；所述烷基化试剂也可以是烷基磺酸内酯、烷基磷酸内酯、烷基内酯等。
第六步，季铵盐吲哚衍生物(化合物E1和E2)与缩合剂F反应得到对磺酸苯氧菁染料(式I化合物)。先将季铵盐吲哚衍生物E1与缩合剂F(0.5～1倍投料量)在乙酸-乙酸酐混合溶剂(乙酸:乙酸酐＝1:1～1:3，体积比)的作用下在50～140℃反应0.5～3小时得到半菁中间体，旋蒸除去溶剂，加入季铵盐吲哚衍生物E2(1～1.5倍投料量)，在乙酸-吡啶混合溶剂(乙酸:吡啶＝0:1～1:1，体积比)的作用下在0～140℃反应0.5～3小时，加入乙醚或者乙酸乙酯等较低极性溶剂沉淀得到粗产物，经过柱色谱层析得到纯的式I化合物。其中，在投料顺序上，也可以先使季铵盐吲哚衍生物E2与缩合剂F反应制备成半菁，再与季铵盐吲哚衍生物E1反应制备得到式I化合物。另外，如果R1与R2相同，则可以将季铵盐吲哚衍生物E1与缩合剂溶于乙醇或其它质子性溶剂中，加入碱，在0～140℃得到反应0.5～3小时，加入乙醚或者乙酸乙酯等较低极性溶剂沉淀得到粗产物，经过柱色谱层析得到纯的式I化合物。
本发明方法所涉及的原料易于制备，合成路线短，反应条件温和，适用于大规模生产。本发明所制备的对磺酸苯氧菁染料具有很好的稳定性、生物相容性，肿瘤细胞成像分辨率很高。
本发明所涉及的对磺酸苯氧菁染料作为荧光分子探针、光敏剂、声敏剂等生物医药试剂，稳定好、毒性低，可用于乳腺癌、卵巢癌、脑癌、肺腺癌、子宫内膜癌、结直肠癌、睾丸癌等恶性肿瘤的荧光成像，也可以用于作为恶性肿瘤的光动力或声动力的诊断与治疗的药物。
附图说明
图1是本发明实施例5制得的对磺酸苯氧菁染料的核磁氢谱。
图2是本发明实施例5制得的对磺酸苯氧菁染料在水中的吸收光谱。
图3是本发明实施例5制得的对磺酸苯氧菁染料在水中的荧光光谱。
具体实施方式
以下具体实施例将有助于理解本发明，但并不限制本发明的内容。
实施例1
本实施例为对(4-硝基苯氧基)苯磺酸的制备，合成方法如下：
将对羟基苯磺酸(2g)与对硝基氟苯(1.62g)溶于20mL二甲基甲酰胺(DMF)，加入碳酸钾1.57g，常温下搅拌12小时，将反应物过滤，通过旋转蒸发仪除去滤液中的溶剂，得到粗品对(4-硝基苯氧基)苯磺酸钾(化合物A)，产率95％。
经检测，产物结构正确。1H NMR(500MHz,D2O)δ8.26(d,J＝9.2Hz,2H),7.85(d,J＝8.8Hz,2H),7.25(d,J＝8.8Hz,2H),7.18(d,J＝9.2Hz,2H).
实施例2
本实施例为对(4-氨基苯氧基)苯磺酸钾的制备，，合成方法如下：
将对(4-硝基苯氧基)苯磺酸钾(化合物A)(2g)与Pd/C(100mg)置于250mL三口瓶中，氮气吹5分钟，加入50mL甲醇，加1L氢气，常温搅拌24小时。过滤除去Pd/C催化剂，通过旋转蒸发仪除去滤液中的溶剂，得到对(4-氨基苯氧基)苯磺酸钾(化合物B)，产率90％。
经检测，产物结构正确。1H NMR(500MHz,DMSO)δ7.61–7.46(m,2H),6.78–6.68(m,4H),6.59(d,J＝8.8Hz,2H),4.95(s,2H).
MS C12H10KNO4S(FTMS)，理论值[M+H]+＝304.0，实验值[M+H]+＝304.0。
实施例3
本实施例为对磺酸钾基吲哚(化合物D)的制备，合成步骤如下：
(1)在冰水浴下将对(4-氨基苯氧基)苯磺酸(化合物B)(1g)加入到5mL浓盐酸中，将亚硝酸钠(300mg)的水溶液(2mL)缓慢滴加到上述溶液中，搅拌15分钟后，再慢慢加入二氯化锡(1.49g)的盐酸溶液(2mL)，撤去冰水浴，常温搅拌2小时。离心，得到固体使用5mL水洗涤，再使用10mL浓盐酸洗涤两次。常温下真空干燥，得到苯肼衍生物(化合物C)粗品。
(2)将粗品苯肼化合物C与3-甲基丁酮(1.35mL)混合，加入15mL乙酸，在140℃下反应18小时，旋干除去溶剂，得到粗品对磺酸苯氧基吲哚衍生物(化合物D)，产率93％。
经检测，产物结构正确。1H NMR(500MHz,DMSO)δ7.63–7.57(m,2H),7.43(d,J＝8.3Hz,1H),7.19(d,J＝2.5Hz,1H),6.94(dd,J＝8.3,2.5Hz,1H),6.93–6.90(m,2H),2.14(s,3H),1.26(s,6H).
实施例4
本实施例为季铵盐吲哚衍生物的制备，合成方法如下：
将对磺酸苯氧基吲哚衍生物(化合物D)(755mg)与丁磺酸内酯(2mL)混合，在140℃下反应18小时。冷却至室温，使用5mL丙酮洗涤三次。残余物通过反相C18柱层析色谱分离，得到季铵盐吲哚衍生物E，产率50％。
经检测，产物结构正确，分子式为C21H25NO7S2。1H NMR(500MHz,D2O)δ7.89–7.75(m,3H),7.47–7.38(m,1H),7.36–7.22(m,1H),7.25–7.03(m,2H),4.50(t,J＝7.6Hz,2H),3.03–2.95(m,2H),2.16–2.06(m,2H),1.87(ddd,J＝21.3,11.9,6.6Hz,2H),1.53(s,6H).
MS(MALDI-TOF)：理论值[M+Na]+＝492.1，实验值[M+H]+＝492.3。
实施例5
本实施例为对R1＝R2＝4-磺酸基丁基的式I化合物的制备，合成方法如下：
将季铵盐吲哚衍生物E(150mg)与缩合剂盐酸-N-(3-苯氨基-2-丙烯亚基)苯胺(46mg)溶于乙醇中，加入乙酸钠(26mg)，在85℃反应12小时，加入乙醚沉淀得到粗产物，经过柱色谱层析得到纯的化合物I。产率53％。
经检测，产物结构正确，分子式为C50H55ClN2O14S4，其核磁氢谱如图1所示。1H NMR(500MHz,D2O)δ8.02(s,2H),7.68(d,J＝7.5Hz,4H),7.16(s,2H),6.80(s,4H),6.70(s,4H),6.12(d,J＝9.9Hz,2H),3.97(s,4H),2.85(s,4H),2.57(s,4H),1.80(s,10H),1.40(s,12H).
MS(MALDI-TOF)：理论值[M+H]+＝1071.22，实验值[M+H]+＝1071.30。
实施例6
将实施例5制备的对磺酸苯氧菁染料溶于水中，用紫外-可见分光光度计测试其吸收光谱，结果如图2所示。在水中，双染料的特征吸收在787nm左右，符合Cy7化合物的吸收谱特征。经计算，该化合物的摩尔吸光系数为1.55×105M-1cm-1。用荧光分光光度计测试其荧光光谱，如图3所示。
Claims (10)
1.一种对磺酸苯氧菁染料，其结构如式I所示：
式I中，R1、R2相同或不同，各自独立为烷基、磺酸基烷基、磷酸基烷基或羧基烷基。
2.如权利要求1所述的对磺酸苯氧菁染料，其特征在于，所述烷基为C1～C20烷基；所述磺酸基烷基表示为-RSO3H，所述磷酸基烷基表示为-RPO(OH)2，所述羧基烷基表示为-RCOOH，其中R代表C1～C20亚烷基。
3.如权利要求1所述的对磺酸苯氧菁染料，其特征在于，所述对磺酸苯氧菁染料的结构式如下所示：
4.权利要求1～3任一所述对磺酸苯氧菁染料的制备方法，包括以下步骤：
1)对羟基苯磺酸与对硝基氟苯在碱的作用下反应，得到对(4-硝基苯氧基)苯磺酸即化合物A；
2)对(4-硝基苯氧基)苯磺酸在Pd/C催化作用下，使用氢气还原硝基，得到对(4-氨基苯氧基)苯磺酸即化合物B；
3)对(4-氨基苯氧基)苯磺酸与亚硝酸钠在盐酸的作用下进行重氮化反应，再使用还原剂还原得到苯肼衍生物即化合物C；
4)苯肼衍生物与3-甲基丁酮反应得到对磺酸苯氧基吲哚衍生物即化合物D；
5)对磺酸苯氧基吲哚衍生物与烷基化试剂反应得到带有R1基团的季铵盐吲哚衍生物E1或带有R2基团的季铵盐吲哚衍生物E2；
6)季铵盐吲哚衍生物E1和E2与缩合剂F反应得到所述对磺酸苯氧菁染料；
其中，R1、R2相同或不同，各自独立为烷基、磺酸基烷基、磷酸基烷基或羧基烷基。
5.如权利要求4所述的制备方法，其特征在于，步骤1)反应的溶剂为质子极性溶剂或非质子极性溶剂，所用碱为有机碱或无机碱，反应温度为0～80℃，反应时间为6～48小时；步骤2)反应的溶剂为质子极性溶剂，反应温度为0～80℃，反应时间为6～48小时；步骤3)反应温度为0～25℃，反应时间为0.5～48小时；步骤4)反应的溶剂为质子性溶剂，反应温度为0～140℃，反应时间为6～48小时。
6.如权利要求4所述的制备方法，其特征在于，步骤5)中所述烷基化试剂为R1Y或R2Y，其中R1、R2代表烷基、磺酸基烷基、磷酸基烷基或羧基烷基，Y代表卤素。
7.如权利要求4所述的制备方法，其特征在于，步骤5)中所述烷基化试剂为烷基磺酸内酯、烷基磷酸内酯或烷基内酯。
8.如权利要求4所述的制备方法，其特征在于，当R1与R2不同时，步骤6)先将季铵盐吲哚衍生物E1与缩合剂F在乙酸-乙酸酐混合溶剂的作用下在50～140℃反应0.5～3小时得到半菁中间体，除去溶剂，然后加入季铵盐吲哚衍生物E2，在乙酸-吡啶混合溶剂的作用下在0～140℃反应0.5～3小时，加入低极性溶剂沉淀得到粗产物，经过柱色谱层析得到纯的式I化合物；当R1与R2相同时，将季铵盐吲哚衍生物与缩合剂溶于质子性溶剂中，加入碱，在0～140℃得到反应0.5～3小时，加入低极性溶剂沉淀得到粗产物，经过柱色谱层析得到纯的式I化合物。
9.如权利要求8所述的制备方法，其特征在于，步骤6)中所述乙酸-乙酸酐混合溶剂按体积比乙酸:乙酸酐＝1:1～1:3；所述乙酸-吡啶混合溶剂按体积比乙酸:吡啶＝0:1～1:1。
10.权利要求1～3任一所述的对磺酸苯氧菁染料作为荧光分子探针、光敏剂或声敏剂的用途。
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| CN103146220A (zh) * | 2012-10-25 | 2013-06-12 | 西安电子科技大学 | 对称五甲川菁染料及其在分子影像中的应用 |
| CN106999609A (zh) * | 2014-11-26 | 2017-08-01 | 利康公司 | 用于荧光成像的ir染料 |
| CN107011282A (zh) * | 2017-04-07 | 2017-08-04 | 上海应用技术大学 | N‑[4‑(烷氧基)‑苯磺酰基]‑5‑芳基‑恶唑‑2‑硫酮类神经氨酸酶抑制剂 |
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| CN103146220A (zh) * | 2012-10-25 | 2013-06-12 | 西安电子科技大学 | 对称五甲川菁染料及其在分子影像中的应用 |
| CN106999609A (zh) * | 2014-11-26 | 2017-08-01 | 利康公司 | 用于荧光成像的ir染料 |
| CN107011282A (zh) * | 2017-04-07 | 2017-08-04 | 上海应用技术大学 | N‑[4‑(烷氧基)‑苯磺酰基]‑5‑芳基‑恶唑‑2‑硫酮类神经氨酸酶抑制剂 |
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