CN113278304A - 一种双比率型半花菁类染料分子及其合成方法和应用 - Google Patents
一种双比率型半花菁类染料分子及其合成方法和应用 Download PDFInfo
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Abstract
本发明公开了一种双比率型半花菁类染料分子及其合成方法和应用。本发明提供的双比率近红外荧光和光声诊疗染料分子，以可视化、量化和评估与肿瘤治疗效果直接相关的硝基还原酶水平，通过比率近红外荧光和光声成像实时、无创监测肿瘤缺氧水平以进行预后和治疗评估，并且染料分子BS‑Cy‑NO2具有良好的光热效果，可以用于肿瘤光热治疗。本发明染料分子合成步骤简单、纯化方便，成像优异，作为双比率近红外荧光和光声成像的分子诊疗剂，具有广阔的应用前景。本发明染料分子结构式如下：
。
Description
技术领域
本发明属于有机小分子染料的技术领域，具体涉及一种双比率型半花菁类染料分子及其合成方法和应用。
背景技术
恶性肿瘤在其生长和增殖过程中表现出轻、中、重度缺氧的不同缺氧水平。缺氧水平与放疗、化疗等癌症治疗的疗效密切相关，甚至引发肿瘤侵袭、突变、转移和耐药。因此，准确描述实体瘤中乏氧的分布和程度，将有助于获得有关肿瘤恶性程度和迁移的准确信息，开发用于定量检测体内肿瘤乏氧水平的无创成像技术对于癌症预后和诊断的有效性至关重要。光学成像，能够以高灵敏度和特异性对疾病相关生物标志物进行非侵入性和实时可视化。近红外荧光(NIRF)成像和光声(PA)成像的双模成像具有荧光和光声互补优势的结合，有望改善肿瘤乏氧水平的成像效果。
然而，大部分监测肿瘤乏氧探针为打开型，这种单一开启模式的分子成像通常不够稳健，无法提供区分乏氧水平部位所需的信号，导致潜在的假阳性或假阴性诊断和治疗结果。为了进一步克服成像伪影，提高癌症治疗的精确能力，开发能够输出双比率信号多模态分子成像染料，用于准确和特定的癌症成像和肿瘤治疗评估具有非常重要的意义。
发明内容
本发明的目的是针对现有技术的不足，而提供一种双比率型半花菁类染料分子及其合成方法和应用。本发明染料分子的合成步骤简单、纯化方便，成像优异。
实现本发明目的技术方案是：
本发明一种双比率型半花菁类染料分子，其结构式如下：
所述染料分子SS-Cy-1—CS-Cy-2的合成路线如下：
染料分子SS-Cy-1—CS-Cy-2的具体合成步骤为：
将原料1a、1b、1c或1d分别溶解于N,N-二甲基甲酰胺DMF中，随后加入原料2和氢化纳，在氮气保护和40℃条件下搅拌反应8小时；
反应完毕后，将反应液倒入冰水中混合，加入0.5ml高氯酸静置析出固体，抽滤得到粗产品；
将得到的粗产品，用体积比为50:1的二氯甲烷与甲醇为洗脱剂，用200-300目硅胶层析柱进行纯化，得到染料分子SS-Cy-1—CS-Cy-2固体。
染料分子SS-Cy-1—CS-Cy-2的合成步骤中，所述原料2结构式中R＝OH或NH2；
所述原料1a、1b、1c或1d与原料2的摩尔比为1:1；
所述原料1a、1b、1c或1d和氢化纳的摩尔比为1:1；
N,N-二甲基甲酰胺DMF的用量以能溶解原料1a、1b、1c或1d为准。
染料分子AS-Cy-NO2和BS-Cy-NO2的合成路线如下：
染料分子AS-Cy-NO2或BS-Cy-NO2的具体合成步骤为：
将原料AS-Cy-1或BS-Cy-1分别溶于N,N-二甲基甲酰胺DMF中，随后加入溴代对硝基甲苯和碳酸钾，在氮气保护和60℃条件下搅拌反应4小时；
反应完毕后，将反应液倒入冰水中混合，加入0.5ml高氯酸静置析出固体，抽滤得到粗产品；
将得到的粗产品，用体积比为60:1的二氯甲烷与甲醇为洗脱剂，用200-300目硅胶层析柱进行纯化，得到染料分子AS-Cy-NO2或BS-Cy-NO2固体。
染料分子AS-Cy-NO2或BS-Cy-NO2的合成步骤中，所述原料AS-Cy-1或BS-Cy-1与溴代对硝基甲苯的摩尔比为1:1；
所述原料AS-Cy-1或BS-Cy-1与碳酸钾的摩尔比为4:1；
N,N-二甲基甲酰胺DMF的用量以能溶解原料AS-Cy-1或BS-Cy-1为准。
另外，本发明还要求保护所述染料分子的用途，所述染料分子AS-Cy-NO2或BS-Cy-NO2用于制备硝基还原酶检测试剂，以及用于双比率定量检测硝基还原酶来监测肿瘤乏氧水平与肿瘤治疗评估。
本发明染料分子AS-Cy-NO2用于双比率定量检测硝基还原酶来监测肿瘤乏氧水平，并以比率近红外荧光和光声成像对肿瘤乏氧进行成像，具体步骤为：
(1)将染料分子溶于二甲亚砜(DMSO)，制成AS-Cy-NO2染料分子母液；
(2)将染料分子母液加入到待测液和生物样品中；
(3)加入硝基还原酶后，用紫外和荧光光谱仪观察含有染料分子AS-Cy-NO2的待测液的紫外和荧光光谱的变化；
(4)将染料分子AS-Cy-NO2原位注入荷瘤小鼠瘤内，然后进行近红外荧光和光声成像，从而得到动物活体内硝基还原酶近红外荧光和光声图像。
本发明染料分子BS-Cy-NO2用于双比率定量检测硝基还原酶来监测肿瘤乏氧水平，并对肿瘤进行光热治疗，且以比率近红外荧光和光声成像对肿瘤治疗进行预后评估，具体步骤为:
(1)将染料分子溶于二甲亚砜(DMSO)，制成BS-Cy-NO2染料分子母液；
(2)将染料分子母液加入到待测液和生物样品中；
(3)加入硝基还原酶后，用紫外和荧光光谱仪观察含有染料分子BS-Cy-NO2的待测液的紫外和荧光光谱的变化；
(4)将染料分子BS-Cy-NO2原位注入荷瘤小鼠瘤内，并对荷瘤小鼠进行光热治疗，然后进行近红外荧光和光声成像，从而得到治疗后荷瘤小鼠的近红外荧光和光声图像。
本发明提供的双比率近红外荧光和光声诊疗染料分子，以可视化、量化和评估与肿瘤治疗效果直接相关的硝基还原酶水平，通过比率近红外荧光和光声成像实时、无创监测肿瘤缺氧水平以进行预后和治疗评估，并且染料分子BS-Cy-NO2具有良好的光热效果，可以用于肿瘤光热治疗。
与现有技术相比，本发明的优点和有益效果为：
(1)本发明提供的染料分子合成步骤简单、纯化方便，成像优异；
(2)本发明染料分子能定量检测和评估硝基还原酶水平，通过比率近红外荧光和光声成像实时、无创监测肿瘤缺氧水平以进行肿瘤预后和治疗评估；
(3)本发明采用双比率型荧光和光声检测，检测信号精准。
附图说明
图1是染料分子AS-Cy-1的1H NMR图谱；
图2是染料分子AS-Cy-1的13C NMR图谱；
图3是染料分子BS-Cy-NO2的1H NMR图谱；
图4是染料分子BS-Cy-NO2的13C NMR图谱；
图5是染料分子BS-Cy-NO2对硝基还原酶的滴定紫外光谱图的变化情况及其线性关系拟合图；
图6是染料分子BS-Cy-NO2对硝基还原酶的滴定荧光光谱图的变化情况及其线性关系拟合图；
图7是染料分子BS-Cy-NO2皮下注射荷瘤小鼠瘤内比率近红外荧光成像图；
图8是染料分子BS-Cy-NO2皮下注射荷瘤小鼠瘤内比率光声成像图。
具体实施方式
下面结合实施例和附图对本发明内容做进一步说明，但本发明不受下述实施例的限制。
实施例1
染料分子AS-Cy-1的合成与表征
将255.5mg(0.5mmol)原料1b用N,N-二甲基甲酰胺(DMF)溶解后加入63.1mg(0.5mmol)间苯硫酚和12mg氢化纳置于圆底烧瓶中，在氮气保护和40℃条件下搅拌8小时；
反应完毕后，将反应液倒入冰水中混合，加入0.5ml高氯酸静置析出固体，抽滤得到粗产品；
将得到的粗产品，用体积比为50:1的二氯甲烷与甲醇为洗脱剂，用硅胶(200-300目)层析柱进行纯化，得到106.3mg蓝色固体(产率为：51.3％)。
参照图1，1H NMR(500MHz,DMSO-d6)δ8.26(d,J＝14.4Hz,1H),7.77(dd,J＝39.7,7.7Hz,2H),7.58–7.53(m,2H),7.49(t,J＝7.4Hz,1H),7.37(s,1H),7.11(d,J＝2.3Hz,1H),6.94(dd,J＝8.5,2.3Hz,1H),6.70(d,J＝14.5Hz,1H),4.46(q,J＝7.2Hz,2H),2.71(dt,J＝29.6,6.0Hz,4H),1.87–1.83(m,2H),1.76(s,6H),1.39(t,J＝7.3Hz,3H)。
参照图2，13C NMR(125MHz,DMSO-d6)δ177.25,159.88,152.91,152.81,144.96,144.91,142.89,141.48,136.22,135.39,133.22,131.53,130.11,129.47,127.80,126.51,123.34,121.88,117.52,113.72,111.13,106.26,50.97,40.90,32.13,27.99,26.72,13.25。
其他染料分子SS-Cy-1、SS-Cy-2、AS-Cy-2、BS-Cy-1、BS-Cy-2、CS-Cy-1和CS-Cy-2的合成步骤与AS-Cy-1不同在于原料1的选择不同，其他合成步骤相同。
实施例2
染料分子BS-Cy-NO2的合成与表征
将282.1mg(0.5mmol)BS-Cy-1用N,N-二甲基甲酰胺(DMF)溶解后加入108mg(0.5mmol)溴代对硝基甲苯和17.3mg碳酸钾置于圆底烧瓶中，在氮气保护和60℃条件下搅拌反应4小时；
反应完毕后，将反应液倒入冰水中混合，加入0.5ml高氯酸静置析出固体，抽滤得到粗产品；
将得到的粗产品，用体积比为60:1的二氯甲烷与甲醇为洗脱剂，用硅胶(200-300目)层析柱进行纯化，得到227.6mg蓝色固体(产率为：65.1％)。
参照图3，1H NMR(600MHz,DMSO-d6))δ8.38(t,J＝11.8Hz,1H),8.32(d,J＝8.6Hz,1H),8.26(d,J＝8.9Hz,1H),8.19(d,J＝8.2Hz,1H),8.02(d,J＝8.9Hz,1H),7.77(d,J＝8.6Hz,2H),7.73–7.60(m,2H),7.48(s,1H),7.33(s,1H),7.18(t,J＝7.7Hz,2H),6.97–6.88(m,2H),6.85(d,J＝14.7Hz,1H),6.67(d,J＝8.2Hz,1H),5.77(s,1H),5.46(d,J＝18.1Hz,2H),4.64(d,J＝7.4Hz,2H),2.92–2.71(m,4H),2.02(s,6H),1.87(s,2H),1.46(t,J＝7.1Hz,3H)。
参照图4，13C NMR(151MHz,DMSO-d6))δ179.00,162.77,159.36,158.61,150.48,147.63,144.61,144.30,139.11,137.18,134.84,134.39,133.04,132.57,131.50,130.78,130.56,130.11,128.83,127.49,127.12,124.21,123.54,123.14,117.66,115.06,113.44,113.05,110.29,107.26,69.08,55.40,52.88,36.26,32.17,31.62,27.55,13.69。
染料分子AS-Cy-NO2的合成步骤与BS-Cy-NO2不同在于原料为AS-Cy-1，其他合成步骤相同。
实施例3
染料分子BS-Cy-NO2对硝基还原酶响应的光谱：
配置实施例2中制备的染料分子BS-Cy-NO2的DMSO母液，浓度为10mM；然后分别在紫外和荧光皿中加入1998μL液体(PBS：甲醇＝8：2)和2μL探针母液，在皿中加入硝基还原酶和NADH，可以观察到紫外光谱峰在670nm下降750nm上升，荧光光谱峰在760nm下降800nm上升，呈现一个双比率的变化，如图5、图6所示。
实施例4
染料分子BS-Cy-NO2对肿瘤乏氧水平的比率近红外荧光成像：
配置染料分子BS-Cy-NO2的DMSO母液15mM，对荷瘤小鼠进行原位瘤内注射，然后分别在30min、45min、60min、85min对荷瘤小鼠进行近红外荧光成像，可以看到通道一荧光无明显变化，而通道二荧光逐渐增强，如图7所示。
实施例5
染料分子BS-Cy-NO2对肿瘤乏氧水平的比率光声成像：
配置染料分子BS-Cy-NO2的DMSO母液15mM，对荷瘤小鼠进行原位瘤内注射，然后分别在30min、45min、60min、85min对荷瘤小鼠进行光声成像，可以看到通道一光声信号逐渐减弱，而通道二光声信号逐渐增强，如图8所示。
Claims (9)
1.一种双比率型半花菁类染料分子，其特征在于，所述染料分子的结构式如下：
2.权利要求1所述双比率型半花菁类染料分子的合成方法，其特征在于，染料分子SS-Cy-1—CS-Cy-2的合成路线如下：
3.权利要求1所述双比率型半花菁类染料分子的合成方法，其特征在于，染料分子AS-Cy-NO2和BS-Cy-NO2的合成路线如下：
4.根据权利要求2所述双比率型半花菁类染料分子的合成方法，其特征在于，染料分子SS-Cy-1—CS-Cy-2的具体合成步骤为：
将原料1a、1b、1c或1d分别溶解于N,N-二甲基甲酰胺DMF中，随后加入原料2和氢化纳，在氮气保护和40℃条件下搅拌反应8小时；
反应完毕后，将反应液倒入冰水中混合，加入0.5ml高氯酸静置析出固体，抽滤得到粗产品；
将得到的粗产品，用体积比为50:1的二氯甲烷与甲醇为洗脱剂，用200-300目硅胶层析柱进行纯化，得到染料分子SS-Cy-1—CS-Cy-2固体。
5.根据权利要求4所述双比率型半花菁类染料分子的合成方法，其特征在于：
所述原料2结构式中R＝OH或NH2；
所述原料1a、1b、1c或1d与原料2的摩尔比为1:1；
所述原料1a、1b、1c或1d和氢化纳的摩尔比为1:1。
6.根据权利要求3所述双比率型半花菁类染料分子的合成方法，其特征在于，染料分子AS-Cy-NO2或BS-Cy-NO2的具体合成步骤为：
将原料AS-Cy-1或BS-Cy-1分别溶于N,N-二甲基甲酰胺DMF中，随后加入溴代对硝基甲苯和碳酸钾，在氮气保护和60℃条件下搅拌反应4小时；
反应完毕后，将反应液倒入冰水中混合，加入0.5ml高氯酸静置析出固体，抽滤得到粗产品；
将得到的粗产品，用体积比为60:1的二氯甲烷与甲醇为洗脱剂，用200-300目硅胶层析柱进行纯化，得到染料分子AS-Cy-NO2或BS-Cy-NO2固体。
7.根据权利要求6所述双比率型半花菁类染料分子的合成方法，其特征在于：所述原料AS-Cy-1或BS-Cy-1与溴代对硝基甲苯的摩尔比为1:1；
所述原料AS-Cy-1或BS-Cy-1与碳酸钾的摩尔比为4:1。
8.权利要求1所述双比率型半花菁类染料分子的应用，其特征在于：染料分子AS-Cy-NO2或BS-Cy-NO2用于制备硝基还原酶检测试剂。
9.权利要求1所述双比率型半花菁类染料分子的应用，其特征在于：染料分子AS-Cy-NO2或BS-Cy-NO2用于双比率定量检测硝基还原酶来监测肿瘤乏氧水平与肿瘤治疗评估。
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