CN116444548A - 一种含噻唑的bodipy二聚体荧光探针dou-bodipy及其制备方法和应用 - Google Patents
一种含噻唑的bodipy二聚体荧光探针dou-bodipy及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于有机合成技术领域,公开了一种含噻唑的BODIPY二聚体荧光探针DOU‑BODIPY及其制备方法和应用,本发明采用氟硼吡咯荧光染料和醛类化合物发生诺文格尔缩合反应而合成SIN‑BODIPY,然后使SIN‑BODIPY与发生偶联反应生成二聚体DOU‑BODIPY;阿尔茨海默症(AD)患者的大脑中有斑块的沉积,斑块主要由β‑淀粉样蛋白(Aβ)纤维的聚集后沉淀而成。噻唑有很强的供电子和电子转移能力,作为电子供体基团,BODIPY单体为荧光团化合物,通常作为电子受体基团。BODIPY二聚体的具有高吸收系数、强发射、相对较好的耐热性和耐光性等优势,这些优异的性能使得BODIPY被广泛应用于现代生物、医学等领域。此DOU‑BODIPY可以有效地提高BODIPY染料的光子吸收能力和荧光强度的能力,从而对AD的诊断具有重要价值。
Description
技术领域
本发明属于有机合成技术领域,涉及用于AD诊断的荧光探针的制备,具体涉及一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY及其制备方法和应用。
背景技术
阿尔茨海默症(AD)是一种神经退行性疾病,由数据统计可知,全球老龄化加剧,AD的患病人数逐年攀升,中国是全球AD患者数量最多的国家。在中国65岁以上人群老年痴呆病逐渐上升,但是就诊率、治疗率非常低。目前针对 AD 的研究主要围绕淀粉样蛋白β(Aβ) 在细胞外沉积形成的老年斑。大量研究表明 Aβ 通过脑部多种生理途径产生神经毒性,是脑部其他生理病变的导火线。现在AD诊断的方法就两种:神经影像学检查和脑脊液CSF检查,但是这两种诊断方法都存在着一些弊端。
氟化硼络合二毗咯甲川类(简称BODIPY)荧光染料是一类性能优异的新型荧光染料,受到了众多科学研究者的极大关注和认可。对于荧光染料的研究已经有 100 多年的历史,随着理论研究的深入和系统化,实际应用范围逐渐渗透到各个领域,如材料、环境、医学、生物和能源。在此基础上研究出具有高灵敏度和高选择性的新型荧光探针对AD的诊断具有重要意义。
发明内容
针对现有技术的不足,本发明的目的在于提供一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY,该荧光探针可用于AD的诊断,具有近红外长波长、高亲和性、高选择性的优点;本发明的另一目的在于提供该荧光探针的制备方法。
本发明是通过以下技术方案实现的:
一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY,其结构式如下所示:
。
本发明的进一步改进方案为:
一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY的制备方法,包括以下步骤:
(1)使噻唑-2-甲醛与2,4-二甲基吡咯发生环合反应制得中间产物SIN-BODIPY;
(2)使SIN-BODIPY发生偶联反应生成二聚体DOU-BODIPY;
反应路线如下所示:
;
。
进一步的,步骤(1)的具体过程为:将噻唑-2-甲醛、2,4-二甲基吡咯混合溶解到二氯甲烷中,在搅拌下依次加入 2,3-二甲基-5,6-二氰基苯醌、新蒸过的三乙胺并继续搅拌,冰浴中缓慢滴加三氟化硼乙醚,继续搅拌反应,反应完全后,柱层析,减压蒸馏除去溶剂后,置于强酸性溶液加水进行醛基的脱保护反应,进行干燥和提纯,得到SIN-BODIPY。
进一步的,所述噻唑-2-甲醛、2,4-二甲基吡咯、三乙胺、三氟化硼乙醚以及2,3-二甲基-5,6-二氰基苯醌的摩尔比为1:(1.8~2.3):(0.3~2.3):(1~3):(0.8~1.2)。
进一步的,步骤(2)的具体过程为:取FeCl3·6H2O和SOCl2,回流1 h~3 h,减压除去SOCl2与水,然后加入SIN-BODIPY,溶解在干燥过的CH2Cl2中,溶液迅速由深绿-红-紫,室温搅拌反应 0.25 h~3h,再加入甲醇淬灭,水洗,MgSO4干燥,过滤,旋蒸得粗产物,进一步硅胶柱层析得产物DOU-BODIPY。
进一步的,所述SIN-BODIPY与FeCl3·6H2O的摩尔比为1﹕1.8~2.25。
本发明的更进一步改进方案为:
所述含噻唑的BODIPY二聚体荧光探针DOU-BODIPY在AD诊断领域的应用。
与现有技术相比,本发明的有益效果为:
本发明先采用氟硼吡咯荧光染料和醛类化合物发生诺文格尔缩合反应而合成SIN-BODIPY,然后将SIN-BODIPY与自身相同的化合物共价相连合成DOU-BODIPY。用于检测阿尔茨海默症的生物标志物Aβ纤维。噻唑有很强的供电子和电子转移能力,作为电子供体基团,BODIPY单体为荧光团化合物,通常作为电子受体基团。而与单体SIN-BODIPY相比,二聚体DOU-BODIPY具有高吸收系数、强发射、高荧光量子产率和相对较好的耐热性和耐光性等优势,这些优异的性能使得 BODIPY 被广泛应用于现代生物、医学等领域。
附图说明
图1为本发明实施例1得到的DOU-BODIPY的核磁氢谱图;
图2为本发明实施例1得到的DOU-BODIPY化合物对AD小鼠脑组织切片的荧光染色呈现。
实施方式
下面结合具体实施例对本发明进行详细的介绍。
实施例
(1)称取204mg(2.0 mmol)噻唑-2-甲醛,溶解到200 mL新蒸过的二氯甲烷中,注入无色的2,4-二甲基吡咯液体412 mg(4.4 mmol),在搅拌下加入 2,3-二甲基-5,6-二氰基苯醌454 mg(2 mmol)。加入 3mL 新蒸过的三乙胺并搅拌 10 分钟。冰浴中缓慢滴加3 mL三氟化硼乙醚,1.5个小时后,TLC跟踪至原料反应完全后,柱层析,减压蒸馏除去溶剂后,置于强酸性溶液加水进行醛基的脱保护反应,进行干燥和提纯,得到SIN-BODIPY。
(2)取FeCl3·6H2O(245 mg,0.90 mmol),SOCl2(2 mL),回流1 h,减压除去 SOCl2与水,得到无水FeCl3,然后加入SIN-BODIPY(130 mg,0.40 mmol),溶解在干燥过的CH2Cl2(10mL)中,溶液迅速由深绿-红-紫,室温搅拌反应 25 min,再加入MeOH(10mL)淬灭,水洗(2x150 mL),MgSO4干燥,过滤,旋蒸得粗产物,进一步硅胶柱层析(CH2Cl2: petroleumether = 2:1)得产物DOU-BODIPY(7 mg),产率 6%。所述化合物通过核磁1H NMR谱图确定目标产物。
实施例
取FeCl3·6H2O(390 mg,1.5 mmol),SOCl2(2 mL),回流1 h,减压除去 SOCl2与水,得到无水FeCl3,然后加入实施例1制得的SIN-BODIPY(260 mg,0.80 mmol),溶解在干燥过的CH2Cl2(10mL)中,溶液迅速由深绿-红-紫,室温搅拌反应 25 min,再加入MeOH(10mL)淬灭,水洗(2x150 mL),MgSO4干燥,过滤,旋蒸得粗产物,进一步硅胶柱层析(CH2Cl2:petroleum ether = 2:1)得产物DOU-BODIPY(38 mg),产率 15%。所述化合物通过核磁1HNMR谱图确定目标产物。
实施例
取FeCl3·6H2O(540 mg,2 mmol),SOCl2(2 mL),回流1 h,减压除去 SOCl2与水,得到无水FeCl3,然后加入实施例1制得的SIN-BODIPY(312 mg,1 mmol),溶解在干燥过的CH2Cl2(10mL)中,溶液迅速由深绿-红-紫,室温搅拌反应 25 min,再加入MeOH(10mL)淬灭,水洗(2x150 mL),MgSO4干燥,过滤,旋蒸得粗产物,进一步硅胶柱层析(CH2Cl2: petroleumether = 2:1)得产物DOU-BODIPY(76 mg),产率 20%。所述化合物通过核磁1H NMR谱图确定目标产物。
实施例
DOU-BODIPY对AD脑组织切片的荧光染色呈现识别分析
采用成年阿尔茨海默病模型小鼠APPswe/PS1dE9脑组织进行组织学分析。使用石蜡包埋海马体的部分组织,切片为12µm厚,并用40%乙醇DOU-BODIPY化合物溶液(120uM)染色2小时,使用40%乙醇洗涤30分钟,在640 nm的共聚焦激光显微镜(尼康A1R)下,使用荧光保存试剂冲洗覆盖所有切片,发现DOU-BODIPY使 Aβ呈现红色荧光,这说明DOU-BODIPY化合物对AD的准确诊断有很好的潜在应用价值。
上述实施方式只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰,都应涵盖在本发明的保护范围之内。
Claims (7)
1.一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY,其特征在于,结构式如下所示:
。
2.一种如权利要求1所述的一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY的制备方法,其特征在于,包括以下步骤:
(1)使噻唑-2-甲醛与2,4-二甲基吡咯发生环合反应制得中间产物SIN-BODIPY;
(2)使SIN-BODIPY发生偶联反应生成二聚体DOU-BODIPY;
反应路线如下所示:
;
。
3.根据权利要求2所述的一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY的制备方法,其特征在于:步骤(1)的具体过程为:将噻唑-2-甲醛、2,4-二甲基吡咯混合溶解到二氯甲烷中,在搅拌下依次加入 2,3-二甲基-5,6-二氰基苯醌、新蒸过的三乙胺并继续搅拌,冰浴中缓慢滴加三氟化硼乙醚,继续搅拌反应,反应完全后,柱层析,减压蒸馏除去溶剂后,置于强酸性溶液加水进行醛基的脱保护反应,进行干燥和提纯,得到SIN-BODIPY。
4.根据权利要求3所述的一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY的制备方法,其特征在于:所述噻唑-2-甲醛、2,4-二甲基吡咯、三乙胺、三氟化硼乙醚以及2,3-二甲基-5,6-二氰基苯醌的摩尔比为1:(1.8~2.3):(0.3~2.3):(1~3):(0.8~1.2)。
5.根据权利要求2所述的一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY的制备方法,其特征在于:步骤(2)的具体过程为:取FeCl3·6H2O和SOCl2,回流1 h~3 h,减压除去SOCl2与水,然后加入SIN-BODIPY,溶解在干燥过的CH2Cl2中,溶液迅速由深绿-红-紫,室温搅拌反应 0.25 h~3h,再加入甲醇淬灭,水洗,MgSO4干燥,过滤,旋蒸得粗产物,进一步硅胶柱层析得产物DOU-BODIPY。
6.根据权利要求5所述的一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY的制备方法,其特征在于:所述SIN-BODIPY与FeCl3·6H2O的摩尔比为1﹕1.8~2.25。
7.一种如权利要求1所述的一种含噻唑的BODIPY二聚体荧光探针DOU-BODIPY在AD诊断领域的应用。
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