CN116143812A - 一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针及其制备方法 - Google Patents
一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针(TFF‑BODIPY)及其制备方法,该TFF‑BODIPY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,获得BODIPY衍生物再与2‑氨基苯硫醇反应而合成。通过反应形成的新化合物在三氯甲烷中的最大吸收和最大发射波长在可见光区。研究表明β‑淀粉样蛋白(Aβ)的错误折叠和聚集是阿尔茨海默症发生的主要原因之一。其中苯丙氨酸二肽(FF)作为Aβ肽的核心基序,在Aβ折叠和诱导AD过程中起着关键作用,FF两个芳香环的距离约为13.4Å,此TFF‑BODIPY两端芳香环与FF的两个苯环正好重叠,TFF‑BODIPY通过与FF的多重π‑π作用识别Aβ纤维,从而达到诊断阿尔茨海默症的目的。
Description
技术领域
本发明属于有机合成技术领域,涉及荧光探针的制备,具体涉及一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针及其制备方法。
背景技术
人口老龄化加剧,阿尔茨海默症(AD)患者逐年增多,有效地检测其发病已成为世界性难题。中国患者居全球首位,现有的诊断手段主要有两种,一种是试剂盒检测病理蛋白,需要腰椎穿刺来提取脑脊液,用试剂盒里的试剂对脑脊液进行检查,另一种为β-淀粉样蛋白(Aβ)的PET检查。研究表明,Aβ肽的错误的折叠和聚集,导致神经元的死亡,从而引发AD,然而在Aβ折叠和聚集的过程中,苯丙氨酸二肽(FF)在其中起着关键的作用,FF作为Aβ的核心基序可以自组装成纤维,加速AD的发生。如果能快速有效检测出人体中FF,也就能识别出Aβ聚集体,从而诊断AD。
与脑脊液检测和基于放射性核素的成像技术相比,光学成像具有非侵入性、非放射性、相对廉价等特点,并能在体内和体外的实时的荧光成像。然而,荧光成像的关键局限是其穿透能力不强,尤其是一些发射波长较短的荧光探针。BODIPY类探针可以很好的解决这一问题,BODIPY是最常用的小分子荧光团之一,其支架可以功能化,调整其光物理特性到所需的范围,进而增强荧光的发射强度。因此研究高灵敏性、特异性,针对Aβ中FF的BODIPY荧光探针,对于诊断AD具有重要的意义。
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苯并噻唑识别Aβ纤维的BODIPY荧光探针,该荧光探针具有长波长、高亲和性、高选择性,对于诊断AD具有重要的意义。
本发明是通过以下技术方案实现的:
一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针,具有如下所示的分子结构式:
式中二吡咯甲川氟硼络合物的8位有一个苯并噻唑化合物取代基,1,3,5,7-位有四个甲基。
本发明的进一步改进方案为:
一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,包括以下步骤:
(1)以对苯二甲醛、乙二醇为原料,苯为溶剂,在催化剂732#强酸性阳离子交换树脂的作用下,反应制备4-(1,3-二氧戊环-2-基)苯甲醛;
(2)以4-(1,3-二氧戊环-2-基)苯甲醛以及二甲基吡咯为原料,二氯甲烷作为溶剂,2,3-二甲基-5,6-二氰基苯醌为催化剂,三氟化硼乙醚为络合剂,先得到橙黄色固体产物BODIPY-1,再由BODIPY-1进行醛基的脱保护反应制备中间产物BODIPY-2;
(3)BODIPY-2和2-氨基苯硫醇为原料,无水乙醇为溶剂,浓缩盐酸和过氧化氢溶液为催化剂,制备荧光探针TFF-BODIPY化合物;
反应路线如下式所示:
本发明的更进一步改进方案为:
步骤(1)的具体过程为:将对苯二甲醛、乙二醇的混合溶液放到三角瓶中,再加入催化剂732#强酸性阳离子交换树脂和溶剂苯,加热并开启搅拌器,温度在70~110℃,进行缩醛化反应,冷凝回流,反应生成的水由苯共沸时收集到分水器,反应1h~2h后结束,稍冷,用减压过滤除去催化剂,滤液常压蒸馏除去低沸点物质,减压蒸馏,收集馏分,得到4-(1,3-二氧戊环-2-基)苯甲醛。
进一步的,所述苯二甲醛、乙二醇、732#强酸性阳离子交换树脂的摩尔比为(1~1.5)∶(1~1.75)∶(0.1~0.5)。
进一步的,步骤(1)过程中,苯二甲醛的两个醛基,其中一个醛基用一分子乙二醇进行了缩醛化反应,对醛基进行了保护,制备得到了4-(1,3-二氧戊环-2-基)苯甲醛;反应过程中,溶剂苯同时作为带水剂,带走反应生成的水。
进一步的,步骤(2)的具体过程为:将二甲基吡咯、4-(1,3-二氧戊环-2-基)苯甲醛混合溶解到二氯甲烷中,加入三乙胺,室温搅拌0.5h~6h,冰浴中缓慢滴加三氟化硼乙醚,搅拌0.5h~6h,加入2,3-二甲基-5,6-二氰基苯醌,二氯甲烷萃取,无水Na2SO4干燥,真空除去溶剂,采用层析柱分离提纯,得到橙黄色固体产物BODIPY-1(B1);将BODIPY-1置于氯化氢水溶液中进行醛基的脱保护反应,进行干燥和提纯,最终得到淡黄色固体产物BODIPY-2。
进一步的,所述二甲基吡咯、4-(1,3-二氧戊环-2-基)苯甲醛、三乙胺、三氟化硼乙醚配合物以及2,3-二甲基-5,6-二氰基苯醌的摩尔比为(1~3.3)∶(0.3~2.3)∶(0.3~4.3)∶(0.3~3)∶(0.01~0.43)。
进一步的,步骤(3)的具体过程为:向烘干的烧瓶中加入BODIPY-2和2-氨基苯硫醇,然后加入无水乙醇溶解固体,用冰浴冷却烧瓶,剧烈搅拌,浓缩盐酸和过氧化氢被顺序加入到溶液中,混合物在室温下搅拌过夜,薄层色谱法显示起始材料完全消失,然后过滤混合物,用无水乙醇洗涤滤液三次并干燥,得到黄色固体产物TFF-BODIPY。
进一步的,所述BODIPY-2、2-氨基苯硫醇、浓缩盐酸以及过氧化氢的摩尔比为(0.5~1.75)∶(0.5~1.78)∶(2.2~2.8)∶(3.2~3.8)。
与现有技术相比,本发明的有益效果是:
本发明首先对反应物中的苯二甲醛当中的一个醛基进行保护,生成4-(1,3-二氧戊环-2-基)苯甲醛,然后在与二甲基吡咯与发生诺文葛耳缩合反应,合成BODIPY化合物荧光染料,与2-氨基苯硫醇发生缩合反应,最后得到TFF-BODIPY。β-淀粉样蛋白缠结作为阿尔茨海默症主要原因之一,其中苯丙氨酸二肽(FF)作为Aβ肽的核心基序,在Aβ折叠和具体过程中起着关键作用,FF两个芳香环的距离约为此TFF-BODIPY中的分子大小长度与Aβ纤维中FF的两个苯环分子之间的距离相同,所以TFF-BODIPY可以通过π-π相互作用识别Aβ纤维中的FF,结合后荧光强度增强,进而荧光显现Aβ纤维的形貌,从而达到诊断阿尔茨海默症的目的。
附图说明
图1是本发明实施例1得到的TFF-BODIPY的核磁氢谱图;
图2是本发明实施例1得到的TFF-BODIPY对AD小鼠脑切片荧光染色呈现。
具体实施方式
为使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施方式,进一步阐述本发明。
以下实施例中所用的BODIPY-2制备方法如下:
(1)在三角瓶中加入536mg(4.0mmol)对苯二甲醛和248mg(4.0mmol)乙二醇,再加入0.1g 732#强酸性阳离子交换树脂和40ml苯为带水剂,加热并开启搅拌器,温度在90℃,进行缩醛化反应,冷凝回流,反应生成的水由带水剂共沸时带到分水器,反应时间90min后结束。稍冷,过滤反应产物(用减压过滤除去催化剂),滤液常压蒸馏除去低沸点物质,在减压蒸馏,收集馏分,得到4-(1,3-二氧戊环-2-基)苯甲醛。
(2)取356mg(2.0mmol)4-(1,3-二氧戊环-2-基)苯甲醛,溶解到200mL新蒸过的二氯甲烷中,用注射器注入412mg(4.4mmol)2,4-二甲基吡咯和3ml三乙胺,快速磁力搅拌、避光、室温下搅过夜,氮气保护,冰浴中缓慢滴加3mL三氟化硼乙醚,搅拌10分钟,然后在搅拌下加入2,3-二甲基-5,6-二氰基苯醌45.4mg(0.2mmol),TLC跟踪至原料反应完全后,柱层析,减压蒸馏除去溶剂后,二氯甲烷萃取,无水Na2SO4干燥,50℃真空除去溶剂,采用层析柱分离提纯,得到橙黄色固体产物BODIPY-1;将BODIPY-1置于盐酸溶液(3毫升,6当量)搅拌反应6小时,进行醛基的脱保护反应,得到的粗产品用乙酸乙酯萃取,液体溶剂蒸干,固体进行重结晶,进行干燥得到氟硼二吡咯荧光染料BODIPY-2。
实施例1
向烘干的烧瓶中加616mg(1.75mmol)BODIPY-2和224mg(1.78mmol)2-氨基苯硫醇,然后加入80毫升无水乙醇溶解固体。用冰浴冷却烧瓶。剧烈搅拌,浓缩盐酸(0.14毫升,2.6当量)和过氧化氢(0.24毫升,4.5当量)被顺序加入到溶液中。混合物在室温下搅拌过夜。薄层色谱法(TLC)显示起始材料完全消失。然后过滤混合物。用无水乙醇洗涤滤液三次并干燥,得到黄色固体产物TFF-BODIPY(247mg,产率30%),所述化合物通过核磁1H NMR谱图确定目标产物。
实施例2
向烘干的烧瓶中加352mg(1.0mmol)BODIPY-2和125mg(1.0mmol)2-氨基苯硫醇,然后加入60毫升无水乙醇溶解固体。用冰浴冷却烧瓶。剧烈搅拌,浓缩盐酸(0.14毫升,2.6当量)和过氧化氢(0.24毫升,4.5当量)被顺序加入到溶液中。混合物在室温下搅拌过夜。薄层色谱法(TLC)显示起始材料完全消失。然后过滤混合物。用无水乙醇洗涤滤液三次并干燥,得到黄色固体产物TFF-BODIPY(132mg,产率28%),所述化合物通过核磁1H NMR谱图确定目标产物。
实施例3
向烘干的烧瓶中加352mg(1.0mmol)BODIPY-2和250mg(2.0mmol)2-氨基苯硫醇,然后加入70毫升无水乙醇溶解固体。用冰浴冷却烧瓶。剧烈搅拌,浓缩盐酸(0.14毫升,2.6当量)和过氧化氢(0.24毫升,4.5当量)被顺序加入到溶液中。混合物在室温下搅拌过夜。薄层色谱法(TLC)显示起始材料完全消失。然后过滤混合物。用无水乙醇洗涤滤液三次并干燥,得到黄色固体产物TFF-BODIPY(142mg,产率30%),所述化合物通过核磁1H NMR谱图确定目标产物。
实施例4:实施例1所制备物质的应用
TFF-BODIPY对阿尔兹海默症小鼠脑组织切片检测分析:
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。石蜡包埋海马体的部分组织,切片10μm厚。切片用50%乙醇TFF-BODIPY溶液(100uM)染色2小时,用50%乙醇洗涤20分钟,在640nm的共聚焦激光显微镜(尼康A1R)下,使用荧光保存试剂(Merck Millipore公司)冲洗并覆盖所有切片进行组织学评价,发现TFF-BODIPY对Aβ纤维有特殊的响应,这说明TFF-BODIPY对阿尔兹海默症诊断有潜在的应用价值。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (8)
2.如权利要求1所述的一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,其特征在于,包括以下步骤:
(1)以对苯二甲醛、乙二醇为原料,苯为溶剂,在催化剂732#强酸性阳离子交换树脂的作用下,反应制备4-(1,3-二氧戊环-2-基)苯甲醛;
(2)以4-(1,3-二氧戊环-2-基)苯甲醛以及二甲基吡咯为原料,二氯甲烷作为溶剂,2,3-二甲基-5,6-二氰基苯醌为催化剂,三氟化硼乙醚为络合剂,先得到橙黄色固体产物BODIPY-1,再由BODIPY-1进行醛基的脱保护反应制备中间产物BODIPY-2;
(3)BODIPY-2和2-氨基苯硫醇为原料,无水乙醇为溶剂,浓缩盐酸和过氧化氢为催化剂,制备荧光探针TFF-BODIPY化合物;
反应路线如下式所示:
3.根据权利要求2所述的一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,其特征在于:步骤(1)的具体过程为:将对苯二甲醛、乙二醇的混合溶液放到三角瓶中,再加入催化剂732#强酸性阳离子交换树脂和溶剂苯,加热并开启搅拌器,温度在70~110℃,进行缩醛化反应,冷凝回流,反应生成的水由苯共沸时收集到分水器,反应1h~2h后结束,稍冷,用减压过滤除去催化剂,滤液常压蒸馏除去低沸点物质,减压蒸馏,收集馏分,得到4-(1,3-二氧戊环-2-基)苯甲醛。
4.根据权利要求3所述的一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,其特征在于:所述苯二甲醛、乙二醇、732#强酸性阳离子交换树脂的摩尔比为(1~1.5)∶(1~1.75)∶(0.1~0.5)。
5.根据权利要求2所述的一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,其特征在于:步骤(2)的具体过程为:将二甲基吡咯、4-(1,3-二氧戊环-2-基)苯甲醛混合溶解到二氯甲烷中,加入三乙胺,室温搅拌0.5h~6h,冰浴中缓慢滴加三氟化硼乙醚,搅拌0.5h~6h,加入2,3-二甲基-5,6-二氰基苯醌,二氯甲烷萃取,无水Na2SO4干燥,真空除去溶剂,采用层析柱分离提纯,得到橙黄色固体产物BODIPY-1;将BODIPY-1置于氯化氢的水溶液中进行醛基的脱保护反应,进行干燥和提纯,最终得到淡黄色固体产物BODIPY-2。
6.根据权利要求5所述的一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,其特征在于:所述二甲基吡咯、4-(1,3-二氧戊环-2-基)苯甲醛、三乙胺、三氟化硼乙醚配合物以及2,3-二甲基-5,6-二氰基苯醌的摩尔比为(1~3.3)∶(0.3~2.3)∶(0.3~4.3)∶(0.3~3)∶(0.01~0.43)。
7.根据权利要求2所述的一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,其特征在于:步骤(3)的具体过程为:向烘干的烧瓶中加入BODIPY-2和2-氨基苯硫醇,然后加入无水乙醇溶解固体,用冰浴冷却烧瓶,剧烈搅拌,浓缩盐酸和过氧化氢被顺序加入到溶液中,混合物在室温下搅拌过夜,薄层色谱法显示起始材料完全消失,然后过滤混合物,用无水乙醇洗涤滤液三次并干燥,得到黄色固体产物TFF-BODIPY。
8.根据权利要求7所述的一种含苯并噻唑识别Aβ纤维的BODIPY荧光探针的制备方法,其特征在于:所述BODIPY-2、2-氨基苯硫醇、浓缩盐酸以及过氧化氢的摩尔比为(0.5~1.75)∶(0.5~1.78)∶(2.2~2.8)∶(3.2~3.8)。
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