CN113651840A - 一种-s-s-双硫键侨联抑制ad的小分子药物的荧光探针及其制备方法 - Google Patents
一种-s-s-双硫键侨联抑制ad的小分子药物的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‑S‑S‑双硫键侨联抑制AD的小分子药物的荧光探针及其制备方法,将BODIPY、4‑N,N‑二苯基胺苯甲醛、催化剂A按照摩尔比1~1.3:2~2.3:0.1~1溶于甲苯和哌啶的混合溶液中(v/v:1/1),置于装有Dean‑Stark装置的圆底烧瓶中,120℃‑140℃加热回流,直到所有溶剂都被Dean‑Stark装置收集,再向反应介质中加入甲苯和哌啶。本发明利用含有双硫键的配体结合BODIPY和抑制AD的小分子药物形成一种‑S‑S‑双硫键侨联抑制AD的小分子药物的荧光探针。NB‑S‑S‑M可通过荧光信号有效区分识别与阿尔兹海默症早期、晚期相关的生物标志物Aβ寡聚体、Aβ纤维,而探针上侨联的小分子药物对Aβ的靶向抑制作用,可实现阿尔兹海默症早期诊断预防的作用;同时该化合物制备条件温和,步骤简单,有很好的潜在应用价值。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M)及其制备方法。
背景技术
阿尔茨海默病(AD)以进行性认知功能障碍和行为损害为特征的神经系统疾病,主要表现为记忆障碍、失语、失用、失认、视空间能力损害、抽象思维和计算能力损害、人格和行为改变等。目前市面上的药物对早期的AD没有作用,更不用说晚期的AD。AD的早期准确诊断抑制和疾病监测的缺乏进一步阻碍了治疗性药物的发展。因此,及时准确的诊断前期AD是预防和抑制AD的关键。研究证实,淀粉样蛋白(β-amyloid proteins,简称Aβ)增高是AD疾病发病主要原因之一,因此Aβ检测在AD早期诊断中具有极其重要的价值[2]。目前,Aβ级联假说揭示了Aβ斑块在脑内的缓慢沉积是AD重要病理特征之一,而尸检在脑部发现Aβ斑块也是AD确诊的金标准。因此,以Aβ斑块为靶点,开发与之具有高亲和力的分子探针,并利用分子影像技术就可以实现AD早期无损伤诊断。过去十年以来,已经开发了各种荧光探针体外Aβ荧光成像技术,但是这些荧光探针仍有一些弊端,比如无法将Aβ寡聚体、Aβ纤维区分开和缺乏早期监测AD的能力,最重要的是绝大多数探针未能实现在荧光探针的基础上通过在人体内环境可断裂的化学键侨联抑制AD药物的技术,达不到对AD靶向治疗与抑制一体化。因此,研究具有亲和性、高选择性和集早期诊断和抑制一体的可携带药物的新型荧光探针对AD的早期诊断与抑制具有重要意义。
发明内容
本发明的主要目的在于提供一种有效区分Aβ寡聚体、Aβ纤维的近红外长波长、高亲和性、高选择性的集阿尔兹海默症早期诊断和抑制于一体的荧光探针,可以有效解决背景技术中的问题。
为实现上述目的,本发明提供如下技术方案:一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M),其分子结构式为:
式中二吡咯甲川氟硼络合物通过linker与抑制AD的小分子药物(M)侨联在一起,linker中间通过双硫键连接,M具体为山柰酚、白藜芦醇和姜黄素中的任一种。
其反应路线如下式所示:
一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M),包括如下步骤:
(1)将甲基吡咯、对-乙羟基苯甲醛按照摩尔比2~2.3:1~1.3混合溶解到二氯甲烷中,加入1~1.3当量三乙胺(M:M),室温搅拌1h~3h,冰浴中缓慢滴加1~3当量的三氟化硼乙醚(M:M),搅拌0.5~3h,加入1~3当量的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;
将BODIPY、4-N,N-二苯基胺苯甲醛、催化剂A按照摩尔比1~1.3:2~2.3:0.1~1溶于甲苯和哌啶的混合溶液中(v/v:1/1),置于装有Dean-Stark装置的圆底烧瓶中,120℃-140℃加热回流,直到所有溶剂都被Dean-Stark装置收集,再向反应介质中加入甲苯和哌啶,重复3-5次,TLC跟踪至原料反应完全后,柱层析,减压蒸馏除去溶剂后,得到黑色固体产物NB;
(2)将抑制AD的小分子药物(M)、DCC/DMAP按照摩尔比1:0.1~1/0.1~1溶解到氯仿中,加入1~1.3当量(M:M)含双硫键的linker,50~70℃搅拌1~6h,25~60℃真空旋蒸除去溶剂,采用层析柱分离提纯,得到固体产物M-LSS;
(3)NB与M-LSS按照摩尔比1:1~1.3溶解到氯仿中,加入0.1~1当量(M:M)催化剂B,60~70℃搅拌1h~12h,25~60℃真空旋蒸除去溶剂,采用层析柱分离提纯,反应结束后得到最终产物NB-S-S-M。
优选地,所述NB的合成步骤:所述催化剂A为对甲苯磺酰胺。
进一步地,所述M-LSS的合成步骤:DCC/DMAP为催化剂。
优选地,所述M-LSS的合成步骤:所述linker具有双硫键,具体为双硫二丙酸。
进一步地,所述M-LSS合成步骤:所述AD的小分子药物(M)和linker的摩尔比为1:1~1.3。
优选地,所述NB-S-S-M的合成步骤:催化剂B为DCC/DMAP,其摩尔比1:0.1~1/0.1~1。
与现有技术相比,本发明的有益效果是:
一、双硫键是动态共价键的一种,其键能为240kJ/mol,在一定条件下可以可逆地断裂或形成的共价键,将其应用在荧光探针的侨联上,拓展其使用有很重要的意义;
二、本发明首先采用氟硼二吡咯荧光染料和醛类化合物合成NB,然后通过具有双硫键的linker分别侨联药物山柰酚、白藜芦醇、姜黄素得到NB-S-S-M化合物。NB-S-S-M可通过荧光信号有效区分识别与阿尔兹海默症早期、晚期相关的生物标志物Aβ寡聚体、Aβ纤维,而探针上侨联的小分子药物对Aβ的靶向抑制作用,可实现阿尔兹海默症早期诊断预防的作用;
三、同时该化合物制备条件温和,步骤简单,有很好的潜在应用价值。
附图说明
图1是本发明得到的-S-S-双硫键侨联抑制AD的小分子药物的荧光探针NB-S-S-K的核磁氢谱图。
图2是本发明得到的-S-S-双硫键侨联抑制AD的小分子药物的荧光探针NB-S-S-R的核磁氢谱图。
图3是本发明得到的-S-S-双硫键侨联抑制AD的小分子药物的荧光探针NB-S-S-C的核磁氢谱图。
图4是本发明得到的-S-S-双硫键侨联抑制AD的小分子药物的荧光探针NB-S-S-C对Aβ寡聚体、Aβ纤维的荧光响应。
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。
以下实施例所用的NB制备方法如下:
(1)将甲基吡咯(1.1mmol)、对-乙羟基苯甲醛(0.5mmol)、和三乙胺(0.2ml)混合溶解到二氯甲烷中,室温搅拌过夜,0℃缓慢滴加三氟化硼乙醚(0.2ml),搅拌10分钟,加入2,3-二甲基-5,6-二氰基苯醌(0.5mmol),二氯甲烷萃取,无水Na2SO4干燥,50℃真空旋蒸除去溶剂,采用层析柱分离提纯,得到橙黄色固体产物BODIPY。
(2)将BODIPY(1mmol)、4-N,N-二苯基胺苯甲醛(2.2mmol)、甲苯磺酰胺(0.5mmol)溶于10ml甲苯和哌啶的混合溶液中(v/v:1/1),置于装有Dean-Stark装置的圆底烧瓶中,140℃加热回流,直到所有溶剂都被Dean-Stark装置收集,再向反应介质中加入甲苯和哌啶,重复4次,TLC跟踪至原料反应完全后,柱层析,减压蒸馏除去溶剂后,得到黑色固体产物NB。所述化合物通过核磁1H NMR谱图进行表征,1H NMR(300MHz,DMSO-D6):δ=7.76(d,J=8.8Hz,4H),7.35(S,2H),7.21-7.26(m,10H),6.93-7.11(m,18H),6.76(s,1H),6.00(s,2H),5.66(s,1H),5.25(s,1H),4.60(s,2H),2.27(s,3H),1.93(s,3H)。
实施例1
将Aβ抑制剂山柰酚(0.3mmol)、DCC(0.02mmol)、DMAP(0.02mmol)溶解到5ml氯仿中,加入含双硫键的linker双硫二丙酸(0.3mmol),60℃搅拌4h,30℃真空旋蒸除去溶剂,采用层析柱分离提纯,得到固体产物K-LSS,所述化合物通过核磁1H NMR谱图进行表征,1H NMR(300MHz,DMSO-D6):δ=16.47(s,1H),12.17(s,1H),10.18(s,1H),9.68(s,1H),7.48(s,2H),6.65(s,2H),5.94-6.02(m,2H),2.83(m,4H),2.49(m,4H)。
将NB(0.5mmol)与K-LSS(0.5mmol)溶解到6ml氯仿中,加入DCC(0.01mmol)、DMAP(0.01mmol),60℃搅拌8h,40℃真空旋蒸除去溶剂,采用层析柱分离提纯,反应结束后得到最终产物NB-S-S-K,所述化合物通过核磁1H NMR谱图进行表征,1H NMR(300MHz,DMSO-D6):δ=16.45(s,1H),10.18(s,1H),9.67(s,1H),7.77(d,J=8.8Hz,4H),7.47(s,2H),7.36(s,2H),6.78-7.23(m,28H),6.96(s,1H),6.63(s,2H),5.94(m,2H),6.00(s,2H),5.65(s,1H),5.22(s,2H),2.81-2.95(m,4H),2.49-2.51(m,4H),2.28(s,3H),1.96(s,3H)。
实施例2
将白藜芦醇(0.1mmol)、DCC(0.01mmol)、DMAP(0.01mmol)溶解到4ml氯仿中,加入含双硫键的linker双硫二丙酸(0.1mmol),50℃搅拌3h,25℃真空旋蒸除去溶剂,采用层析柱分离提纯,得到固体产物R-LSS,所述化合物通过核磁1H NMR谱图进行表征,1H NMR(300MHz,DMSO-D6):δ=12.17(s,1H),9.27(s,2H),7.74(s,2H),7.33(s,2H),6.82-6.92(m,2H),6.38(s,2H),6.12(s,1H),2.71-2.95(m,6H),2.49(s,2H)。
将NB(0.2mmol)与R-LSS(0.2mmol)溶解到3ml氯仿中,加入DCC(0.03mmol)、DMAP(0.03mmol),80℃搅拌10h,50℃真空旋蒸除去溶剂,采用层析柱分离提纯,反应结束后得到最终产物NB-S-S-R,所述化合物通过核磁1H NMR谱图进行表征,1H NMR(300MHz,DMSO-D6):δ=9.07(s,2H),7.74-7.77(m,6H),7.00-7.37(m,14H),6.79-7.24(m,19H),6.82-6.95(m,2H),6.38(s,2H),6.12(s,1H),6.00(s,2H),5.67(s,1H),5.20(s,2H),2.95(m,4H),2.71(m,2H),2.51(m,2H),2.29(s,3H),1.94(s,3H)。
实施例3
将姜黄素(0.1mmol)、DCC(0.01mmol)、DMAP(0.01mmol)溶解到5ml氯仿中,加入含双硫键的linker双硫二丙酸(0.1mmol),70℃搅拌5h,30℃真空旋蒸除去溶剂,采用层析柱分离提纯,得到固体产物C-LSS,所述化合物通过核磁1H NMR谱图进行表征,1H NMR(300MHz,DMSO-D6):δ=12.17(s,1H),9.55(s,1H),7.60(s,2H),7.23-7.30(m,2H),7.10-7.11(m,2H),6.91-6.99(m,3H),6.79(s,1H),4.59(s,2H),3.83-3.87(m,6H),2.95(s,2H),2.83(m,2H),2.71(m,2H),2.49(m,2H)。
将NB(0.2mmol)与C-LSS(0.2mmol)溶解到6ml氯仿中,加入DCC(0.01mmol)、DMAP(0.01mmol),60℃搅拌12h,40℃真空旋蒸除去溶剂,采用层析柱分离提纯,反应结束后得到最终产物NB-S-S-C,所述化合物通过核磁1H NMR谱图进行表征,1H NMR(300MHz,DMSO-D6):δ=9.55(s,1H),7.67(d,J=8.8Hz,4H),7.60(s,2H),6.79-7.37(m,37H),6.79-6.95(m,2H),6.00(s,2H),5.67(s,1H),5.20(s,2H),4.59(s,2H),3.83-3.87(m,6H),2.95(m,4H),2.71(s,2H),2.51(s,2H),2.29(s,3H),1.95(s,3H)。
实施例中所制备NB-S-S-C的应用:
NB-S-S-C对Aβ寡聚体、Aβ纤维的荧光响应:
以NB-S-S-C PBS(5μM,1ml)溶液为参照,分别在10μM的Aβ寡聚体(1ml)、10μM的Aβ纤维(1ml)加入NB-S-S-C,取保NB-S-S-C的工作浓度为5μM,通过荧光仪测试分析NB-S-S-C的荧光强度,从而确认NB-S-S-C对Aβ寡聚体、Aβ纤维的荧光响应。
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 (7)
2.一种权利要求1所述的-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M),其特征在于,包括如下步骤:
(1)将甲基吡咯、对-乙羟基苯甲醛按照摩尔比2~2.3:1~1.3混合溶解到二氯甲烷中,加入1~1.3当量三乙胺(M:M),室温搅拌1h~3h,冰浴中缓慢滴加1~3当量的三氟化硼乙醚(M:M),搅拌0.5~3h,加入1~3当量的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;
将BODIPY、4-N,N-二苯基胺苯甲醛、催化剂A按照摩尔比1~1.3:2~2.3:0.1~1溶于甲苯和哌啶的混合溶液中(v/v:1/1),置于装有Dean-Stark装置的圆底烧瓶中,120℃-140℃加热回流,直到所有溶剂都被Dean-Stark装置收集,再向反应介质中加入甲苯和哌啶,重复3-5次,TLC跟踪至原料反应完全后,柱层析,减压蒸馏除去溶剂后,得到黑色固体产物NB;
(2)将抑制AD的小分子药物(M)、DCC/DMAP按照摩尔比1:0.1~1/0.1~1溶解到氯仿中,加入1~1.3当量(M:M)含双硫键的linker,50~70℃搅拌1~6h,25~60℃真空旋蒸除去溶剂,采用层析柱分离提纯,得到固体产物M-LSS;
(3)NB与M-LSS按照摩尔比1:1~1.3溶解到氯仿中,加入0.1~1当量(M:M)催化剂B,60~70℃搅拌1h~12h,25~60℃真空旋蒸除去溶剂,采用层析柱分离提纯,反应结束后得到最终产物NB-S-S-M。
3.权利要求2所述的一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M)的制备方法,其特征在于:所述NB的合成步骤:所述催化剂A为对甲苯磺酰胺。
4.权利要求2所述的一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M)的制备方法,其特征在于:所述M-LSS的合成步骤:DCC/DMAP为催化剂。
5.权利要求2所述的一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M)的制备方法,其特征在于:所述M-LSS的合成步骤:linker具有双硫键,具体为双硫二丙酸。
6.权利要求2所述的一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M)的制备方法,其特征在于:所述M-LSS合成步骤:AD的小分子药物(M)和linker的摩尔比为1:1~1.3。
7.权利要求2所述的一种-S-S-双硫键侨联抑制AD的小分子药物的荧光探针(NB-S-S-M)的制备方法,其特征在于:所述NB-S-S-M的合成步骤:催化剂B为DCC/DMAP,其摩尔比1:0.1~1/0.1~1。
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