CN116813601A - 一种烷氧基噻吩类粘度荧光探针及其制备方法和应用 - Google Patents
一种烷氧基噻吩类粘度荧光探针及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于荧光探针领域领域,涉及用于溶酶体靶向癌细胞的红色荧光成像探针,特别是指一种粘度敏感的荧光探针的制备方法及应用。具有式(I)结构:,本发明的烷氧基噻吩类粘度荧光探针应用于多细胞生物成像以及区分正常细胞和癌细胞,对于癌症检测具有重要意义。
Description
技术领域
本发明属于荧光探针领域,涉及用于溶酶体靶向癌细胞的红色荧光成像和多细胞生物成像探针,特别是指一种烷氧基噻吩类粘度荧光探针的制备方法及应用。
背景技术
粘度是影响细胞内蛋白质、脂质、多糖等流动状态的重要参数,对于促进细胞内生物分子相互作用、化学信号的传递以及代谢产物的扩散等起着重要的作用。细胞内粘度的检测对某些疾病的早期诊断具有重要意义。细胞粘度异常会直接引起细胞器功能障碍,导致许多疾病的发生,如脂肪肝、溶酶体贮积病、恶性肿瘤等。
传统的粘度测量工具如毛细管粘度计、落球粘度计和旋转粘度计等,只适用于液体,不能应用于生物系统。近年来,用于粘度检测的小分子荧光探针逐渐发展起来。与传统的测量工具相比,荧光探针具有响应速度快、灵敏度高、操作简单等优点,是一种检测体内粘度的有效手段。溶酶体是典型的酸性细胞器,在细胞内消化、细胞凋亡和自噬中起着重要作用。目前,人们对溶酶体粘度的了解仍然不够,因此,实时原位监测溶酶体粘度变化对于了解溶酶体的功能,阐明相关疾病的发生机制具有重要意义。
专利CN111116539A公开了一种双重响应癌细胞内溶酶体粘度和pH的荧光探针,该探针发射的是黄绿光而非红光,不能满足深层组织穿透和低背景信号等限制了其应用;专利CN112939935A和CN114437010A分别公开了溶酶体靶向的双光子荧光探针的制备方法,但都没有应用于癌细胞与正常细胞的区别。因此制备一种分子激发光波长达到近红外I区(650-900 nm),具有深层组织穿透、低背景信号,避免细胞自发荧光及最大限度减少光损伤的荧光探针具有紧迫性。
发明内容
为解决上述技术问题,本发明提出一种烷氧基噻吩类粘度荧光探针及其制备方法和应用,该荧光探针具有D-π-A结构,对粘度敏感且具有溶酶体靶向。
本发明的技术方案是这样实现的:
本发明提供的一种烷氧基噻吩类粘度荧光探针,具有式(I)结构:
。
上述的烷氧基噻吩类粘度荧光探针的制备方法,步骤如下:
(1)5-溴-4-(6-溴-1-己氧基噻吩)-2-醛、4-(二苯氨基)苯基硼酸、二(三叔丁基膦)钯和氢氧化钠混合物中加入无水四氢呋喃和水(经过除氧处理),油浴升温至80~100℃,反应至完全,进行萃取、水洗、干燥,得化合物1;
技术路线为:
。
(2)用无水乙腈溶解化合物1,加入吗啉,油浴升温至80~100 ℃,反应至完全,进行水洗、干燥,得化合物2;
技术路线为:
。
(3)在化合物2中加入(3,5,5-三甲基环己-2-烯亚基)丙二腈,无水乙醇和哌啶,油浴升温至80~100 ℃,反应至完全,冷却,析出的沉淀用乙醇洗涤,离心,得到目标化合物(I)。
技术路线为:
。
上述步骤(1)~(3)均在氮气保护下进行。
上述步骤(1)中5-溴-4-(6-溴-1-己氧基噻吩)-2-醛、4-(二苯氨基)苯基硼酸、二(三叔丁基膦)钯与氢氧化钠的物质的量比为1:1~2:0.03~0.05:2。
上述步骤(2)中化合物1与吗啉的物质的量比为1~5:100。
上述步骤(3)中化合物2与(3,5,5-三甲基环己-2-烯亚基)丙二腈的物质的量比为1:1~2,无水乙醇与哌啶体积比200~300:1。
上述的烷氧基噻吩类粘度荧光探针具有粘度敏感、溶酶体靶向性。
上述的烷氧基噻吩类粘度荧光探针在制备区分正常细胞和癌细胞的化学试剂中的应用。
上述的烷氧基噻吩类粘度荧光探针在制备用于多细胞生物成像试剂中的应用。
本发明具有以下有益效果:
1、本发明提供了一种新型的溶酶体靶向癌细胞成像和多细胞生物成像的荧光探针,该探针的合成方法简单易操作,产率高(≥80%),有利于商业化的推广应用。
2、本发明提供的荧光探针,其分子中的吗啉基团容易进入酸性的溶酶体,具有溶酶体靶向性。同时,分子中含有多个分子转子,如吡啶、氰基、三苯胺。扭曲分子内电荷转移(TICT)过程使荧光分子受粘度影响显著,与对照组相比荧光强度增强了3.5倍,因此本申请的荧光探针属于粘度敏感近红外荧光探针。
3、本申请的荧光探针在区分癌细胞与正常细胞时,激发光波长为600~700 nm,位于近红外I区,具有深层组织穿透、低背景信号的作用,在该条件下正常细胞在探针染色后荧光非常弱,而肿瘤细胞则呈现很强的红色荧光,具有显著的差异可用于区分这两种细胞。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为荧光探针(I)的1H NMR谱图。
图2为荧光探针(I)的1C NMR谱图。
图3为荧光探针(I)的高分辨质谱图。
图4为荧光探针(I)在不同粘度的甲醇-甘油体系荧光光谱图,激发波长为495nm,狭缝宽度为2.5 nm。
图5为荧光探针(I)在甲醇-甘油体系的荧光强度与其粘度的线性关系。
图6为荧光探针(I)在癌细胞和正常细胞的成像图,激发波长为514 nm,比例尺为25 μm,浓度为10 μM,P<0.0001。
图7为荧光探针(I)在SMMC-7721细胞的粘度响应,激发波长为514 nm,比例尺为10μm制霉菌素和探针浓度均为10 μM。
图8为荧光探针(I)在SMMC-7721细胞的溶酶体共定位荧光图和共定位系数,激发波长为514 nm,比例尺为10 μm, 商用探针和探针(I)浓度均为10 μM。
图9为荧光探针(I)在秀丽隐杆线虫成像,探针(10 μM),制霉菌素(50 μM),比例尺100 μm。
具体实施方式
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有付出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
烷氧基噻吩类粘度荧光探针的制备方法,步骤如下:
(1)在50 ml Schlenk中加5-溴-4-(6-溴-1-己氧基噻吩)-2-醛(119.1 mg),4-(二苯氨基)苯基硼酸(113.1 mg),二(三叔丁基膦)钯(4.9 mg)氢氧化钠(25.7 mg),抽真空干燥,氮气保护下,加入无水四氢呋喃6 mL,水(经过除氧处理)2 mL,将Schlenk放入油浴升温至80 ℃;反应4 h后,将反应液转移至分液漏斗中,用二氯甲烷萃取,用水洗涤,加无水MgSO4干燥,得到粗品。粗品再过柱层析得到化合物1(169.2mg),产率98%;
(2)用2 mL无水乙腈溶解化合物1(123.0 mg),转移至Schlenk中,N2保护下,加入吗啉(2 mL),油浴升温至90 ℃,反应8h,将反应液转移至分液漏斗中,大量水洗后得到产物2(113.8mg),产率92%;
(3)50 mL Schlenk加入(3,5,5-三甲基环己-2-烯亚基)丙二腈(19.5 mg),氮气保护下,加入化合物2(56.5 mg),无水乙醇(4 mL),哌啶(0.02 mL),油浴升温至85℃,反应24h。冷却,析出沉淀,沉淀用乙醇洗涤离心得到探针(I)(59.6mg),产率80 %;
其表征如下:
1H NMR (400 MHz, CDCl3)(图1) δ 8.65 (d, J = 6.2 Hz, 2H), 7.72 (d, J =8.8 Hz, 2H), 7.64 (s, 1H), 7.62 (s, 1H), 7.50(d, J = 6.2 Hz, 2H), 7.29 (m,4H), 7.14 (d, J = 7.7 Hz, 4H), 7.07 (t, J = 8.2 Hz, 4H), 4.13 (t, J = 6.4 Hz,2H), 3.70 (m, 2H), 2.40 (m, 24H), 2.32 (m, 2H),1.84 (m, 2H), 1.51 (m, 4H),1.39 (m, 2H)。
13C NMR (100 MHz, CDCl3)(图2) δ153.57, 150.56, 147.71, 147.21, 141.59,135.97, 129.41, 124.96, 123.56, 122.59, 122.20, 119.29, 117.57, 103.28,77.35,77.24, 77.03, 76.72, 71.82, 66.95, 58.99, 53.78, 29.39, 27.17, 26.43,25.98。
HRMS (ESI) m/z: [M+H]+(图3)calcd for: C40H41N4O2S 641.2950; found641.2941。
实施例2
烷氧基噻吩类粘度荧光探针的制备方法,步骤如下:
(1)在50 mL Schlenk中加5-溴-4-(6-溴-1-己氧基噻吩)-2-醛(119.1 mg),4-(二苯氨基)苯基硼酸(139.2 mg),二(三叔丁基膦)钯(5.49 mg)氢氧化钠(25.7 mg),抽真空干燥,氮气保护下,加入无水四氢呋喃4 mL,水(经过除氧处理)4 mL,将Schlenk放入油浴升温至100 ℃;反应4 h后,将反应液转移至分液漏斗中,用二氯甲烷萃取,用水洗涤,加无水MgSO4干燥,得到粗品。粗品再过柱层析得到化合物1 (160.8 mg),产率94%;
(2)用2 mL无水乙腈溶解化合物1 (183.0 mg),转移至Schlenk中,N2保护下,加入吗啉(2 mL),油浴升温至90 ℃,反应8 h,将反应液转移至分液漏斗中,大量水洗后得到产物2 (110 mg),产率88%;
(3)50 mL Schlenk加入(3,5,5-三甲基环己-2-烯亚基)丙二腈(29 mg),氮气保护下,加入化合物2(56.5 mg),无水乙醇(6 mL),哌啶(0.02 mL),油浴升温至85℃,反应24 h。冷却,析出沉淀,沉淀用乙醇洗涤离心得到探针(I)(63.9mg),产率85%;
(4)N2保护下,在50ml Schlenk中加入化合物3(31.5 mg),无水乙腈(3 mL),碘甲烷(0.14 mL),油浴升温至90 ℃,反应10 h,将反应液减压浓缩得到粗品,粗品经过乙醚洗涤,得到探针(I)(33.5 mg),产率89%。
其表征如下:
1H NMR (400 MHz, CDCl3)(图1) δ 8.65 (d, J = 6.2 Hz, 2H), 7.72 (d, J =8.8 Hz, 2H), 7.64 (s, 1H), 7.62 (s, 1H), 7.50(d, J = 6.2 Hz, 2H), 7.29 (m,4H), 7.14 (d, J = 7.7 Hz, 4H), 7.07 (t, J = 8.2 Hz, 4H), 4.13 (t, J = 6.4 Hz,2H), 3.70 (m, 2H), 2.40 (m, 24H), 2.32 (m, 2H),1.84 (m, 2H), 1.51 (m, 4H),1.39 (m, 2H)。
13C NMR (100 MHz, CDCl3)(图2) δ153.57, 150.56, 147.71, 147.21, 141.59,135.97, 129.41, 124.96, 123.56, 122.59, 122.20, 119.29, 117.57, 103.28,77.35,77.24, 77.03, 76.72, 71.82, 66.95, 58.99, 53.78, 29.39, 27.17, 26.43,25.98。
HRMS (ESI) m/z: [M+H]+(图3)calcd for: C40H41N4O2S 641.2950; found641.2941。
实施例3
烷氧基噻吩类粘度荧光探针的制备方法,步骤如下:
(1)在50 mL Schlenk中加5-溴-4-(6-溴-1-己氧基噻吩)-2-醛(119.1 mg),4-(二苯氨基)苯基硼酸(167 mg),二(三叔丁基膦)钯(6.27 mg)氢氧化钠(25.7 mg),抽真空干燥,氮气保护下,加入无水四氢呋喃4 mL,水(经过除氧处理)4 mL,将Schlenk放入油浴升温至100℃;反应4h后,将反应液转移至分液漏斗中,用二氯甲烷萃取,用水洗涤,加无水MgSO4干燥,得到粗品。粗品再过柱层析得到化合物1 (164.3mg),产率96%,重复一次,共制备328.6 mg;
(2)用2mL无水乙腈溶解化合物1 (244.0 mg),转移至Schlenk中,N2保护下,加入吗啉(2 mL),油浴升温至90℃,反应8h,将反应液转移至分液漏斗中,大量水洗后得到产物2(112.5mg),产率90%;
(3)50ml Schlenk加入(3,5,5-三甲基环己-2-烯亚基)丙二腈(34.7 mg),氮气保护下,加入化合物2(56.5 mg),无水乙醇(6 mL),哌啶(0.02 mL),油浴升温至100℃,反应24h。冷却,析出沉淀,沉淀用乙醇洗涤离心得到探针(I)(62.4mg),产率83%;
其表征如下:
1H NMR (400 MHz, CDCl3)(图1) δ 8.65 (d, J = 6.2 Hz, 2H), 7.72 (d, J =8.8 Hz, 2H), 7.64 (s, 1H), 7.62 (s, 1H), 7.50(d, J = 6.2 Hz, 2H), 7.29 (m,4H), 7.14 (d, J = 7.7 Hz, 4H), 7.07 (t, J = 8.2 Hz, 4H), 4.13 (t, J = 6.4 Hz,2H), 3.70 (m, 2H), 2.40 (m, 24H), 2.32 (m, 2H),1.84 (m, 2H), 1.51 (m, 4H),1.39 (m, 2H)。
13C NMR (100 MHz, CDCl3)(图2) δ153.57, 150.56, 147.71, 147.21, 141.59,135.97, 129.41, 124.96, 123.56, 122.59, 122.20, 119.29, 117.57, 103.28,77.35,77.24, 77.03, 76.72, 71.82, 66.95, 58.99, 53.78, 29.39, 27.17, 26.43,25.98。
HRMS (ESI) m/z: [M+H]+(图3)calcd for: C40H41N4O2S 641.2950; found641.2941。
实施例4
烷氧基噻吩类粘度荧光探针的制备方法,步骤如下:
(1)在50 mL Schlenk中加5-溴-4-(6-溴-1-己氧基噻吩)-2-醛(119.1 mg),4-(二苯氨基)苯基硼酸(185.6 mg),二(三叔丁基膦)钯(7.84 mg)氢氧化钠(25.7 mg),抽真空干燥,氮气保护下,加入无水四氢呋喃4 mL,水(经过除氧处理)4 mL,将Schlenk放入油浴升温至90 ℃;反应4 h后,将反应液转移至分液漏斗中,用二氯甲烷萃取,用水洗涤,加无水MgSO4干燥,得到粗品。粗品再过柱层析得到化合物1 (166 mg),产率97%;
(2)用2mL无水乙腈溶解化合物1 (366.0 mg),转移至Schlenk中,N2保护下,加入吗啉(2 mL),油浴升温至90 ℃,反应8 h,将反应液转移至分液漏斗中,大量水洗后得到产物2 (116.3 mg),产率93%;
(3)50 mL Schlenk加入(3,5,5-三甲基环己-2-烯亚基)丙二腈(38.6 mg),氮气保护下,加入化合物2(56.5 mg),无水乙醇(6 mL),哌啶(0.02 mL),油浴升温至90℃,反应24h。冷却,析出沉淀,沉淀用乙醇洗涤离心得到探针(I)(62.4mg),产率83%。
其表征如下:
1H NMR (400 MHz, CDCl3)(图1) δ 8.65 (d, J = 6.2 Hz, 2H), 7.72 (d, J =8.8 Hz, 2H), 7.64 (s, 1H), 7.62 (s, 1H), 7.50(d, J = 6.2 Hz, 2H), 7.29 (m,4H), 7.14 (d, J = 7.7 Hz, 4H), 7.07 (t, J = 8.2 Hz, 4H), 4.13 (t, J = 6.4 Hz,2H), 3.70 (m, 2H), 2.40 (m, 24H), 2.32 (m, 2H),1.84 (m, 2H), 1.51 (m, 4H),1.39 (m, 2H)。
13C NMR (100 MHz, CDCl3)(图2) δ153.57, 150.56, 147.71, 147.21, 141.59,135.97, 129.41, 124.96, 123.56, 122.59, 122.20, 119.29, 117.57, 103.28,77.35,77.24, 77.03, 76.72, 71.82, 66.95, 58.99, 53.78, 29.39, 27.17, 26.43,25.98。
HRMS (ESI) m/z: [M+H]+(图3)calcd for: C40H41N4O2S 641.2950; found641.2941。
应用例1
将实施例1制备的荧光探针(I)置于比色管中,分别加入不同比例的甲醇-丙三醇的混合溶剂,定容至5 mL,终浓度为10 μM。图4为荧光探针(I)在不同粘度的甲醇-丙三醇体系荧光光谱图,激发波长为495 nm,狭缝宽度为2.5 nm。(图4的波长是发射波长,这个图是通过495 nm的激发得到的谱图)。从图4可以看出,随着丙三醇含量的增加,混合溶剂粘度也增大,探针的荧光强度逐渐增强。图5是探针(I)的荧光强度log I与溶剂的粘度log η(η代表粘度值)的线性关系。从图5可以看出,二者呈现良好的线性关系,线性方程为logI=0.2715logη+5.2372(R2=0.972)。
应用例2
利用实施例1制备的探针进行癌细胞与正常细胞的区分:
将探针分别与正常细胞(HL-7702和RAW264.7)和癌细胞(Hela和SMMC-7721)共孵育成像。将细胞分别接种到共聚焦小皿中,培养箱中培养24 h。细胞贴壁后,加入10 μM的探针孵育20 min,弃掉培养基,用PBS洗涤后加入500 μL细胞固定液,在共聚焦显微镜下观察成像,探针采用514 nm激发,收集600~700 nm的光。如图6所示,在相同条件下,正常细胞在探针染色后荧光非常弱,而肿瘤细胞则呈现很强的红色荧光,两者有显著性差异(P<0.0001)。
应用例3
利用实施例1制备的探针进行粘度响应:
制霉菌素能够使细胞功能异常,引起细胞粘度增大。将SMMC-7721细胞接种到共聚焦皿中,放置于培养箱中培养24 h。细胞贴壁后,用PBS洗一次,对照组用制备的探针(10 μM)孵育30 min,实验组用制霉菌素(10 μM)孵育30 min,再用探针(10 μM)孵育30 min,然后弃掉培养基,用PBS洗掉多余的探针,加入500 μL细胞固定液。使用共聚焦显微镜成像,探针采用514 nm激发,收集600~700 nm的光。如图7所示,实验组的荧光强度是对照组的3.5倍,说明了探针可以监测药物刺激下溶酶体粘度的变化。
应用例4
利用实施例1制备的探针进行溶酶体靶向测定:
将SMMC-7721细胞接种到共聚焦小皿中,培养箱中培养24 h。细胞贴壁后,加入10μM的探针孵育20 min,弃掉培养基,用PBS洗掉多余的探针,分别加入商业溶酶体绿色探针(Lyso-Tracker Green),线粒体绿色探针(Mito-Tracker Green)和内质网蓝色探针(ER-Tracker Blue-White DPX),继续孵育20 min,用PBS洗两遍,加入500 μL细胞固定液,使用共聚焦显微镜成像,探针采用514 nm激发,收集600~700nm的光。如图8所示,探针可以定位于SMMC-7721细胞的溶酶体。
应用例5
利用实施例1制备的探针进行线虫成像:
秀丽隐杆线虫是一种光学透明,独特的多细胞生物。为了测试了探针(I)在生物成像中的潜力,对照组用探针(I)(10 μM)孵育秀丽隐杆线虫,实验组用探针(I)(10 μM)和制霉菌素(50 μM)孵育线虫,荧光显微镜下观察成像。如图9所示,探针(I)孵育线虫观察到的红色荧光较弱;然而探针(I)和制霉菌素同时孵育秀丽隐杆线虫后,在线虫中可以观察到明亮的红色荧光。说明探针(I)可以成功地随食物大量摄入线虫并在体内积累,而且制霉菌素可以使线虫粘度增大,进一步表明探针(I)对粘度敏感,适用于生物成像。
以上证明实施例1所合成的烷氧基噻吩类探针可以用于癌细胞的红色荧光成像和多细胞生物成像,具有较好的应用前景。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种烷氧基噻吩类粘度荧光探针,其结构式如式(I):
。
2.权利要求1所述的烷氧基噻吩类粘度荧光探针的制备方法,其特征在于,步骤为:
(1)向5-溴-4-(6-溴-1-己氧基噻吩)-2-醛、4-(二苯氨基)苯基硼酸、二(三叔丁基膦)钯和氢氧化钠的混合物中加入溶剂Ⅰ,油浴升温至80~100℃反应至完全,所得反应物经水洗涤、干燥、过柱层析得化合物1;
(2)化合物1经无水乙腈溶解后,加入吗啉,油浴升温至80~120℃反应至完全,所得反应物经水洗涤后即得化合物2;
(3)向化合物2中加入(3,5,5-三甲基环己-2-烯亚基)丙二腈和溶剂Ⅱ,油浴升温至80~100℃反应至完全,经冷却、离心、乙醇洗涤得到目标化合物(I),即烷氧基噻吩类粘度荧光探针。
3.根据权利要求2所述的烷氧基噻吩类粘度荧光探针的制备方法,其特征在于:所述步骤(1)~(3)均在氮气保护下进行。
4.根据权利要求3所述的烷氧基噻吩类粘度荧光探针的制备方法,其特征在于:所述步骤(1)中溶剂Ⅰ为体积比1~3:1的无水四氢呋喃和水的混合溶液,其中水为经过除氧处理的水。
5.根据权利要求3或4所述的烷氧基噻吩类粘度荧光探针的制备方法,其特征在于:所述5-溴-4-(6-溴-1-己氧基噻吩)-2-醛、4-(二苯氨基)苯基硼酸、二(三叔丁基膦)钯与氢氧化钠的物质的量比为1:1~2:0.03~0.05:2。
6.根据权利要求5所述的烷氧基噻吩类粘度荧光探针的制备方法,其特征在于:所述步骤(2)中化合物1与吗啉的物质的量比为1~5:100。
7.根据权利要求6所述的烷氧基噻吩类粘度荧光探针的制备方法,其特征在于:所述步骤(3)中溶剂Ⅱ为体积比为200~300:1的无水乙醇和哌啶的混合溶液。
8.根据权利要求7所述的烷氧基噻吩类粘度荧光探针的制备方法,其特征在于:所述化合物2与(3,5,5-三甲基环己-2-烯亚基)丙二腈的物质的量比为1:1~2。
9.权利要求1所述的烷氧基噻吩类粘度荧光探针在制备区分正常细胞和癌细胞的化学试剂中的应用。
10.权利要求1所述的烷氧基噻吩类粘度荧光探针在制备用于多细胞生物成像试剂中的应用。
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