CN114621215B - 含n,n-二甲基磺酰胺结构的苯并噻二唑类荧光染料及其应用 - Google Patents
含n,n-二甲基磺酰胺结构的苯并噻二唑类荧光染料及其应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
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- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- G—PHYSICS
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
- C09K2211/1051—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with sulfur
Abstract
本发明涉及一种含N,N‑二甲基磺酰胺结构的苯并噻二唑类荧光染料。本发明所述的含N,N‑二甲基磺酰胺结构的苯并噻二唑类荧光染料由N,N‑二甲基磺酰胺取代氢化吲哚与4,7‑二溴苯并噻二唑通过Suzuki偶联反应得到。本发明所述的含N,N‑二甲基磺酰胺结构的苯并噻二唑类荧光染料具有优异的抗光漂白、斯托克斯位移大(Stokes shift)、光稳定性好、生物相容性优异、溶酶体靶向等特点,可应用于肿瘤细胞长效示踪。
Description
技术领域
本发明涉及有机合成及生物成像领域,具体涉及一种含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料及其生物应用。
背景技术
癌症是威胁人类生命健康的主要宿敌之一,面对癌症发病率持续走高的严峻形势,提高癌症前期诊断效果,为后续癌症治疗提供指导已成为重大的社会关切。传统癌症诊断手段包括CT成像、MRI成像及X-射线成像等,其成像试剂存在与肿瘤亲和力差、设备昂贵、难以区分正常组织与肿瘤等缺陷,导致癌症治疗存在较大滞后性与副作用。相比于传统成像手段,荧光成像因其设备便宜、对比度高、高分辨率、选择性高、低毒副作用等优势受到广泛关注。荧光成像效果很大程度依赖于荧光染料的性质。
截止目前,有机染料、无机量子点、碳点、荧光蛋白、上转化纳米材料及聚合物纳米被相继开发(Small,2019,15,1901517.;Nano Lett.2018,18,1159.;Small.2017,13,1701582.)。然而,上述材料仍面临抗光漂白性能差、较小的斯托克斯位移、生物相容性等诸多技术瓶颈。例如无机材料生物降解性一直被大众所诟病,聚合物纳米材料制备复杂、重复性差,极大限制了其生物应用(Chem.Soc.Rev.2013,42,1236.)。
相比而言,有机荧光染料因其来源丰富、设计灵活、生物相容性高等优势成为最具临床应用前景的成像材料之一。目前吲哚菁绿、卟啉类荧光衍生物已通过美国药监局(FDA)批准用于临床。然而,传统吲哚菁绿、卟啉、方酸、香豆素、Bodipy类荧光染料仍存在难以合成与纯化、易光淬灭和光漂白等缺陷,导致肿瘤细胞长效示踪效果欠佳(Chem.Rev.2021,121,13454.)。苯并噻二唑类荧光染料具有荧光量子效率高、斯托克斯位移大、生物相容性好等优势,已成为荧光成像试剂开发的关键母核结构之一。中国专利CN202110868963.3报道了一种D-苯并噻二唑-TB(-D)衍生物,并将其应用于金属离子检测、光动力治疗及生物成像领域。然而制备复杂,同时在肿瘤细胞长效示踪应用时通常需用两亲性聚合物包裹成纳米离子增强其荧光量子效率及体内稳定性,导致制备工艺复杂、重复性差,限制其临床应用。
磺酰胺类化合物具有广泛的生物活性,主要用于抗癌症、抗炎症、抗细菌、抗病毒治疗等领域。同样,天然先导化合物阿魏酸类衍生物,具有抗肿瘤、抑制和清除氧自由基、抗菌、抗病毒、抗溃疡和解痉挛等多种重要的生物活性,且具有更高的稳定性和更好的溶解性,是具有新药研发潜力的一类化合物。中国专利CN 202110917224.9报道了一种苯磺酰胺化合物在制备治疗急性肾损伤的药物中的应用,说明磺酰胺类基团具有优异的生物活性。近期研究人员将磺酰胺基团替换罗丹明类荧光染料结构的中的羧基,制备的新型荧光染料的水溶性、荧光量子效率、细胞亲和性均得到显著提升,可用于活细胞内免洗成像(Nat.Chem.2020,12,165.)。因此,其结构可改善传统荧光染料的亲水性、细胞亲和性等性能,有效提升荧光染料的生物成像前景。
发明内容
本发明的目的是提供一种含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料,通过以具有优异光学性质的苯并噻二唑为荧光母核,引入具有优异水溶性和生物活性的磺酰胺结构,设计合成一种含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料,并将其应用于肿瘤细胞长效示踪。
为实现上述目的,本发明采用如下技术方案:
一种含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料,其结构式如式(I)所示:
本发明所述的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料由N,N-二甲基磺酰胺取代氢化吲哚与4,7-二溴苯并噻二唑通过Suzuki偶联反应得到。
本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料化合物的合成方法如下所示:
本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料具有聚集诱导发光效应(AIE)、较大的Stokes shift(155nm)、优异的光稳定性与极低的细胞毒性等特性,可应用于肿瘤细胞长效示踪成像。
附图说明
图1为本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的溶剂化响应和AIE效应的吸收-荧光光谱。其中,(a)SIBIS不同溶剂中的吸收曲线;(b)SIBIS不同溶剂中的荧光曲线;(c)SIBIS在不同THF/水体积比中的吸收曲线;(d)SIBIS在不同THF/水体积比中的荧光曲线。
图2为本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的光稳定性图谱。其中,(a)SIBIS在不同时间内吸收变化曲线;(b)SIBIS在不同时间内吸收变化曲线;(c)SIBIS在水、PBS和FBS中氙灯持续照射条件下荧光变化曲线。
图3为本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的细胞毒性。SIBIS在4T1、HeLa和MCF-7等细胞中的细胞毒性,柱状图中左柱代表4T1细胞、中柱代表HeLa细胞、右柱代表MCF-7细胞。
图4为本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的细胞内吞图片。
图5为本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的肿瘤细胞长效示踪图片。
图6为本发明的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料在不同细胞代数4T1细胞内的荧光强度。
具体实施方式
为更好的理解本发明,下面结合实施例对本发明作进一步说明,但本发明要求保护的范围并不局限于实施例表述的范围。
实施例1:N,N-二甲基吲哚-1-磺酰胺的制备
称取氢化吲哚(4.766g,40mmol)和三乙胺(8.095g,20mmol)加入到250mL的单口烧瓶中,然后将取N,N-二甲基磺酰氯(6.462g,45mmol)溶解于40mL二氯甲烷中,使用恒压将漏斗将N,N-二甲基磺酰氯的二氯甲烷溶液逐滴加入到反应系统中,滴加完成后室温反应24小时。TLC点板检测,反应完成后,旋蒸去除有机溶剂,然后用柱色谱(乙酸乙酯:石油醚=1:10)分离纯化,得浅棕色液体产物,置于真空烘箱中干燥,最终得液体产物8.49,收率93.75%。
实施例2:5-溴-N,N-二甲基吲哚-1-磺酰胺的制备
称取N,N-二甲基吲哚-1-磺酰胺(8.3g,36mmol)和四氢呋喃(30mL)加入到锡箔包裹的单颈烧瓶,将N-溴代琥珀酰亚胺(5.19g,44mmol)溶解在四氢呋喃(100mL)中,使用恒压将漏斗将N-溴代琥珀酰亚胺的四氢呋喃溶液逐滴加入到反应系统中,滴加完成后室温避光反应12小时。旋蒸去除有机溶剂,然后通过柱色谱(乙酸乙酯:石油醚=1:4)分离纯化,得到8.96g浅棕色液体产品,收率81.55%。
实施例3:5-频哪醇酯-N,N-二甲基吲哚-1-磺酰胺的制备
称取5-溴-N,N-二甲基吲哚-1-磺酰胺(3.05g,10mmol)、醋酸钾(1.96g,20mmol),二硼酸频那醇酯(3.8g,15mmol)、Pd(dppf)Cl2(0.366g,0.5mmol)和30ml无水DMF加入到250mL单颈烧瓶中,通入氮气去除装置内空气。随后升温至85℃,加热回流反应20小时,通过TLC点板检测反应进程。反应结束后,将反应系统倒入至装有200mL水的烧杯中,静置分层后分液,然后用二氯甲烷萃取水相三次,合并有机相,旋蒸去除有机溶剂,然后通过柱色谱分离纯化(乙酸乙酯:石油醚=1:5),得到白色固体2.3g,收率65.29%。
实施例4:含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的制备
将5-频哪醇酯-N,N-二甲基吲哚-1-磺酰胺(2.28g,6.474mmol)、4,7-二溴-2,1,3-苯并噻二唑(0.735g,2.5mmol)、Pd(PPh3)4(0.289g,0.25mmol)、2M的碳酸钾(1.725g,12.5mmol)加入到250mL单颈烧瓶中,通入氮气去除装置内空气。随后升温至75℃,加热回流反应24小时,通过TLC点板检测反应进程。反应完成后,将反应系统倒入至装有200mL水的烧杯中,静置分层后分液,然后用二氯甲烷萃取水相三次,合并有机相,旋蒸去除有机溶剂,然后通过柱色谱法分离纯化(乙酸乙酯:石油醚=1:3)得到0.71g黄色固体产物,收率48.57%,
化合表征:
1HNMR(DMSO-d6,400MHz),δ(ppm):7.89~7.93(d,2H),7.83~7.85(d,1H),7.58~7.61(m,2H),7.38~7.56(m,2H),4.02~4.06(t,2H),3.23~3.28(t,2H),2.88(s,6H).
13C NMR(DMSO-d6,100MHz),δ(ppm):153.89,143.44,131.82,129.29,128.94,128.12,126.41,113.37,51.20,38.42,28.01.
HRMS(ESI,m/z),calculated for C26H28N6O4S3,584.7423,found[M+H]+,585.1408.
实施例5:含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的光物理性质
配制浓度为1mM的实施例1-4的方法制备得到的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料(简称为SIBIS)的DMSO溶液,取10μL含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料溶液,加入10mL的容量瓶,分别用甲苯、四氢呋喃、二氯甲烷、乙腈、乙醇、DMSO稀释定容至刻度。随后分别采用紫外分光光度计和荧光光谱仪测试荧光染料的光物理性质,其结果如图1所示。图1中,(a)SIBIS不同溶剂中的吸收曲线;(b)SIBIS不同溶剂中的荧光曲线;(c)SIBIS在不同THF/水体积比(THF体积浓度分别为10%、20%、30%、40%、50%、60%、70%、80%、90%、99%)中的吸收曲线;(d)SIBIS在不同THF/水体积比(THF体积浓度分别为10%、20%、30%、40%、50%、60%、70%、80%、90%、99%)中的荧光曲线。结果表明含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料具有溶致变色效应。
随后配制浓度为1mM的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的四氢呋喃溶液,取10μL含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的四氢呋喃溶液,加入10mL的容量瓶,分别用不同体积比例的去离子水稀释定容至刻度。随后分别采用紫外分光光度计和荧光光谱仪测试荧光染料的聚集诱导发光效应,其结果如图1所示。结果表明含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料具有聚集诱导发光效应。
随后配制浓度为1mM的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的四氢呋喃溶液,取10μL含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的四氢呋喃溶液,加入10mL的容量瓶,加入去离子水定容至刻度,随后分别采用紫外分光光度计和荧光光谱仪测试间隔2天后的吸收和荧光变化,同时将配置好的溶液置于荧光光谱仪中持续氙灯照射,测试间隔5分钟后的荧光强度变化情况,进而验证其光稳定性,其结果如图2所示。结果表明含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料具有优异的光稳定性。
实施例6:含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的细胞毒性
随后配制浓度梯度为0μM、0.5μM、1μM、2μM、5μM、10μM、20μM、50μM、100μM的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的水溶液,采用CCK-8法测试染料对于HeLa、4T1、HepG等细胞的细胞毒性影响,其结果如图3所示。SIBIS在4T1、HeLa和MCF-7等细胞中的细胞毒性,柱状图中左柱代表4T1细胞、中柱代表HeLa细胞、右柱代表MCF-7细胞,结果表明含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料具有较低的细胞毒性。
实施例7:含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的细胞内吞
将4T1细胞、HeLa细胞和HePG-2细胞在内的细胞系在RPMI1640培养基中培养。培养基中含有10%胎牛血清(FBS)和1%青霉素链霉素(双抗体)。所有细胞均在37℃及含5%CO2的培养箱培养。将0.5μM含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料与细胞共孵育4h,然后加入商用溶酶体标记荧光染料Lyso-Tracker Red继续孵育2h,采用倒置荧光显微镜分别收集绿色通道和红色通道的细胞图片,ZEN软件和ImageJ软件进行共定位分析,确定含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的细胞定位,其结果如图4所示。结果表明荧光染料能特异性靶向活细胞溶酶体区域。图4中SIBIS在4T1、HeLa和MCF-7等细胞中的共定位图片,其中SIBIS为绿色荧光,商用溶酶体荧光染料Lyso-tracker Red为红色荧光,bright field为亮场内细胞图片,merged为合并图片,pearson’s correlation为共定位系数。
实施例8:含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的肿瘤细胞长效示踪
细胞密度为3×104或5×104的4T1细胞接种在48孔板中或共聚焦显微镜培养皿中。除去培养液后用PBS缓冲溶液洗涤一次,0.5μM含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料溶液添加到孔板中。在37℃环境下培养24h后,细胞群用PBS缓冲溶液洗涤一次,然后重新悬浮在培养基中。在稀释后,不同细胞代数的细胞被接种在含有细胞培养盖玻片的孔板内。在指定的时间间隔内,不同代数的细胞被胰蛋白酶分解悬浮,然后用4%的多聚甲醛处理15min固定细胞。被染色的细胞内的荧光图片分别通过内置Olympus BX51荧光显微镜做综合细胞成像和OLYMPUS FV 1000倒置荧光显微镜做局部细胞成像,其结果如图5所示。结果表明荧光染料可有效示踪肿瘤细胞分裂14代以上。图5中SIBIS在4T1细胞内细胞传代倒置荧光图片,1st、3rd、5th、8th、10th、12th和15th分别为不同细胞代数,SIBIS表示细胞内荧光图片,bright field为亮场内细胞图片,merged为合并图片。
实施例9:含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料的流式曲线
使用BD-LSRFortessa对每代细胞通过流式细胞术测量分析细胞的荧光强度,其结果如图6所示。图6中,SIBIS在不同细胞代数4T1细胞内的荧光强度,结果与长效示踪细胞图片一致,细胞分裂导致细胞内所有物质均分,使得细胞内荧光强度随着细胞传代进行,荧光强度逐渐降低。
Claims (2)
1.含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料,其特征在于,化学结构式如下式(I)所示:
。
2.权利要求1所述的含N,N-二甲基磺酰胺结构的苯并噻二唑类荧光染料在制备肿瘤细胞长效示踪的药物上的应用。
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