CN108069921A - 不对称双磺酰胺类化合物的合成及其用途 - Google Patents

不对称双磺酰胺类化合物的合成及其用途 Download PDF

Info

Publication number
CN108069921A
CN108069921A CN201711366082.1A CN201711366082A CN108069921A CN 108069921 A CN108069921 A CN 108069921A CN 201711366082 A CN201711366082 A CN 201711366082A CN 108069921 A CN108069921 A CN 108069921A
Authority
CN
China
Prior art keywords
compound
cys
fluorescence
asymmetric double
application
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201711366082.1A
Other languages
English (en)
Other versions
CN108069921B (zh
Inventor
厉凯彬
韩得满
屈王波
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taizhou University
Original Assignee
Taizhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taizhou University filed Critical Taizhou University
Priority to CN201711366082.1A priority Critical patent/CN108069921B/zh
Publication of CN108069921A publication Critical patent/CN108069921A/zh
Application granted granted Critical
Publication of CN108069921B publication Critical patent/CN108069921B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • 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
    • 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
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1003—Carbocyclic compounds
    • C09K2211/1011—Condensed systems
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • 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
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • 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
    • C09K2211/1048—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with oxygen

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)

Abstract

本发明涉及一种不对称双磺酰胺类化合物的合成及其用途。所述不对称双磺酰胺类化合物为式I所示化合物(详见说明书)。经实验发现，所述不对称双磺酰胺类化合物与半胱氨酸(Cys)反应后紫外吸收光谱会发生100nm的红移，577nm处荧光会发生显著增强，同时伴随着溶液荧光由蓝变黄，而其它氨基酸以及含硫化合物均不会造成干扰。此外，不同pH溶液中的响应实验证明，该化合物在pH＝5‑12范围内都能选择性的检测Cys。因此，本发明所述化合物可作为检测Cys的荧光探针的应用。

Description

不对称双磺酰胺类化合物的合成及其用途
技术领域
本发明涉及一种不对称双磺酰胺类化合物的合成及其用途。
背景技术
半胱氨酸(Cys)、高半胱氨酸(Hcy)和谷胱甘肽(GSH)同属于细胞内活性含巯基氨基酸，参与了细胞内生物催化、转录修饰、解毒等多种生物化学作用，在生命体的生理和病理过程中发挥着极其重要的作用。当细胞内Cys缺乏时会引起很多并发症，如儿童生长缓慢、肝损伤、水肿、皮肤衰老等；而当Cys含量过高则会引起老年痴呆症、风湿性关节炎、帕金森综合症等一系列生理疾病。因此，有效检测或监控生物样品或环境样品中的Cys已成为近年来相关领域的研究热点。
传统的检测Cys的方法主要依靠高效液相色谱法、电化学检测、光学分析、质谱鉴定等，这些方法操作繁琐、成本昂贵，并且只能实现体外检测。荧光探针的方法由于其操作灵敏便捷、成本低廉、选择性好、检测下限低等优点得到了广泛的关注。然而大多数已报道的荧光探针都无法选择性的区分Cys、Hcy、GSH等三种含巯基氨基酸，使其在实际应用上受到了很大的限制。因此，开发一种能够专一性检测Cys的荧光探针具有重要的意义。
发明内容
本发明涉及一种不对称双磺酰胺类化合物的合成及其用途。所述不对称双磺酰胺类化合物为式I所示化合物(详见说明书)。经实验发现，所述不对称双磺酰胺类化合物与Cys反应后紫外吸收光谱会发生100nm的红移，577nm处荧光会发生显著增强，同时伴随着溶液荧光由蓝变黄，而其它氨基酸、含硫化合物以及常见阴阳离子均不会造成干扰。此外，不同pH溶液中的响应实验证明，该化合物在pH＝5-12范围内都能选择性的检测Cys。因此，本发明所述化合物可作为检测Cys的荧光探针的应用。
本发明的一个目的在于提供一种不对称双磺酰胺类化合物，其为式I所述化合物(简记为化合物I，下同)：
化合物I的合成路线如下：
其中，化合物II、III、V均为市售化合物。
本发明的另一个目的在于揭示上述不对称双磺酰胺类化合物(式I所述化合物)的一种用途，即式I所述化合物作为检测Cys的荧光探针的应用。
附图说明
图1在Cys(750μM)存在条件下，化合物I(15μM)的紫外吸收光谱随时间变化曲线；
图2在Hcy(750μM)存在条件下，化合物I(15μM)的紫外吸收光谱随时间变化曲线；
图3在GSH(750μM)存在条件下，化合物I(15μM)的紫外吸收光谱随时间变化曲线；
图4在430nm激法波长下，化合物I(5μM)的荧光发射光谱随Cys(0-250μM)浓度变化曲线；
图5化合物I(5μM)对系列干扰化合物(250μM)的选择性图；
图6化合物I(5μM)与Cys、Hcy、GSH反应的动力学曲线；
图7化合物I(5μM)与Cys(250μM)在不同pH溶液中的响应结果；
具体实施方式
以下将结合实施例对本发明做进一步说明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明。
实施例1
在氮气保护下，准确称取哌嗪III(189mg,2.20mmol)，三乙胺(222mg,2.20mmol)，溶解在10mL二氯甲烷中，再用恒压滴液漏斗向混合液中滴加丹酰氯II(269mg,1.00mmol)二氯甲烷溶液10mL的，边滴加边搅拌，滴加完毕后继续搅拌反应1小时。TLC检测反应完全，停止反应，减压蒸馏除去溶剂，并用柱层析分离提纯得到浅绿色产物(化合物IV)304mg，产率95.5％。1H NMR(400MHz,CDCl3)δ8.56(d,J＝8.0Hz,1H),8.43(d,J＝8.0Hz,1H),8.19(d,J＝4.0Hz,1H),7.53(t,J＝8.0Hz,2H),7.18(t,J＝8.0Hz,1H),3.15(t,J＝8.0Hz,4H),2.86-2.88(m,10H)；13C NMR(100MHz,CDCl3)δ151.7,132.5,130.7,130.6,130.5,130.1,128.0,123.2,119.8,115.2,46.4,45.5,45.4.
实施例2
在氮气保护下，准确称取化合物IV(200mg,0.63mmol)，三乙胺(76mg,0.75mmol)，溶解在10mL二氯甲烷中，再用恒压滴液漏斗向混合液中滴加化合物V(155mg,0.63mmol)二氯甲烷溶液10mL的，边滴加边搅拌，滴加完毕后继续搅拌反应1小时。TLC检测反应完全，停止反应，减压蒸馏除去溶剂，并用柱层析分离提纯得到黄色产物(化合物I)323mg，产率96％。1H NMR(400MHz,CDCl3)δ8.50(d,J＝8.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.08(d,J＝8.0Hz,1H),7.98(d,J＝4.0Hz,1H),7.89(d,J＝4.0Hz,1H),7.64(t,J＝8.0Hz,1H),7.55(t,J＝8.0Hz,1H),7.23(d,J＝4.0Hz,1H),3.24(s,8H),2.83(s,6H)；13C NMR(100MHz,CDCl3)δ151.9,149.5,146.4,136.7,133.3,131.0,130.9,130.2,129.8,129.6,128.7,126.7,124.6,124.1,119.1,115.7,45.6,45.5；HR-ESI-MS m/z:[M]+calcd.for536.0824found536.0817.
将实施例中制备的化合物I应用于Cys的检测，其具体操作方法及结果如下应用实例：
应用实例1
向1cm×1cm×4cm的比色皿中依次加入3mL PBS缓冲溶液，9μL 5mM化合物Ⅰ的DMSO溶液，制备浓度为15μM的化合物Ⅰ溶液。依次向上述溶液中加入750μM的Cys溶液，并测定其紫外吸收光谱随时间变化曲线(图1)。从图1可以看出，随着时间的推移，333nm处的紫外吸收峰逐渐减弱，同时，396nm处紫外吸收峰的增强，在356nm处出现等吸收点；随后，396nm处紫外吸收峰又会减弱，伴随着433nm处紫外吸收峰的增强，在414nm处出现等吸收点。说明Cys能够使化合物I的紫外光谱发生红移，分两个过程进行，两个过程分别为Cys中的巯基取代化合物I中的Cl原子，随后Cys的氨基又发生分子内亲核取代反应，而Hcy、GSH均只发生过程一反应(图2、图3)，从而化合物I可用于选择性检测Cys。
应用实例2
向1cm×1cm×4cm的比色皿中依次加入3mL PBS缓冲溶液，3μL 5mM化合物Ⅰ的DMSO溶液，制备浓度为5μM的化合物Ⅰ溶液。依次向上述溶液中加入0-250μM的Cys溶液。在430nm激发波长下，测定其荧光发射光谱变化曲线(图4)。从图4可以看出，在加入Cys前，化合物I在496nm附近有一荧光发射峰，峰值较小，溶液呈现较弱的蓝色荧光；随着体系中Cys浓度的增加，577nm处的荧光发射峰逐渐增强，并具备较好的浓度依赖关系，此时溶液呈现亮黄色荧光，说明577nm处的荧光变化可以作为特征发射峰实现Cys的定量检测。
应用实例3
分别向浓度为5μM的化合物Ⅰ溶液中加入250μM的天冬氨酸(Asp)、甲硫氨酸(Met)、色氨酸(Trp)、组氨酸(His)、苏氨酸(Thr)、甘氨酸(Gly)、亮氨酸(Leu)、丙氨酸(Ala)、脯氨酸(Pro)、精氨酸(Arg)、丝氨酸(Ser)、苯丙氨酸(Phe)、抗环血酸(Vc)、Cys、Hcy、GSH、H2O2、HClO、NO2 -、NO3 2-、S2O3 2-、S2-、SO4 2-、OAc-、Na+、K+、Ca2+、Cu2+、Fe3+、Fe2+、Zn2+，并测定其荧光光谱曲线。图5所示为上述氨基酸、活性小分子及常见阴阳离子的选择性柱状图(从左往右：1代表空白化合物I，2-32依次代表上述系列干扰物质)，化合物I与Cys响应特别强烈，Hcy、GSH会引起很弱的荧光变化，其他物质均不产生干扰，说明化合物I对Cys具备高选择性。图6所示结果为化合物I与Cys、Hcy、GSH反应的动力学曲线，进一步排除了Hcy、GSH对检测Cys的干扰。
应用实例4
分别向3mL pH＝2-12的溶液中加入3μL 5mM化合物Ⅰ的DMSO溶液，制备浓度为5μM的不同pH的化合物Ⅰ溶液。然后分别测定其荧光光谱曲线；随后分别向上述溶液中加入250μM的Cys，再次测定各溶液荧光光谱曲线。取577nm处荧光强度值作点线图，如图7所示。结果显示该化合物在pH＝5-12范围内都能与Cys发生反应并引起荧光强度发生变化。因此，本发明所述化合物I可作为检测Cys的荧光探针的应用。

Claims (2)

1.一种不对称双磺酰胺类化合物，其为式I所述化合物：
。
2.如权利要求1所述的化合物作为检测半胱氨酸(Cys)的荧光探针的应用。
CN201711366082.1A 2017-12-18 2017-12-18 不对称双磺酰胺类化合物的合成及其用途 Active CN108069921B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201711366082.1A CN108069921B (zh) 2017-12-18 2017-12-18 不对称双磺酰胺类化合物的合成及其用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201711366082.1A CN108069921B (zh) 2017-12-18 2017-12-18 不对称双磺酰胺类化合物的合成及其用途

Publications (2)

Publication Number Publication Date
CN108069921A true CN108069921A (zh) 2018-05-25
CN108069921B CN108069921B (zh) 2019-02-26

Family

ID=62158891

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711366082.1A Active CN108069921B (zh) 2017-12-18 2017-12-18 不对称双磺酰胺类化合物的合成及其用途

Country Status (1)

Country Link
CN (1) CN108069921B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109761969A (zh) * 2019-03-04 2019-05-17 台州学院 一种水溶性萘酰亚胺类化合物的合成及其用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104017039A (zh) * 2014-06-11 2014-09-03 华东理工大学 含糖基萘酰亚胺类化合物及其用途
CN105524055A (zh) * 2016-01-15 2016-04-27 中南大学 一种能够区分半胱氨酸/同型半胱氨酸和谷胱甘肽荧光探针的制备与应用
TWI535710B (zh) * 2014-05-21 2016-06-01 國立交通大學 以苯并噁－１，３－二唑骨架爲主的化合物及偵測一待測品中是否存有生物硫醇的方法
CN106588912A (zh) * 2016-11-30 2017-04-26 济南大学 一种可区分检测半胱氨酸/高半胱氨酸、谷胱甘肽和硫化氢的荧光探针及其制备方法、应用
CN106939015A (zh) * 2016-12-29 2017-07-11 济南大学 一种丙二醛荧光探针及其制备方法和应用
CN107056769A (zh) * 2017-04-07 2017-08-18 济南大学 一种l‑半胱氨酸荧光探针及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI535710B (zh) * 2014-05-21 2016-06-01 國立交通大學 以苯并噁－１，３－二唑骨架爲主的化合物及偵測一待測品中是否存有生物硫醇的方法
CN104017039A (zh) * 2014-06-11 2014-09-03 华东理工大学 含糖基萘酰亚胺类化合物及其用途
CN105524055A (zh) * 2016-01-15 2016-04-27 中南大学 一种能够区分半胱氨酸/同型半胱氨酸和谷胱甘肽荧光探针的制备与应用
CN106588912A (zh) * 2016-11-30 2017-04-26 济南大学 一种可区分检测半胱氨酸/高半胱氨酸、谷胱甘肽和硫化氢的荧光探针及其制备方法、应用
CN106939015A (zh) * 2016-12-29 2017-07-11 济南大学 一种丙二醛荧光探针及其制备方法和应用
CN107056769A (zh) * 2017-04-07 2017-08-18 济南大学 一种l‑半胱氨酸荧光探针及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109761969A (zh) * 2019-03-04 2019-05-17 台州学院 一种水溶性萘酰亚胺类化合物的合成及其用途

Also Published As

Publication number Publication date
CN108069921B (zh) 2019-02-26

Similar Documents

Publication Publication Date Title
Yang et al. A dual emission fluorescent probe enables simultaneous detection of glutathione and cysteine/homocysteine
Li et al. Chromogenic and fluorogenic chemosensors for hydrogen sulfide: review of detection mechanisms since the year 2009
Xu et al. A simple naphthalene-based fluorescent probe for high selective detection of formaldehyde in toffees and HeLa cells via aza-Cope reaction
Zhang et al. A near-infrared fluorescent probe for rapid, colorimetric and ratiometric detection of bisulfite in food, serum, and living cells
Gao et al. BODIPY-based turn-on fluorescent probes for cysteine and homocysteine
Fan et al. A fluorescent probe for the dual-channel detection of Hg2+/Ag+ and its Hg2+-based complex for detection of mercapto biomolecules with a tunable measuring range
Peng et al. A novel fluorescent probe for selective detection of hydrogen sulfide in living cells
Yang et al. A fluorescent dyad with large emission shift for discrimination of cysteine/homocysteine from glutathione and hydrogen sulfide and the application of bioimaging
Wang et al. Thiazolyl substituted NBD as fluorescent probe for the detection of homocysteine and cysteine
Yang et al. A highly sensitive fluorescent probe for the detection of bisulfite ion and its application in living cells
Yang et al. A novel mitochondria-targeted ratiometric fluorescent probe for endogenous sulfur dioxide derivatives as a cancer-detecting tool
Gonçalves et al. A seleno-pyrene selective probe for Hg2+ detection in either aqueous or aprotic systems
Mishra et al. Hydrogen sulfide mediated cascade reaction forming an iminocoumarin: applications in fluorescent probe development and live-cell imaging
Zhang et al. A rapid and highly sensitive fluorescent imaging materials for thiophenols
Zhu et al. A novel colorimetric and ratiometric fluorescent probe for cysteine based on conjugate addition-cyclization-elimination strategy with a large Stokes shift and bioimaging in living cells
Chen et al. A turn-on fluorescent probe for simultaneous sensing of cysteine/homocysteine and hydrogen sulfide and its bioimaging applications
Wang et al. Reaction-based fluorescent turn-on probe for selective detection of thiophenols in aqueous solution and living cells
KR101472318B1 (ko) 넓은 범위의 pH 측정이 가능한 비율계량적 pH 프로브
Zhou et al. A highly sensitive fluorescent probe for selective detection of cysteine/homocysteine from glutathione and its application in living cells and tissues
Zhang et al. Highly sensitive and selective detection of biothiols by a new low dose colorimetric and fluorescent probe
Mao et al. A ratiometric fluorescent probe for rapidly detecting bio-thiols in vitro and in living cells
Li et al. A colorimetric/fluorescence dual-channel probe for highly discriminating detection of cysteine
Peng et al. Hydrogen Sulfide Detection Using Nucleophilic Substitution–Cyclization-Based Fluorescent Probes
Wang Molecular engineering of an efficient iminocoumarin-based probe for practical sensing applications
CN108069921B (zh) 不对称双磺酰胺类化合物的合成及其用途

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant