KR101476639B1 - Composition for detecting γ-l-glutamyl-l-cystenylglycine - Google Patents

Composition for detecting γ-l-glutamyl-l-cystenylglycine Download PDF

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KR101476639B1
KR101476639B1 KR20140024980A KR20140024980A KR101476639B1 KR 101476639 B1 KR101476639 B1 KR 101476639B1 KR 20140024980 A KR20140024980 A KR 20140024980A KR 20140024980 A KR20140024980 A KR 20140024980A KR 101476639 B1 KR101476639 B1 KR 101476639B1
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ethylidene
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하현준
임수연
윤두하
정재훈
권혁만
김해조
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한국외국어대학교 연구산학협력단
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Abstract

The present invention provides a composition containing a cyanine derivative for detecting gamma L-glutamyl-L-cystenylglycine (GSH). The cyanine derivative can selectively detect GSH from amino acid including a thiol group or an amino acid derivative ex vivo and/or in vivo.

Description

L-glutamyl-L-cystenylglycine < RTI ID = 0.0 >

The present invention relates to a composition for detecting gamma-L-glutamyl-L-cystenylglycine (GSH) containing a cyanine derivative. The cyanine derivative can selectively detect gamma-L-glutamyl-L-cysteinylglycine (GSH) among amino acids or amino acid derivatives containing a thiol group ex vivo and / or in vivo can do.

Amino acids or amino acid derivatives containing thiol groups are present in vivo. Representative amino acid derivatives containing a thiol group are cysteine, and representative amino acid derivatives containing a thiol group include homocysteine, gamma -L-glutamyl-L-cystenylglycine, GSH), and their structures are as follows.

Figure 112014020770645-pat00001

Among the amino acid derivatives containing thiol groups, gamma-L-glutamyl-L-cysteinylglycine plays a myriad of roles in the activity of cells related to life support. For example, the homeostasis between the oxidation-reduction (Redox Homeostasis;.... TP Dalton, HG Shertzer and A. Puga, Annu Rev Pharmacol Toxicol, 1999, 39, 67), cell growth (cellulargrowth; Wood ZA, E. Schroeder, JR Harris and LB Poole, TransBiochem. Sci., 2003, 28, 32) is involved in the process, but also cancer, is known to be related to HIV (AIDS) (DM Townsend, KD Tew and H. Tapiero, Biomed. Pharmacother. , 2003, 57 , 145).

The present inventors have disclosed a coumarin derivative as a novel compound capable of effectively detecting thiol group-containing biomaterials not only ex vivo but also in vivo (Korea Patent No. 10-1328000 number). However, the method of selectively separating and detecting gamma-L-glutamyl-L-cysteinylglycine (GSH) among amino acid or amino acid derivatives containing a thiol group has not yet been developed due to the structural similarity of these compounds. In particular, if a probe capable of selectively detecting gamma-L-glutamyl-L-cysteinylglycine, which plays various roles in vivo, is developed, it may contribute a great deal to reveal the cell activity process at the molecular level It is expected.

The present inventors have been able to selectively detect gamma-L-glutamyl-L-cystenylglycine (GSH) in vivo as well as ex vivo Was designed. Especially, considering various nucleophilic properties of thiol, various derivatives have been devised to selectively react with cyanine using Nucleophilic aromatic substitution reaction (S N Ar).

Accordingly, the object of the present invention is to provide a composition capable of selectively detecting gamma-L-glutamyl-L-cystenylglycine (GSH), which comprises a cyanine derivative do.

According to one aspect of the present invention there is provided a composition for detecting gamma-L-glutamyl-L-cysteinylglycine comprising a compound of formula (I) or a compound of formula (Ib)

<Formula 1a>

Figure 112014020770645-pat00002

&Lt; EMI ID =

Figure 112014020770645-pat00003

Wherein R 1 is nitro, halogen, C 1 to C 4 alkyl, or amino, R 2 and R 3 are independently C 1 to C 4 alkyl, and R 4 is hydrogen or 2,5- Lt; / RTI &gt; and X is halogen.

The compound of formula (1a) or the compound of formula (1b) is selectively reacted with gamma-L-glutamyl-L-cystenylglycine (GSH) among amino acid or amino acid derivatives containing a thiol group , And can be used as a GSH-detecting probe in vitro or ex vivo in vivo.

FIG. 1 shows the ex vivo binding characteristics of a compound according to the present invention and a thiol-containing compound (2-mercaptoethanol) through 200 MHz NMR analysis. 1, A is a 200 MHz NMR spectrum of the compound of the present invention (compound of Example 1). B to D show spectra showing the mechanism by which the product is made over time after adding 2-mercaptoethanol to the compound of the present invention (the compound of Example 1). E represents the spectrum of the final reaction product of the compound of the present invention (compound of Example 1) with 2-mercaptoethanol.
FIG. 2 shows the results of analysis of the binding properties of the compounds according to the present invention with various amino acids and thiol-containing amino acids by means of ratiometric fluorescence responses.
FIG. 3 shows the results of evaluating the kinetics of the compound of the present invention and gamma -L-glutamyl-L-cystenylglycine (GSH).
FIG. 4 shows the results of analysis of selective binding properties of the compound of the present invention and gamma-L-glutamyl-L-cysteinylglycine in cells through confocal laser scanning microscope imaging.

The present invention relates to a process for the introduction of a group of Michael acceptors to cyanines, specifically the unsaturated alpha, beta, gamma, and delta of imines and to the use of nucleophilic aromatic substitution reactions in which the thiol acts as a Micahel donor L-glutamyl-L-cysteinylglycine, which comprises a cyanine derivative which is designed so that a substitution reaction (S N Ar) can selectively take place.

That is, the present invention provides a composition for detecting gamma-L-glutamyl-L-cysteinylglycine comprising a compound of the formula (I) or a compound of the formula (Ib)

<Formula 1a>

Figure 112014020770645-pat00004

&Lt; EMI ID =

Figure 112014020770645-pat00005

Wherein R 1 is nitro, halogen, C 1 to C 4 alkyl, or amino, R 2 and R 3 are independently C 1 to C 4 alkyl, and R 4 is hydrogen or 2,5- Lt; / RTI &gt; and X is halogen.

In which is used as a probe in detecting composition of the present invention compounds, the compound of R 2 is hydrogen is a separate counter anion may be present in the form of the formula 1b binary ion (Zwitterion) form without (counter anion, i.e., X) . Further, R 2 is C 1 to alkyl of C 4 is a counter anion (counter anion) as the halogen anions (i.e., - X) going may be present in the form of the general formula 1a, wherein the halogen anion is preferably a bromine anion (I.e., - Br).

The compound of formula (Ia) or the compound of formula (Ib) may exist in racemic or stereoisomeric forms (for example, diastereomeric form), and the present invention includes both racemics and stereoisomers.

Preferably, R 1 is nitro, bromo, methyl, or amino, R 2 and R 3 are butyl, R 4 is hydrogen or 2,5-dioxaphosphorane, Lt; / RTI &gt; and X is bromine.

More preferred compounds of the compounds of formula (1a) or (1b) are:

1- (3-butoxy-3-oxopropyl) -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl Ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium bromide;

2 - ((E) -2 - ((E) -2- (4- bromo-phenylthio) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl) -3 Ylidene) ethylidene) cyclohex-1-yl) vinyl) -1- (3-butoxy-3-oxopropyl) -3,3-dimethyl-3H- indoleium bromide ;

1- (3-butoxy-3-oxopropyl) -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl Ylidene) ethylidene) -2- ( p -tolylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indoleium bromide;

2 - ((E) -2 - ((E) -2- (4- amino-phenylthio) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl) -3 2-ylidene) ethylidene) cyclohex-1-yl) vinyl) -1- (3-butoxy-3-oxopropyl) -3,3-dimethylindolium bromide;

( E ) -2 - (( E ) -3 - (( E ) -2- (1- (2- carboxyethyl) -3,3-dimethylindolin- Ylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate;

3- (2 - ((E) -2 - ((E) -2- (4- bromo-phenylthio) -3 - ((E) -2- (1- (2- carboxyethyl) 3,3 2-ylidene) ethylidene) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate;

( E ) -2 - (( E ) -3 - (( E ) -2- (1- (2- carboxyethyl) -3,3-dimethylindolin- Lidene) -2- ( p -tolylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indol-1-yl) propanoate;

3- (2 - ((E) -2 - ((E) -2- (4- amino-phenylthio) -3 - ((E) -2- (1- (2- carboxyethyl) 3,3- Ylidene) ethylidene) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate; And

3- (( E ) -2 - (( E ) -3 - (( E ) -2- (1- (3- (2,5-dioxopyrrolidin- 2-ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indole 1-yl) propanoate.

Of the above compounds, particularly preferred compounds are 1- (3-butoxy-3-oxopropyl) -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3 Ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3- Dimethyl-3H-indolium bromide; ( E ) -2 - (( E ) -3 - (( E ) -2- (1- (2- carboxyethyl) -3,3-dimethylindolin- Ylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate; And ( E ) -2 - (( E ) -3 - (( E ) -2- (1- (3- (2,5-dioxopyrrolidin- Ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H- Indolium-1-yl) propanoate.

( E ) -2 - (( E ) -3 - (( E ) -2- (1- (3- (2,5-dioxopyrrolidin- Ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl -3H-indolium-1-yl) propanoate, the 2,5-dioxopyrrolidin-1-yloxy group functions as a linker for binding monoclonal antibodies such as trastuzumab and the like can do.

( E ) -2 - (( E ) -3 - (( E ) -2- ( Ylidene) ethylidene) -2-chlorocyclohexy-1-yl) vinyl) -3,3-dimethyl-3-oxo- (4-nitrophenylthiol, 4-methylphenylthiol, 4-bromophenylthiol, 4-aminophenylthiol, etc.) with the corresponding substituted-phenylthiol Can be obtained.

(2)

Figure 112014020770645-pat00006

The compound of formula 2 may be prepared by a known method, for example, by S. Achilefu, Z. Zhang, Org . Lett ., 2004, 6 , 2067.

The reaction of the compound of Formula 2 with the substituted phenylthiol can be carried out by Nucleophilic aromatic substitution reaction (S N Ar). The nucleophilic aromatic substitution reaction can be carried out in the presence of a solvent such as dimethylformamide.

Compounds of formula (Ib) wherein R &lt; 4 &gt; is hydrogen can be obtained by hydrolysis of the compound prepared as described above. The hydrolysis reaction can be carried out by reacting with sodium t -butoxide and then reacting with trifluoroacetic acid (TFA). The hydrolysis reaction may be carried out in the presence of a solvent such as tetrahydrofuran.

R 3 is 2,5-dioxide Sophie Raleigh dill the formula 1b compounds are the compounds (i.e., R 4 is hydrogen A compound of formula 1b) was prepared in N, N '- dicyclohexyl-hexene ilka carbodiimide and N - Hydroxy-succinimide. &Lt; / RTI &gt; The reaction can be carried out in the presence of a solvent such as dichloromethane and can be carried out by reacting at a low temperature (for example, about 0 ° C). If desired, the resulting product may be crystallized in diethyl ether.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are provided for illustrating the present invention and are not intended to limit the present invention.

Example  1. 1- (3- Buxoxy -3- Oxopropyl )-2-(( E )-2-(( E ) -3 - (( E ) -2- (1- (3- Buxoxy -3-ox Sopro Phil) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene ) -2- (4- Nitrophenylthio ) Cyclo Hex-1- Count ) Vinyl) -3,3-dimethyl-3H- Indole  Bromide

Figure 112014020770645-pat00007

1- (3-butoxy-3-oxo-propyl) To a round bottom flask -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3-butoxy- Ylidene) ethylidene) -2-chlorocyclohexy-1-yl) vinyl) -3,3-dimethyl-3H-indol-1-yll bromide , And dissolved in 3 ml of dimethylformamide (DMF). 0.078 g of p -nitrobenzenethiol was added to the solution, and the reaction was carried out at room temperature for 2 hours. When the color of the solution became dark green, when the starting material disappeared by TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 80%

1 H NMR (CDCl 3, 400MHz ) 8.48 (d, 2H, J = 14 Hz), 8.06 (d, 2H, J = 9.2 Hz), 7.30-7.11 (m, 10H), 6.39 (d, 2H, J = 14 Hz), 4.54 (t, 4H, J = 6.4 Hz), 3.94 (t, 4H, J = 6.8 Hz), 2.86 (t, 4H, J = 6.4 Hz), 2.81 (t, 4H, J = 6 Hz ), 2.01 (q, 2H, J = 6 Hz), 1.45-1.37 (m, 16H), 1.24 (q, 4H, J = 7.2 Hz), 0.79 (t, 6H, J = 7.2 Hz).

13 C NMR (CDCl 3 , 100 MHz): δ 172.23, 170.66, 147.31, 146.50, 145.17, 144.96, 141.53, 140.70, 134.70, 128.63, 125.75, 125.41, 124.38, 122.01, 111.14, 102.71, 65.00, 32.14, 30.22, 27.68, 26.66, 20.56, 18.81, 13.46.

HRMS (MALDI + , DHB): m / z obs'd 830.4167 ([M] +, cal'd 830.4197 for C 50 H 60 N 3 O 6 S).

Example  2. 2 - (( E )-2-(( E ) -2- (4- Bromophenylthio ) -3 - (( E ) -2- (1- (3- Buxoxy -3- Oxopropyl ) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene ) Cyclohexane -One- Count ) Vinyl) -1- (3- Buttock -3- Oxopropyl ) -3,3-dimethyl-3H- Indole  Bromide

Figure 112014020770645-pat00008

1- (3-butoxy-3-oxo-propyl) To a round bottom flask -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3-butoxy- Ylidene) ethylidene) -2-chlorocyclohexy-1-yl) vinyl) -3,3-dimethyl-3H-indol-1-yll bromide , And dissolved in 3 ml of dimethylformamide (DMF). To the solution was added 0.098 g of p -bromobenzenethiol, and the mixture was reacted at room temperature for 2 hours. When the color of the solution became dark green, when the starting material disappeared by TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 80%

1 H NMR (CDCl 3, 400MHz ): δ 8.56 (d, 2H, J = 14 Hz), 7.30- 7.12 (m, 10H), 7.01 (d, 2H J = 8.4 Hz), 6.32 (d, 2H, J = 14 Hz), 4.51 (t , 4H, J = 6.4 Hz), 3.93 (t, 4H, J = 6.8 Hz), 2.85 (t, 4H, J = 6.4 Hz), 2.74 (t, 4H, J = 6 Hz), 1.96 (q, 2H, J = 6 Hz), 1.45-1.40 (m, 16H), 1.23 (q, 4H, J = 7.2 Hz), 0.79 (t, 6H, J = 7.2 Hz).

13 C NMR (CDCl 3 , 100 MHz):? 172.07, 170.68, 150.25, 145.61, 141.56, 140.72, 136.15, 134.60, 132.22, 128.55, 127.41, 125.18, 121.96, 119.06, 110.99, 102.24, 64.95, 48.97, 40.55, 32.10, 30.20, 27.71, 26.50, 20.60, 18.79, 13.44.

HRMS (MALDI + , DHB): m / z obs'd 863.3451 ([M] +, cal'd 863.3452 for C 50 H 60 BrN 2 O 4 S).

Example  3. 1- (3- Buxoxy -3- Oxopropyl )-2-(( E )-2-(( E ) -3 - (( E ) -2- (1- (3- Buxoxy -3-ox Sopro Phil) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene )-2-( p - Tolylthio ) Cyclohexane -1-senyl) vinyl) -3,3-dimethyl-3H- Indole  Bromide

Figure 112014020770645-pat00009

1- (3-butoxy-3-oxo-propyl) To a round bottom flask -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3-butoxy- Ylidene) ethylidene) -2-chlorocyclohexy-1-yl) vinyl) -3,3-dimethyl-3H-indol-1-yll bromide , And 1.5 ml of dimethylformamide (DMF) was added to dissolve the solution. 0.031 g of p -methylbenzenethiol was added to the solution, and the reaction was allowed to proceed at room temperature for 2 hours. When the color of the solution became dark green, when the starting material disappeared by TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 70%

1 H NMR (CDCl 3, 400MHz ): δ 8.64 (d, 2H, J = 14 Hz), 7.29-6.98 (m, 10H), 6.28 (d, 2H, J = 14 Hz), 4.49 (t, 4H, J = 6.4 Hz), 3.94 ( t, 4H, J = 6.4 Hz), 2.84 (t, 4H, J = 6.4 Hz), 2.72 (t, 4H, J = 6 Hz), 2.14 (s, 3H), 1.96 (q, 2H, J = 5.6 Hz), 1.45-1.40 (m, 16H), 1.24 (q, 4H, J = 7.6 Hz), 0.79 (t, 6H, J = 7.6 Hz).

13 C NMR (CDCl 3 , 100 MHz): δ 171.94, 170.68, 152.48, 146.11, 141.57, 140.72, 135.48, 134.62, 133.30, 129.95, 128.48, 125.01, 110.86, 101.86, 48.92, 40.41, 32.06, 27.72, 26.41, , 20.63, 18.77, 13.43.

HRMS (MALDI + , DHB): m / z obs'd 799.4503 ([M] +, cal'd 799.4506 for C 51 H 63 N 2 O 4 S).

Example 4 . 2-(( E )-2-(( E ) -2- (4- Aminophenylthio ) -3 - (( E ) -2- (1- (3- Buxoxy -3- Oxopropyl ) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene ) Cyclohexane -One- Count ) Vinyl) -1- (3- Buttock -3- Oxopropyl ) -3,3- Dimethyl indole  Bromide

Figure 112014020770645-pat00010

1- (3-butoxy-3-oxo-propyl) To a round bottom flask -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3-butoxy- Ylidene) ethylidene) -2-chlorocyclohexy-1-yl) vinyl) -3,3-dimethyl-3H-indol-1-yll bromide , And 1.5 ml of dimethylformamide (DMF) was added to dissolve the solution. 0.031 g of p -methylbenzenethiol was added to the solution, and the reaction was allowed to proceed at room temperature for 2 hours. When the color of the solution became dark green, when the starting material disappeared by TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 80%

1 H NMR (CDCl 3, 400MHz ): δ 8.66 (d, 2H, J = 14 Hz), 7.24-7.06 (m, 8H), 6.87 (d, 2H, J = 8.4 Hz), 6.54 (d, 2H, J = 8.4 Hz), 6.17 ( d, 2H, J = 14 Hz), 4.39 (t, 4H, J = 6.4 Hz), 3.90 (t, 4H, J = 6.8 Hz), 2.79 (t, 4H, J = 6.4 Hz), 2.61 (t, 4H, J = 5.6 Hz), 1.87 (q, 2H, J = 5.6 Hz), 1.41-1.34 (m, 16H), 1.19 (q, 4H, J = 7.2 Hz), 0.74 (t, 6H, J = 7.2 Hz).

13 C NMR (CDCl 3 , 100 MHz): δ 171.72, 170.50, 154.96, 146.39, 145.58, 141.38, 140.56, 134.27, 128.29, 127.87, 124.79, 123.51, 121.86, 115.89, 110.54, 101.39, 64.79, 48.80, , 30.03, 27.67, 26.17, 20.53, 18.62, 13.28.

HRMS (MALDI + , DHB): m / z obs'd 800.4649 ([M] +, cal'd 800.4458 for C 50 H 63 N 3 O 4 S).

Example  5. 3- (2 - (( E )-2-(( E ) -3 - (( E ) -2- (1- (2- Carboxyethyl ) -3,3- Dimethyl indoline -2 days Lee Dean) Ethylidene ) -2- (4- Nitrophenylthio ) Cyclohexane -One- Count ) Vinyl) -3,3-dimethyl-3H- sign 1-yl) Propanoate

Figure 112014020770645-pat00011

1- (3-butoxy-3-oxo-propyl) To a round bottom flask -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3-butoxy- Ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H- 0.100 g of indolium bromide was added, and 6 mL of tetrahydrofuran (THF) was added to dissolve it. 0.058 g of sodium t -butoxide was added to the solution, and the reaction was carried out at room temperature for 20 hours. Trifluoroacetic acid (TFA) was added to the solution, and the mixture was reacted at room temperature for 6 hours. When the starting material disappeared with TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 73%.

1 H NMR (CD 3 OD, 400MHz): δ 8.60 (d, 2H, J = 14 Hz), 8.11 (d, 2H, J = 9.2 Hz), 7.43 (d, 2H, J = 9.2 Hz), 7.41- 7.16 (m, 8H), 6.48 (d, 2H, J = 14 Hz), 4.36 (t, 4H, J = 7.2 Hz), 2.82 (t, 4H, J = 5.6 Hz), 2.60 (t, 4H, J = 7.2 Hz), 1.99 (q, 2H, J = 5.6 Hz), 1.39 (s, 12H).

13 C NMR (CD 3 OD, 100MHz): δ 177.60, 174.07, 148.29, 148.26, 146.79, 146.56, 143.32, 142.67, 135.17, 129.84, 127.31, 126.52, 125.60, 123.46, 112.46, 103.52, 50.49, 43.04, 36.06, 28.12, 27.42, 22.10.

HRMS (MALDI + , DHB): m / z obs'd 718.2945 ([M] + , calc'd 718.2947 for C 42 H 44 N 3 O 6 S).

Example  6. 3- (2 - (( E )-2-(( E ) -2- (4- Bromophenylthio ) -3 - (( E ) -2- (1- (2- Carboxyethyl ) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene ) Cyclohexane -One- Count ) Vinyl) -3,3-dimethyl-3H-indol-1-yl) Propanoate

Figure 112014020770645-pat00012

To a round bottom flask was added 2 - ((E) -2 - ((E) -2- (4- bromo-phenylthio) -3 - ((E) -2- (1- (3- butoxy-3-oxo Ylidene) ethylidene) cyclohex-1-yl) vinyl) -1- (3-butoxy-3-oxopropyl) -3,3-dimethyl- - indolium bromide (0.104 g) was added, and 6 ml of tetrahydrofuran (THF) was added to dissolve the solution. 0.058 g of sodium t -butoxide was added to the solution, and the reaction was carried out at room temperature for 20 hours. Trifluoroacetic acid (TFA) was added to the solution, and the mixture was reacted at room temperature for 6 hours. When the starting material disappeared with TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 68%.

1 H NMR (CD 3 OD, 400MHz): δ 8.74 (d, 2H, J = 14 Hz), 7.43-7.34 (m, 8H), 7.24-7.20 (m, 2H), 7.18 (d, 2H, J = 8.8 Hz), 6.50 (d, 2H, J = 14 Hz), 4.38 (t, 4H, J = 7.2 Hz), 2.84 (t, 4H, J = 6.0 Hz), 2.62 (t, 4H, J = 7.2 Hz ), 2.03 (q, 2H, J = 6.0 Hz), 1.48 (s, 12H).

13 C NMR (CD 3 OD, 100 MHz): δ 176.55, 172.62, 149.33, 145.82, 142.03, 141.33, 136.80, 133.77, 132.18, 128.38, 127.42, 124.93, 121.91, 118.73, 110.95, 101.76, 49.07, 41.72, 26.78, 26.00, 20.80.

HRMS (MALDI + , DHB): m / z obs'd 751.2233 ([M] + , calc'd 751.2201 for C 42 H 44 BrN 2 O 4 S).

Example  7. 3- (2 - (( E )-2-(( E ) -3 - (( E ) -2- (1- (2- Carboxyethyl ) -3,3- Dimethyl indoline -2 days Lee Dean) Ethylidene )-2-( p - Tolylthio ) Cyclohexane -One- Count ) Vinyl) -3,3-dimethyl-3H- Indole -1 day) Propanoate

Figure 112014020770645-pat00013

1- (3-butoxy-3-oxo-propyl) To a round bottom flask -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3-butoxy- Ylidene) ethylidene) -2- ( p -tolylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indole (0.106 g) was dissolved in 6 mL of tetrahydrofuran (THF). 0.058 g of sodium t -butoxide was added to the solution, and the reaction was carried out at room temperature for 20 hours. Trifluoroacetic acid (TFA) was added to the solution, and the mixture was reacted at room temperature for 6 hours. When the starting material disappeared with TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 70%.

1 H NMR (CD 3 OD, 400MHz): δ 8.80 (d, 2H, J = 14 Hz), 7.41-7.34 (m, 6H), 7.21-7.08 (m, 6H) 6.47 (d, 2H, J = 14 Hz), 4.37 (t, 4H , J = 7.2 Hz), 2.82 (t, 4H, J = 6.0 Hz), 2.61 (t, 4H, J = 7.2 Hz), 2.22 (s, 3H), 2.03 (q, 2H, J = 6.0 Hz), 1.49 (s, 12H).

13 C NMR (CD 3 OD, 100 MHz): δ 176.59, 172.51, 151.26, 146.32, 142.06, 141.33, 135.50, 133.85, 133.79, 129.83, 128.32, 125.84, 124.78, 121.87, 110.84, 101.48, 49.02, 41.63, 26.80, 25.99, 20.89, 19.46.

HRMS (MALDI + , DHB): m / z obs'd 687.3244 ([M] + , calc'd 687.3253 for C 43 H 47 N 2 O 4 S).

Example  8. 3- (2 - (( E )-2-(( E ) -2- (4- Aminophenylthio ) -3 - (( E ) -2- (1- (2- Carboxy Yl) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene ) Cyclohexane -One- Count ) Vinyl) -3,3-dimethyl-3H- sign 1-yl) Propanoate

Figure 112014020770645-pat00014

To a round bottom flask was added 2 - ((E) -2 - ((E) -2- (4- amino-phenylthio) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl Ylidene) ethylidene) cyclohexanone) vinyl) -1- (3-butoxy-3-oxopropyl) -3,3-dimethylindoleium bromide Was dissolved in 6 ml of tetrahydrofuran (THF). 0.058 g of sodium t -butoxide was added to the solution and the reaction was allowed to proceed at room temperature for 20 hours. Trifluoroacetic acid (TFA) was added to the solution, and the mixture was reacted at room temperature for 6 hours. When the starting material disappeared with TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 71%.

1 H NMR (CD 3 OD, 400MHz): δ 8.87 (d, 2H, J = 14 Hz), 7.42-7.19 (m, 8H), 7.03 (d, 2H, J = 8.8 Hz), 6.64 (d, 2H , J = 8.8 Hz), 6.45 (d, 2H, J = 14 Hz), 4.37 (t, 4H, J = 6.8 Hz), 2.80 (t, 4H, J = 6.0 Hz), 2.61 (t, 4H, J = 6.8 Hz), 2.00 (q, 2H, J = 6.0 Hz), 1.57 (s, 12H).

13 C NMR (CD 3 OD, 100 MHz): δ 178.06, 173.82, 154.93, 148.06, 147.84, 143.54, 142.76, 135.27, 129.74, 129.06, 126.11, 125.50, 123.29, 117.49, 112.19, 102.72, 50.44, 42.99, 28.34, 24.42, 22.38.

HRMS (MALDI + , DHB): m / z obs'd 688.3055 ([M] + , calc'd 688.3205 for C 42 H 46 N 3 O 4 S).

Example  9. 3- (2 - (( E )-2-(( E ) -3 - (( E ) -2- (1- (3- (2,5- Dioxopyrrolidine -1 day) Oxy ) -3- Oxopropyl ) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene ) -2- (4- Nitrophenylthio )city Cloak -One- Count ) Vinyl) -3,3-dimethyl-3H- Indole -1 day) Propanoate

Figure 112014020770645-pat00015

To a round bottom flask was added 3- (2 - (( E ) -2 - (( E ) -3 - (( E ) -2- (1- (2-carboxyethyl) -3,3- Ethylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H- indolium-1-yl) propanoate, Methane (0.5 ml) was added to dissolve it. 0.020 g of N, N' -dicyclohexen eicarbodiimide and 0.011 g of N -hydroxysuccinimide were added to the solution, and the mixture was allowed to react at 0 ° C for 1 hour. When the starting material disappeared with TLC, it was washed with 1M HCl and concentrated under reduced pressure. 0.5 ml of diethyl ether was added to the concentrate to crystallize, followed by filtration and drying to obtain the title compound.

Yield: 40%.

1 H NMR (CDCl 3, 400MHz ): δ 8.84 (d, 1H, J = 14.4 Hz), 8.33 (d, 1H, J = 13.2 Hz), 8.18 (d, 2H, J = 8.8 Hz), 7.54-6.91 (m, 11H), 5.96 ( d, 1H, J = 13.2 Hz), 4.82 (t, 2H, J = 7.2 Hz), 4.32 (t, 2H, J = 6.8 Hz), 3.29 (t, 2H, J = 7.2 Hz), 3.12 (t, 2H, J = 6.8 Hz), 3.05 (t, 2H, J = 6.8 Hz), 2.90 (s, 4H), 2.77 (t, 2H, J = 6.8 Hz), 2.07 (q , 2H, J = 6.8Hz), 1.44 (s, 6H), 1.28 (s, 6H).

HRMS (MALDI + , DHB): m / z obs'd 815.3116 ([M] + , calc'd 815.3111 for C 46 H 47 N 4 O 8 S).

Example  10. Cyanine - Antibody Conjugate

Figure 112014020770645-pat00016

To a round bottom flask trastuzumab (trastuzumab) 2.5mg and 3- (2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3- (2,5- Ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohexyl-1-yl) oxy) -3-oxopropyl) -3,3-dimethylindolin- ) Vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate was added thereto and stirred for 2 hours in 0.10M sodium phosphate aqueous solution. The reaction product was purified by size exclusion gel (Sephadex (R) G-25) column chromatography to give the title compound.

Reference Example  1. 1- (3- Buxoxy -3- Oxopropyl )-2-(( E )-2-(( E ) -3 - (( E ) -2- (1- (3- Buxoxy -3-ox Sopro Phil) -3,3- Dimethyl indoline -2- Ylidine ) Ethylidene ) -2- (2- Hydroxyethylthio ) Sycelle 0.0 &gt; Count ) Vinyl) -3,3-dimethyl-3H- Indole  Bromide

Figure 112014020770645-pat00017

1- (3-butoxy-3-oxo-propyl) To a round bottom flask -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3-butoxy- Ylidene) ethylidene) -2-chlorocyclohexy-1-yl) vinyl) -3,3-dimethyl-3H-indol-1-yll bromide And 0.05 mL of triethylamine (TEA), and 4 mL of ethanol was added to dissolve the solution. To this solution was added 0.059 g of 2-mercaptoethanol and the reaction was carried out at room temperature for 2 hours. When the color of the solution became dark green, when the starting material disappeared by TLC, it was concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give the title compound.

Yield: 75%

1 H NMR (DMSO-d 6 , 200MHz): δ 8.82 (d, 2H, J = 14 Hz), 7.62-7.22 (m, 8H), 6.39 (d, 2H, J = 14 Hz), 4.98 (t, 2H, J = 5.4Hz), 4.48 (t, 4H, J = 6.4Hz), 3.99 (t, 4H, J = 6.4Hz), 3.56 (q, 2H, J = 5.4Hz), 2.90-2.79 (m, 3H), 2.68 (t, 4H , J = 5.8Hz), 1.81 (m, 2H), 1.70 (s, 12H), 1.53 (q, 4H, J = 7.2 Hz), 1.33 (q, 4H, J = 7.2 Hz), 0.86 (t, 6H, J = 7.2 Hz).

HRMS (MALDI + , DHB): m / z obs'd 753.4863 ([M] + , calc'd 753.4298 for C 46 H 61 N 2 O 5 S).

Test Example  One. In vitro ( ex vivo ) Thiol  Bonding properties with compounds

4.55 mg of the compound obtained in Example 1 was dissolved in an NMR tube using 0.5 mL of DMSO-d 6 . To the solution, 0.005 mL of 2-mercaptoethanol was added. After 1 hour, 3 hours, and 5 hours, 200 MHz NMR analysis confirmed the structure of the material before and after the reaction. The results are shown in Fig. 1, A is the 200 MHz NMR spectrum of the compound obtained in Example 1, and B to D are the concentrations of the reactants obtained after 1 hour, 3 hours and 5 hours by adding 2-mercaptoethanol to the compound obtained in Example 1 200 MHz NMR spectrum, and E is the 200 MHz NMR spectrum of the compound obtained in Reference Example 1.

From the results shown in Fig. 1, it was confirmed that the nitrophenyl thio group of the compound of Example 1 was converted into the 2-mercaptoethanol ( N-2 ) through the Nucleophilic aromatic substitution reaction (S N Ar) of the thiol compound and the compound obtained in Example 1 Thiol group.

Test Example  2. In vitro  ( ex vivo ) Thiol group - Selective Binding Properties with Containing Amino Acids

The compound obtained in Example 1 was dissolved in fourteen cuvettes at a concentration of 10 mu M in 100 mM HEPES buffer (pH = 7.4). 1000 equivalents of each of blank, Ala, Pro, Phe, Ser, Val, Arg, His, Asn, Asp, Lys, Cys, Hcy, Glu and Gly were added to each cuvette. After 2 hours, L-glutamyl-L-cystenylglycine (GSH) was added in an amount of 1000 equivalents, and after 2 hours, fluorescence reaction was again performed using a fluorescence spectrometer Were measured. The results are shown in Fig.

From the results of FIG. 2, it can be confirmed that the reaction did not occur with amino acids having no thiol group, but the reaction selectively occurs when gamma-L-glutamyl-L-cysteinylglycine (GSH) is added. In addition, it was confirmed that the reaction of Cys and Hcy caused the modification of the compound, and that the reaction did not occur with gamma-L-glutamyl-L-cysteinylglycine. Accordingly, the compounds according to the present invention can be usefully used as probes for the selective detection of gamma-L-glutamyl-L-cysteinylglycine among amino acids containing thiol groups.

Test Example  3. With GSH  Rate of reaction rate

The compounds of Examples 5 to 8 were each dissolved in four cuvettes at a concentration of 10 μM in 100 mM HEPES buffer (pH = 7.4). After that, 1000 equivalents of gamma-L-glutamyl-L-cysteinylglycine (GSH) was added to each cuvette, and the absorbance was measured with time using a light absorber after 2 hours. From this, The Hammett plot was obtained according to the value, and the result is shown in FIG.

From the results shown in FIG. 3, it can be seen that the compounds of Examples 5 to 8 were substituted with the thiol group of GSH through the corresponding substituted-phenylthio group through GSH and a nucleophilic aromatic substitution reaction (S N Ar), respectively, The compound having a p-nitrophenylthio group is the fastest.

Test Example  4. Intracellular ( in vivo ) FSH Coupling characteristics with.

(BT-474: HER2 (+)) in BT-474 cells and McCoy5A medium in RPMI-1640 medium containing 100 units / mL of penicillin, 100 mg / mL of streptomycin and 10% heat-inactivated fetal bovine serum. MCF7: HER2 (-)) was cultured alone. The cell cultures were inoculated into two 35 mm-diameter culture dishes at a concentration of 2 x 10 5 cells for BT-474 cells and 0.8 x 10 5 cells for MCF7 cells, and the Herceptin-conjugation Lt; RTI ID = 0.0 &gt; 10 M &lt; / RTI &gt; Each cultured cell was incubated for 1 hour at 37 ° C and visualized using confocal laser scanning microscope imaging. Confocal microscopy imaging was activated using three channels, with each wavelength (λ ex ) at 405 nm, 488 nm, and 555 nm. The result is shown in Fig.

From the results shown in Fig. 4, it can be confirmed that the Herceptin-conjugated compound prepared in Example 10 has high fluorescence detected in BT-474 cells in which the Herceptin receptor is highly expressed. On the other hand, relatively low fluorescence is detected in MCF7 cells in which the expression of the Herceptin receptor is less. The compound according to the present invention can be usefully used as a probe for detecting GSH which can visualize the diagnostic and therapeutic action of an anticancer agent (for example, Herceptin, etc.) in the treatment of cancer cells expressing GSH.

Claims (2)

A composition for detecting gamma-L-glutamyl-L-cysteinylglycine comprising a compound of formula (I) or a compound of formula
<Formula 1a>
Figure 112014020770645-pat00018

&Lt; EMI ID =
Figure 112014020770645-pat00019

Wherein,
R 1 is nitro, halogen, C 1 to C 4 alkyl, or amino,
R 2 and R 3 are independently C 1 to C 4 alkyl,
R &lt; 4 &gt; is hydrogen or 2,5-dioxopyrrolidyl,
X is halogen. 2. A compound according to claim 1, wherein the compound of formula (1a) or the compound of formula (1b)
1- (3-butoxy-3-oxopropyl) -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl Ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium bromide;
2 - ((E) -2 - ((E) -2- (4- bromo-phenylthio) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl) -3 Ylidene) ethylidene) cyclohex-1-yl) vinyl) -1- (3-butoxy-3-oxopropyl) -3,3-dimethyl-3H- indoleium bromide ;
1- (3-butoxy-3-oxopropyl) -2 - ((E) -2 - ((E) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl Ylidene) ethylidene) -2- ( p -tolylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indoleium bromide;
2 - ((E) -2 - ((E) -2- (4- amino-phenylthio) -3 - ((E) -2- (1- (3- butoxy-3-oxopropyl) -3 2-ylidene) ethylidene) cyclohex-1-yl) vinyl) -1- (3-butoxy-3-oxopropyl) -3,3-dimethylindolium bromide;
( E ) -2 - (( E ) -3 - (( E ) -2- (1- (2- carboxyethyl) -3,3-dimethylindolin- Ylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate;
3- (2 - ((E) -2 - ((E) -2- (4- bromo-phenylthio) -3 - ((E) -2- (1- (2- carboxyethyl) 3,3 2-ylidene) ethylidene) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate;
( E ) -2 - (( E ) -3 - (( E ) -2- (1- (2- carboxyethyl) -3,3-dimethylindolin- Lidene) -2- ( p -tolylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indol-1-yl) propanoate;
3- (2 - ((E) -2 - ((E) -2- (4- amino-phenylthio) -3 - ((E) -2- (1- (2- carboxyethyl) 3,3- Ylidene) ethylidene) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indolium-1-yl) propanoate; And
3- (( E ) -2 - (( E ) -3 - (( E ) -2- (1- (3- (2,5-dioxopyrrolidin- 2-ylidene) ethylidene) -2- (4-nitrophenylthio) cyclohex-1-yl) vinyl) -3,3-dimethyl-3H-indole 1-yl) propanoate &lt; / RTI &gt;
L-glutamyl-L-cysteinylglycine. &Lt; / RTI &gt;
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN105949112A (en) * 2016-05-05 2016-09-21 中国科学院长春应用化学研究所 Compound used for optical imaging, and preparation method and bonding substance thereof
KR101772428B1 (en) 2015-03-31 2017-08-30 한국외국어대학교 연구산학협력단 Composition for detecting γ-glutamyl transferase, detection probe comprising thereof and method of detecting
CN109776379A (en) * 2019-03-08 2019-05-21 武汉大学 It is a kind of to can be used for responding the near infrared fluorescent probe and preparation method thereof that in living cells and pH changes in chronic wounds development process
CN115819643A (en) * 2022-11-30 2023-03-21 北京化工大学 Application of sulfur-containing cyanine molecules as near-infrared two-zone photoinitiator

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US20120276649A1 (en) * 2009-12-30 2012-11-01 The Oregon Board Of Higher Education On Behalf Of Portland State University Thiol detection
KR101328000B1 (en) * 2011-05-24 2013-11-13 한국외국어대학교 연구산학협력단 Coumarine derivative for detecting thiol compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120276649A1 (en) * 2009-12-30 2012-11-01 The Oregon Board Of Higher Education On Behalf Of Portland State University Thiol detection
KR101328000B1 (en) * 2011-05-24 2013-11-13 한국외국어대학교 연구산학협력단 Coumarine derivative for detecting thiol compounds

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101772428B1 (en) 2015-03-31 2017-08-30 한국외국어대학교 연구산학협력단 Composition for detecting γ-glutamyl transferase, detection probe comprising thereof and method of detecting
CN105949112A (en) * 2016-05-05 2016-09-21 中国科学院长春应用化学研究所 Compound used for optical imaging, and preparation method and bonding substance thereof
CN109776379A (en) * 2019-03-08 2019-05-21 武汉大学 It is a kind of to can be used for responding the near infrared fluorescent probe and preparation method thereof that in living cells and pH changes in chronic wounds development process
CN109776379B (en) * 2019-03-08 2021-01-15 武汉大学 Near-infrared fluorescent probe capable of responding to pH change in living cells and in chronic wound development process and preparation method thereof
CN115819643A (en) * 2022-11-30 2023-03-21 北京化工大学 Application of sulfur-containing cyanine molecules as near-infrared two-zone photoinitiator

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