CN114621754A - Preparation of fluorescent probe and application of fluorescent probe in histone deacetylase - Google Patents

Preparation of fluorescent probe and application of fluorescent probe in histone deacetylase Download PDF

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CN114621754A
CN114621754A CN202210405806.3A CN202210405806A CN114621754A CN 114621754 A CN114621754 A CN 114621754A CN 202210405806 A CN202210405806 A CN 202210405806A CN 114621754 A CN114621754 A CN 114621754A
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fluorescent probe
histone deacetylase
fluorescent
phenyl
hdac
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李媛媛
陈新
赵玲
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Wuhan Polytechnic University
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
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    • G01—MEASURING; TESTING
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    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • 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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    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/978—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • G01N2333/98—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)

Abstract

The invention belongs to the technical field of medicines, and particularly discloses preparation of a fluorescent probe and application of the fluorescent probe in histone deacetylase. Aniline compounds and methyl 8-chloro-8-oxooctanoate compounds are used as raw materials, a series of fluorescent probes are prepared under the catalysis of triethylamine, and finally the fluorescent probes are reacted with ammonium chloride under alkaline conditions to obtain the fluorescent probes containing hydroximes. The compound can be used as an HDAC inhibitor for preparing a medicine taking HDAC as a target, can be used for specifically detecting histone deacetylase 6 aiming at the HDAC inhibitor, can be used for preparing a kit for specifically detecting fluorescence of histone deacetylase, and has a unique starting mechanism and a specific HDAC6 fluorescent probe, thereby showing good prospects in cancer cell diagnosis and imaging.

Description

Preparation of fluorescent probe and application of fluorescent probe in histone deacetylase
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to preparation of a fluorescent probe and application of the fluorescent probe in histone deacetylase.
Background
Histone Deacetylases (HDACs) regulate a myriad of cellular processes by catalyzing the hydrolysis of acetyl-l-lysine residues in histones and other cellular proteins. Aberrant expression of HDACs has been found to be associated with tumorigenesis, developmental disorders and neurodegenerative diseases, and thus diagnosis of specific HDAC isozymes associated with specific disease phenotypes is of great clinical interest. To date, 18 human HDAC isozymes have been identified. Among them, HDAC6 is unique in that it has a unique deacetylated substrate in the cytoplasm, the K40 residue of α -tubulin in the microtubule lumen. Thus, HDAC6 inhibition leads to microtubule hyperacetylation and inhibition of microtubule dynamics, leading to cycle arrest and cell death. Therefore, HDAC6 is considered to be a promising biomarker for tumor diagnosis and treatment.
Several HDAC fluorescent probes have been reported, and although they can be used for dynamic detection and tracking of HDACs in living cells and tissues, they have several problems. First, the probe remains fluorescent throughout, thus requiring cumbersome washing steps to avoid non-specific binding; secondly, the excess probe generates background fluorescence, preventing real-time detection of intracellular HDACs; finally, specific differentiation between HDAC isoforms remains a significant challenge. Therefore, the development of novel probes specific for HDAC is of great interest.
The invention discloses preparation of a fluorescent probe and application of the fluorescent probe in preparation of a histone deacetylase inhibitor. The target compound shows good antitumor activity and fluorescence imaging capability in biological tests.
Disclosure of Invention
The invention aims to provide a preparation method of a novel HDAC6 specific fluorescent probe and application of the fluorescent probe in detecting histone deacetylase.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, there is provided a fluorescent probe, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, having a structure represented by the following general formula I:
Figure 6725DEST_PATH_IMAGE001
general formula I
Wherein, the first and the second end of the pipe are connected with each other,
r1 is (diphenylamino) phenyl, (1,2, 2-triphenylethenyl) phenyl;
x is O, N;
n is 0 to 3;
the compound shown in the general formula I, or pharmaceutically acceptable salt, stereoisomer or tautomer thereof, is characterized in that R1 is 4- (diphenylamino) phenyl or 3- (1,2, 2-triphenylvinyl) phenyl.
In a second aspect, a method for preparing the novel HDAC6 specific fluorescent probe is provided, which comprises the following specific steps:
adding aniline (1 mmoL), 8-chloro-8-oxo methyl octanoate compounds (1.1-1.2 mmoL), triethylamine (1 mmoL) and dichloromethane solution under anhydrous and oxygen-free conditions, reacting in a single-neck round-bottom flask at 25-30 ℃, monitoring by TLC, separating by column chromatography, and adding a mixed solution of ammonium chloride (5 mmoL) and potassium hydroxide (6 mmoL) dropwise under ice bath conditions to obtain a reaction product.
Figure 189445DEST_PATH_IMAGE003
Wherein the content of the first and second substances,
r1 is triphenylamine group or tetraphenylethylene group;
x is O, N;
n is 0 to 3;
the specific operation process can be as follows:
adding 0.1mmoL aniline or phenols, 1.11-0.12 mmoL 8-chloro-8-oxo methyl caprylate compounds, 1mmoL triethylamine and 10 ml dichloromethane solution under anhydrous and anaerobic conditions, reacting in a single-mouth round-bottom flask at 25-30 ℃, monitoring by TLC, separating by column chromatography after the raw materials are basically reacted completely to obtain a pure fluorescent probe containing an ester group, and then dropwise adding a mixed solution of ammonium chloride (5 mmoL) and potassium hydroxide (6 mmoL) under ice bath conditions to obtain a reaction product.
The above general formula I of the present invention can form a pharmaceutically acceptable salt thereof with an acid, which may include inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, according to methods common in the art to which the present invention pertains.
In a third aspect, the application of the novel HDAC6 specific fluorescent probe compound and the pharmaceutically acceptable salts thereof in detecting histone deacetylase is provided.
In a fourth aspect, a composition as a histone deacetylase inhibitor is provided, which comprises a compound of the general formula I and pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable auxiliary agents.
Compared with the prior art, the invention has the beneficial effects that:
first, the fluorescent group of the HDAC fluorescent probe of the present invention has aggregation-induced emission characteristics, and compared to the conventional fluorescent probe, the aggregation-induced emission probe modifies the water-soluble group so that it can not emit fluorescence by intramolecular rotation in vivo. However, once its intramolecular movement is restricted, fluorescence can be restored upon binding to the target protein. Thus, the HDAC6 specific fluorescent probe provided by the invention can realize the washing-free and real-time detection of target protein with high signal-to-noise ratio.
Secondly, the fluorescent probe is an HDAC6 specific fluorescent probe, and can be used as an HDAC inhibitor to realize diagnosis and treatment integration. Since HDAC subtypes are diverse and have high homology, preparation of a fluorescent probe specific to HDAC6 is difficult. The present invention retains Zn of SAHA by integrating fluorophores ((dianilino) phenyl or (1,2, 2-triphenylvinyl) phenyl) and SAHA (HDAC inhibitor) of aggregation-induced emission characteristics into one molecule2+Binding groups and linkers, and thus the probes can specifically bind to the catalytic pocket of HDACs, exerting an inhibitory effect. Due to the bulky capping groupsSelective inhibition at HDAC 6. Thus, large and rigid fluorophores with aggregation-induced emission properties ((diphenylamino) phenyl or (1,2, 2-triphenylvinyl) phenyl) would confer HDAC6 selectivity on the probe.
In conclusion, the compound can be used as an HDAC inhibitor for preparing a medicine taking HDAC as a target, can be used for preparing a kit for specific fluorescence detection of histone deacetylase by aiming at specific fluorescence detection of histone deacetylase 6, and has a unique starting mechanism and a specific HDAC6 fluorescent probe, thereby showing good prospects in cancer cell diagnosis and imaging.
Drawings
FIG. 1 is a graph showing the fluorescence and size of the accumulated in PBS of representative target compounds TPAsaha and TPEsaha synthesized in accordance with the present invention.
Detailed Description
Further features and advantages of the present invention will be understood by reference to the following detailed description when considered in conjunction with the accompanying drawings. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way.
Example 1
Preparation of N1- (4- (dianilino) phenyl) -N8-hydroxyoctylenediamine (TPAsaha):
Figure 624975DEST_PATH_IMAGE004
adding 0.1mmoL of triphenylamine, 0.12mmoL of 8-chloro-8-oxo methyl octanoate, 1mmoL of triethylamine and 10 ml of dichloromethane solution under the anhydrous and anaerobic conditions, reacting in a single-neck round-bottom flask at 25 ℃, monitoring the reaction by TLC, carrying out column chromatography separation to obtain a pure triphenylamine compound, and then dropwise adding a mixed solution of ammonium chloride (5 mmoL) and potassium hydroxide (6 mmoL) under the ice bath condition to obtain a reaction product. The product was a pale yellow solid with a yield of 60%.1H NMR (600 MHz, DMSO-d 6) δ 10.31 (s, 1H), 9.78 (s, 1H), 8.63 (s, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.0 Hz, 3H), 7.10 – 7.02 (m, 6H), 6.93 (dd, J = 19.1, 9.3 Hz, 6H), 6.83 (d, J = 8.1 Hz, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.90 (t, J = 7.4 Hz, 2H), 1.51 (t, J = 7.1 Hz, 2H), 1.45 (t, J = 7.0 Hz, 2H), 1.23 (qd, J = 7.6, 4.3 Hz, 4H).13C NMR (600 MHz, DMSO-d 6) δ 173.76 , 146.02 , 145.93 , 145.86 , 142.62 , 140.31 , 133.63 , 133.31 , 133.26 , 130.48 , 130.37 , 129.10 , 129.04 , 120.90 , 38.95 , 34.86 , 31.01 , 27.62 .
Example 2
Preparation of N1-hydroxy-N8- (3- (1,2, 2-triphenylvinyl) phenyl) octanediamine (TPEsaha):
Figure 285763DEST_PATH_IMAGE005
adding 0.1mmoL 4- (1,2, 2-triphenylvinyl) aniline, 0.12mmoL methyl 8-chloro-8-oxooctanoate, 1mmoL triethylamine and 10 ml dichloromethane solution under anhydrous and anaerobic conditions, reacting in a single-neck round-bottom flask at 25 ℃, monitoring the reaction by TLC, separating by column chromatography to obtain pure triphenylamine compounds, and adding a mixed solution of ammonium chloride (5 mmoL) and potassium hydroxide (6 mmoL) dropwise under ice bath conditions to obtain a reaction product. The product was a pale yellow solid with a yield of 65%.1H NMR(600 MHz, DMSO-d6) δ 7.42 (d, J = 8.9 Hz, 2H), 7.20 (dd, J = 8.6, 7.3 Hz, 4H), 6.99 – 6.96 (m, 4H), 6.96 – 6.92 (m, 4H), 2.34 (t, J = 7.5 Hz, 2H), 2.08 (t, J = 7.4 Hz, 2H), 1.65 (dp, J = 37.3, 7.2 Hz, 5H), 1.43 – 1.33 (m, 5H). 13C NMR (600 MHz, Chloroform-d) δ 160.95, 152.85, 147.21, 146.30, 139.43, 132.40, 132.09, 131.69, 130.08, 128.39, 127.97, 127.65, 127.63, 127.41, 127.37, 126.66, 126.12, 126.01, 125.96, 124.51, 123.57, 115.89, 104.42, 99.80, 55.36.
Example 3
Aggregation-induced emission performance detection experiment of fluorescent probe
TPAsaha exhibits strong fluorescence at 422 nm in Phosphate Buffered Saline (PBS) due to aggregation-induced emission properties (fig. 1A). In contrast, TPAsaha emits little at a concentration of 1.0. mu.M. Dynamic Light Scattering (DLS) measurements showed that at a concentration of 1.0. mu.M, TPAsaha did not form aggregates, while the average particle size of TPAsaha particles was 51.4 nm. As the TPAsaha concentration increased to 10. mu.M, aggregates with a diameter of 11.5 nm appeared and the fluorescence intensity increased (FIG. 1C). A similar phenomenon was also found for TPEsaha, as shown in fig. 1B and 1D. We can observe weak fluorescence of Compound 2 aggregated at 478 nm. The highly enhanced emissions in highly viscous solvents further confirm the AIE properties of TPAsaha and TPEsaha, as shown in figure 1.
Example 4
And (3) determining the histone deacetylase inhibitory activity by using a fluorescent probe:
the specific operation steps are as follows: the inhibition activity of fluorescent probes against HDACs 1,2, 3, 6, 8 was tested using the HDAC kit. BSA, HDAC fluorogenic substrate, HDAC enzyme (HDAC1 or HDAC6) and the fluorescent probe to be tested were added to each well of the test plate according to the kit protocol at a concentration gradient of: 1X 10-10 M，1×10-9 M，1×10-8 M，1×10-7M，1×10-6M，1×10-5And M. After the test plate was reacted at 37 ℃ for 30 min, HDAC Developer was added to each well and the incubation at 37 ℃ was continued for 15 min. The fluorescence value of each well was measured at 359 nm and 440 nm using a microplate reader, the experimental results were analyzed, and IC was calculated50. Analyzing the experimental results and calculating IC50. The inhibitory activity is shown in Table 1.
Table 1 results of histone deacetylase inhibitory activity of representative fluorescent probes TPAsaha and TPEsaha synthesized in the present invention (nM, avg. ± SD., sample = 3).
Figure 506660DEST_PATH_IMAGE006
As can be seen from Table 1, the fluorescent probe shown in formula I of the invention has very good inhibitory effect on histone deacetylase, and the inhibitory activity of the compound on histone deacetylase 6 is stronger than that of the homologous histone deacetylase 1,2, 3 and 8. The compound can be used for preparing a medicine of a histone deacetylase inhibitor.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.

Claims (4)

1. A fluorescent probe and pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, characterized by having the structure of the following general formula:
Figure 458228DEST_PATH_IMAGE001
wherein the content of the first and second substances,
the R1 is (diphenylamino) phenyl, (1,2, 2-triphenylethenyl) phenyl;
said X is O, N;
n is 0 to 3;
the compound is specifically:
n1- (4- (dianilino) phenyl) -N8-hydroxyoctylenediamine (TPAsaha);
N1-hydroxy-N8- (3- (1,2, 2-triphenylvinyl) phenyl) octanediamine (TPEsaha).
2. The fluorescent probe and pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, according to claim 1, wherein R1 is 4- (dianilino) phenyl, or 3- (1,2, 2-triphenylvinyl) phenyl.
3. The fluorescent probe of claim 1, wherein the fluorescent probe and its pharmaceutically acceptable salts, stereoisomers, or tautomers thereof are used for preparing histone deacetylase inhibitors.
4. A composition of histone deacetylase inhibitor, comprising the fluorescent probe compound of claim 1 and pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable auxiliaries.
CN202210405806.3A 2022-04-18 2022-04-18 Preparation of fluorescent probe and application of fluorescent probe in histone deacetylase Pending CN114621754A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115590982A (en) * 2022-09-01 2023-01-13 湖南大学（Cn） Deacetylase self-sacrifice system and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007148A1 (en) * 1991-10-04 1993-04-15 Sloan-Kettering Institute For Cancer Research Novel potent inducers of terminal differentiation and methods of use thereof
CN102933558A (en) * 2010-01-22 2013-02-13 埃斯泰隆制药公司 Reverse amide compounds as protein deacetylase inhibitor and methods of use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993007148A1 (en) * 1991-10-04 1993-04-15 Sloan-Kettering Institute For Cancer Research Novel potent inducers of terminal differentiation and methods of use thereof
CN102933558A (en) * 2010-01-22 2013-02-13 埃斯泰隆制药公司 Reverse amide compounds as protein deacetylase inhibitor and methods of use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAO LI等: "AIEgen based turn-on fluorescent probes of histone deacetylase 6 via restriction of molecular motion" *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115590982A (en) * 2022-09-01 2023-01-13 湖南大学（Cn） Deacetylase self-sacrifice system and application thereof
CN115590982B (en) * 2022-09-01 2024-04-02 湖南大学 Deacetylase self-sacrifice system and application thereof

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Application publication date: 20220614