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Micro-molecule fluorescent probe of phenyl furan hERG potassium channel and application thereof

A technology of potassium ion channels and fluorescent probes, which is applied in the direction of fluorescence/phosphorescence, luminescent materials, analytical materials, etc., can solve the problems of lagging development of biological and physiological properties, and achieve the effect of reducing false positive results

Active Publication Date: 2015-03-25
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no literature reporting the application of small molecule fluorescent probes in the study of ion channel structure and function and the pathophysiological mechanism of ion channel participation. Most of the literature reports the use of functional fluorescent protein (FPs) labeling technology, immunofluorescence technology, application Ca in cells 2+ or Na + Fluorescent probes and other studies on ion channels have made the use of fluorescent small molecule probes to study the biological and physiological properties of ion channels lag behind.

Method used

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  • Micro-molecule fluorescent probe of phenyl furan hERG potassium channel and application thereof
  • Micro-molecule fluorescent probe of phenyl furan hERG potassium channel and application thereof
  • Micro-molecule fluorescent probe of phenyl furan hERG potassium channel and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: (E)-2-(5-allyl-2,7-dichloro-4-((4-(4-(3-(((5-(4-chlorophenyl)furan- 2-yl)methylene)amino)-2,5-dioximidazol-1-yl)butyl)piperazin-1-yl)methyl)-6-hydroxy-3-oxo-3H-oxanthene -9-yl) preparation of benzoic acid

[0035] Concrete synthetic route is as follows:

[0036]

[0037] (1) Preparation of Intermediate 1:

[0038] Add 20mL of distilled water and 14mL of concentrated hydrochloric acid to p-chloroaniline (2.55g, 20mmol), white turbidity appeared, heated to 70°C, completely dissolved; after cooling to 0°C, slowly added dropwise sodium nitrite solution (1.38g dissolved in 10mL Distilled water, 20mmol), after dripping, the reaction solution was clarified, continued to react for 20min, added furfural (2.88g, 30mmol) and copper chloride (0.54g, 4mmol), the reaction solution was green, stirred overnight, and a brown solid was precipitated, which was obtained by suction filtration. Brown-green solid, the filter cake was washed successively with a small amount of...

Embodiment 2

[0055] Example 2: Preparation of naphthalene diimide fluorophore probes

[0056] Concrete synthetic route is as follows:

[0057]

[0058] In the synthetic route of this example, the preparation of intermediates 1-5 is the same as that of intermediates 1-5 in Example 1.

[0059] (1) Preparation of intermediate 7a:

[0060] To 1,8-naphthalene diimide (2.00 g, 10.14 mmol) was added anhydrous K 2 CO 3 (5.59,40.56mmol), 1,3-dibromopropane (6.14g, 30.43mmol) and 20mL of acetonitrile, reflux for 12h. After suction filtration, the filtrate was concentrated and passed through a column to obtain a white solid with a yield of 44.4%. M.p.:140.0-142.0℃. 1 H-NMR (300MHz, CDCl 3 ):δ8.63(dd, J=7.5,1.2Hz,2H),8.24(dd,J=8.1,1.2Hz,2H),7.79(dd,J=8.1,7.5Hz,2H),4.36(t, J=7.2Hz, 2H), 3.53(t, J=6.9Hz, 2H), 2.39-2.29(m, 2H).ESI-MS: ([M+H] + ): 318.2.

[0061] (2) Preparation of intermediate 7b:

[0062] According to the preparation method of intermediate 7a, the difference is: compound 6 ...

Embodiment 3

[0106] Embodiment 3: the mensuration of biological activity

[0107] Azimilide (Azimilide) and astemizole (Astemizole) were used as positive drugs, and a radioligand competitive binding experiment was used (reference: Identification of Human Ether-`a-go-go Related GeneModulators by Three Screening Platforms in an Academic Drug-Discovery Setting), measure the binding activity of fluorescent probe molecule and hERG potassium ion channel, the results are shown in Table 1, the activity of synthetic probe molecule is all improved than recognition group Azimilde, probe molecule and hERG potassium ion channel Have higher activity. However, there is a big difference in the fluorescence properties. The probe molecule L2-4 has no substituents on the naphthalene diimide ring, the fluorescence is weak and the excitation wavelength and emission wavelength are relatively short. Therefore, in further research, we L1 and L5 were selected for further screening and imaging studies.

[0108] T...

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Abstract

The invention discloses a micro-molecule fluorescent probe of a phenyl furan hERG potassium channel and application thereof. The structure general formula of the fluorescent probe is as shown in a formula (I), wherein R1 is a single substituted group or a polysubstituted group of halogen, alkyl or alkoxy; R2 is fluorophore; n is 1-6; the piperazine ring and the fluorophore are connected by an alkyl chaing containing 1-6 carbons. The molecule of the fluorescent probe can be used for marking an hERG potassium channel, can be used for screening activity of an hERG potassium channel inhibitor and evaluating the cardiotoxicity of commercial medicines, or used as a tool drug for pharmacological, pathological and physiological researches related to hERG potassium channels. Furthermore, the preparation method of the compound is mild in reacting condition, the raw materials have low price and are easily available, and the operation and posttreatment are simple.

Description

technical field [0001] The invention relates to a phenylfuran derivative and its small molecule fluorescent probe for hERG potassium ion channel, and its application in hERG potassium ion channel inhibitor activity screening, new drug cardiotoxicity evaluation and cell imaging, belonging to pharmaceutical technology field. Background technique [0002] The full name of hERG is human ether-a-go-go related gene, which is a gene isolated from the human hippocampal nerve. The hERG gene codes to form a voltage-activated delayed inward rectifier potassium ion channel, which is widely distributed in the human nervous system and heart tissue. In the heart tissue, it forms a rapidly activated delayed rectifier potassium channel (IKr) with the regulatory β subunit KCNE2, which is the fast phase component of the delayed rectifier potassium current in the third phase of cardiac action potential repolarization. hERG gene mutation will cause LQTS (long QT syndrome), SQTS (shortening QT ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C09K11/06C07D405/12C07D405/14C07D413/14G01N21/64
CPCC09B11/24C09B19/00C09B23/0066C09B57/02C09B57/08G01N33/582G01N33/6872G01N33/84
Inventor 杜吕佩李敏勇刘真真
Owner SHANDONG UNIV
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