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Phenyl imidazopyrazinone compound as well as preparation method and application thereof

A technology of phenylimidazole and compound, which is applied to phenylimidazopyrazinone compounds and the fields of preparation and application, can solve the problems of improving background signal, short emission wavelength, poor stability and the like

Active Publication Date: 2020-04-28
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the NanoLuc / Furimazine bioluminescent system has an unparalleled luminescent advantage, the inventors of the present disclosure found that it has the following defects: the emission wavelength is only 460nm, which is lower than other bioluminescent systems, so it cannot be used for in vivo luminescence. Imaging; poor stability, easy to be oxidized in neutral or alkaline medium to produce chemiluminescence, which improves the background signal; single substrate, etc.

Method used

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  • Phenyl imidazopyrazinone compound as well as preparation method and application thereof
  • Phenyl imidazopyrazinone compound as well as preparation method and application thereof
  • Phenyl imidazopyrazinone compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1: Study on in vitro enzymatic activity of NanoLuc-type derivatives and NanoLuc luciferase.

[0076] 1. Determination of bioluminescence intensity and calculation of kinetic constants of enzymatic reactions: the measured values ​​were calculated using GraphPad Prism to calculate the reaction kinetic constants and half life of different compounds. Based on the test results of Furimazine (2 μM), the relative bioluminescent intensity values ​​of all compounds were converted.

[0077] 2. Determination of the maximum wavelength of bioluminescence: Add 0.5ml NanoLuc (0.6μg / ml) to 0.5ml of different target compounds dissolved in Tris-HCl (50mM, pH=7.42) and Furimazine (25μM), respectively, and use F- The 2500 fluorescence spectrophotometer is in the lamp off luminescence mode, the response time is set to 0.4s, and the emission spectrum is scanned to obtain the maximum biological emission wavelength.

[0078] Table 1. In vitro bioluminescent properties of NanoLuc-type ...

Embodiment 2

[0081] Example 2: Study on the luminous intensity of NanoLuc-type derivatives and Renilla luciferase in vitro.

[0082] Add 50 μL of the target compound and Furimazine at different concentrations (0, 0.25, 0.5, 1, 2, 5, 10, 25 μM) dissolved in Tris-HCl (50 mM, pH=7.42) to 50 μL of Renilla fluorescent Sulfase (1 μg / ml) was placed in a black 96-well plate, and the intensity of bioluminescence was measured with the IVIS Kinetic small animal in vivo imaging system.

[0083] Table 2. In vitro bioluminescence intensities of NanoLuc-type derivatives and Renilla luciferase

[0084]

[0085] The results showed that all the target compounds gradually increased the luminescence intensity with the increase of the concentration, but were far lower than the luminescence intensity (lower three orders of magnitude) under NanoLuc luciferase, which also indicated that the target compound had a strong effect on NanoLuc luciferase. With high selectivity, it can be used as a probe to specifica...

Embodiment 3

[0086] Example 3: Study on the luminescence intensity of NanoLuc-type derivatives and Gaussisa luciferase in vitro.

[0087] Add 50 μL of the target compound and Furimazine at different concentrations (0, 0.25, 0.5, 1, 2, 5, 10, 25 μM) dissolved in Tris-HCl (50 mM, pH=7.42) to 50 μL of Gaussisa luciferase (0.5 μg / ml) in a completely black 96-well plate, the bioluminescence intensity was measured with the IVIS Kinetic small animal in vivo imaging system.

[0088] Table 3. In vitro bioluminescence intensity of NanoLuc type derivatives and Gaussisa luciferase

[0089]

[0090]

[0091] The results showed that compared with Furimazine, A1 and A2 exhibited stronger bioluminescence under the action of Gaussisa luciferase; however, the luminescence intensity of all compounds was much lower than that of NanoLuc luciferase, which indicated that the target compound had a strong NanoLuc luciferase is highly selective.

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Abstract

The invention provides a phenyl imidazopyrazinone compound as well as a preparation method and application thereof. The chemical structure is shown as a formula (I), wherein R1 is selected from phenoxy, thiophenyl, 5-methylfuryl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorphenyl, 4-bromophenyl, 3-fluoro-4-aminophenyl, 3-furyl, 4-methylfuryl, naphthalene-2-yl, 4-methylphenyl, 3, 5-dimethylphenyl, 4-hydroxymethylphenyl, 4-hydroxymethylphenyl and 4-hydroxyphenyl. The C8 site of a Furimazine substrate is modified, so that the imaging wavelength of the Furimazine substrate can generate red shift, theluminous intensity of the Furimazine substrate is enhanced, and particularly, bioluminescence imaging at an animal level is enhanced.

Description

technical field [0001] The disclosure relates to a phenylimidazopyrazinone compound, a preparation method and application thereof. Background technique [0002] The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art. [0003] Bioluminescent imaging (BLI) is a sensitive, reliable, and non-invasive monitoring method that can be used to monitor tumor growth and metastasis, expression of target genes, protein-protein interactions, and high-throughput drug delivery. Screening and in vivo ATP levels, etc. Bioluminescence imaging has the following advantages: first, the signal-to-noise ratio (SNR) is high, and the background signal of the bioluminescence system can be ignored, so the bioluminescence is more sensitive; Evaluation of biological activity; third, bioluminescence does not require an external light source, thus avoiding its own photobleaching and phototoxicity risks; fourth, bioluminesc...

Claims

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Application Information

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IPC IPC(8): C07D487/04C09K11/06C12Q1/66
CPCC07D487/04C09K11/06C09K2211/1007C09K2211/1059C09K2211/1088C12Q1/66
Inventor 李敏勇闫崇政
Owner SHANDONG UNIV
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