A kind of c-6 modified nanoluc type analogue and its preparation method and application

A kind of analogue and type technology, which is applied in the field of modification and preparation of NanoLuc type analogues at the C-6 position, can solve the problems of poor penetration into tissues and skin, poor substrate stability, short emission wavelength, etc., and achieve design and synthesis Effects of facilitation, improved stability, and low detection limit

Active Publication Date: 2021-05-28
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0004] However, the inventors of the present disclosure found that the NanoLuc / Furimazine bioluminescence system has shortcomings such as short emission wavelength, poor substrate stability, and single substrate.
In vivo imaging is the most prominent application of bioluminescent imaging. The optimal wavelength for in vivo imaging is 650-800nm, while the maximum wavelength emitted by NanoLuc catalyzed Furimazine is 460nm, which is easily absorbed and scattered by tissues and cannot penetrate tissues and skin well. therefore not well suited for in vivo imaging

Method used

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  • A kind of c-6 modified nanoluc type analogue and its preparation method and application
  • A kind of c-6 modified nanoluc type analogue and its preparation method and application
  • A kind of c-6 modified nanoluc type analogue and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: 2-(furan-2-methyl)-6-(4-fluorophenyl)-8-imidazo[1,2-a]pyrazin-3-(7H)-one (A1) preparation.

[0088] Preparation of intermediate 2-amino-5-bromo-3-phenylmethylpyrazine (intermediate 1-1):

[0089]Under nitrogen protection, mix activated zinc powder (5 g, 77 mmol) and elemental iodine (500 mg), add DMF, and stir at room temperature for 10 minutes until the color of iodine disappears. Then benzyl bromide (3.6ml, 25.6mmol) was added and refluxed in an oil bath at 85°C for 3h. After 3h, it was moved to room temperature, and 2-amino-3,5-dibromopyrazine (5 g, 20 mmol) and bistriphenylphosphine palladium dichloride (700 mg, 1 mmol) were added. Reaction at room temperature for 12h. The reaction solution was filtered with diatomaceous earth, ethyl acetate and saturated ammonium chloride solution were added to extract repeatedly three times, the ethyl acetate phase was dried with anhydrous sodium sulfate, filtered, and purified on 200-300 mesh silica gel to obtain in...

Embodiment 2

[0106] Example 2: 2-(furan-2-methyl)-6-(4-chlorophenyl)-8-benzylimidazo[1,2-a]pyrazin-3-(7H)-one (A2 ) preparation.

[0107] Preparation of intermediate 2-((3-benzyl-5-(4-chlorophenyl)pyrazin-2-yl)amino)-3-(furan-2-yl)acrylate tert-butyl ester:

[0108] Under nitrogen protection conditions, 2-((3-benzyl-5-bromopyrazin-2-yl)amino)-3-(furan-2-yl) tert-butyl acrylate (200mg, 0.438mmol), Pd( PPh 3 ) 4 (50.6mg, 0.0438mmol) was dissolved in 1,4-dioxane, then a solution of 4-chlorophenylboronic acid (136.7mg, 0.876mmol) in 1,4-dioxane was added, and Na 2 CO 3 (2M, 0.2ml), heated to reflux at 85°C for 4h. After the reaction was terminated, it was extracted three times by adding distilled water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, and purified on 200-300 mesh silica gel to obtain 186.2 mg of a yellow solid with a yield of 87.3%.

[0109] Preparation of intermediate 2-((3-benzyl-5-(4-chlorophenyl)pyrazin-2-yl)amino)-3-(furan-2-yl)acrylic acid:

[0110...

Embodiment 3

[0115] Example 3: 2-(furan-2-methyl)-6-(thienyl-2)-8-benzylimidazo[1,2-a]pyrazin-3-(7H)-one (A5) preparation.

[0116] Preparation of intermediate 2-((3-benzyl-5-(thienyl-2)pyrazin-2-yl)amino)-3-(furan-2-yl)acrylate tert-butyl ester

[0117] Under nitrogen protection conditions, 2-((3-benzyl-5-bromopyrazin-2-yl)amino)-3-(furan-2-yl) tert-butyl acrylate (200mg, 0.438mmol), Pd( PPh 3 ) 4 (50.6mg, 0.0438mmol) was dissolved in 1,4-dioxane, then a solution of 2-thiopheneboronic acid (112.1mg, 0.876mmol) in 1,4-dioxane was added, and Na 2 CO 3 (2M, 0.2ml), heated to reflux at 85°C for 4h. After the reaction was terminated, distilled water and ethyl acetate were added to extract three times, dried over anhydrous sodium sulfate, filtered, and purified on 200-300 mesh silica gel to obtain 153.8 mg of a yellow solid with a yield of 72.1%.

[0118] Preparation of intermediate 2-((3-benzyl-5-(thienyl-2)pyrazin-2-yl)amino)-3-(furan-2-yl)acrylic acid:

[0119] 2-((3-Benzyl-5-(thienyl...

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Abstract

The present disclosure provides a modified NanoLuc type analog at the C-6 position and its preparation method and application, which has the structure shown in formula I: R 1 selected from 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-fluoro-4-aminophenyl, thienyl, furyl, 5-methylfuryl, naphthalene-2-yl, benzene Furanyl, 4‑methylphenyl, 3,5‑dimethylphenyl, 4‑hydroxymethylphenyl, 4‑methoxyphenyl, 4‑mercaptophenyl. This type of compound can be used as a substrate for bioluminescence to study protein:protein and protein:ligand interactions, monitor protein stability and bioluminescence resonance energy transfer and other fields, and use bioluminescence as a probe to detect the effect of NanoLuc luciferase Under the application of in vitro, cellular and in vivo distribution imaging, in the presence of NanoLuc luciferase as a reporter signal to detect the pharmacological and toxic effects of drugs at the enzyme level, cellular level, and animal level.

Description

technical field [0001] The disclosure belongs to the technical field of medicines, and relates to a modified NanoLuc type analog at the C-6 position, 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] Bioluminescence (bioluminescence) is a very common phenomenon in nature, and it is also a special type of chemiluminescence. The efficiency of converting chemical energy into light energy is almost 100%. Bioluminescence requires at least three elements: luciferase, the corresponding luciferin substrate, and oxygen. Different bioluminescent systems require different luciferases and luciferin substrates, but their luminescent mechanism is roughly the same: the luciferin substrate is catalyzed and oxidized by luciferase under oxygen conditions to generate excited-state Electron intermediates, when the excite...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C09K11/06G01N21/76
CPCC07D487/04C09K11/06C09K2211/1007C09K2211/1011C09K2211/1059C09K2211/1088C09K2211/1092G01N21/76G01N21/763
Inventor 李敏勇崔媛媛闫崇政
Owner SHANDONG UNIV
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