C-6 site modified NanoLuc type analogues and preparation method and application thereof

An analog and type technology, which is applied in the field of C-6 modification of NanoLuc type analogs and preparation, can solve the problems of inability to penetrate tissue and skin well, poor substrate stability, short emission wavelength, etc., and achieve design synthesis. Effects of promotion, improved stability, low detection limit

Active Publication Date: 2020-05-08
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 im

Method used

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  • C-6 site modified NanoLuc type analogues and preparation method and application thereof
  • C-6 site modified NanoLuc type analogues and preparation method and application thereof
  • C-6 site modified NanoLuc type analogues and preparation method and application thereof

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 invention provides C-6 site modified NanoLuc type analogues and a preparation method and application thereof. The C-6 site modified NanoLuc type analogues have a structure as shown in a formula Iwhich is described in the specification. In the formula I, R1 is selected from a group consisting of a 4-fluorophenyl group, a 4-chlorphenyl group, a 4-bromophenyl group, a 3-fluoro-4-aminophenyl group, a thienyl group, a furyl group, a 5-methylfuryl group, a naphth-2-yl group, a benzofuryl group, a 4-methylphenyl group, a 3,5-dimethylphenyl group, a 4-hydroxymethylphenyl group, a 4-methoxyphenylgroup and a 4-mercaptophenyl group. The analogues can be used as a bioluminescent substrate for researching protein-protein and protein-ligand interactions, monitoring protein stability and bioluminescence resonance energy transfer and the like. The invention provides application of the analogues to in-vitro, cellular and in-vivo distribution imaging under the action of NanoLuc luciferase in virtue of bioluminescence and application of the analogues as a report signal to detect the pharmacological action and toxic action of a drug at an enzyme level, a cellular level and an animal level in thepresence of NanoLuc luciferase.

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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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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