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Coelenterazine-h-based deuterated compound as well as preparation method and application thereof

A technology of deuterated compounds and coelenterazine, applied in the field of deuterated compounds based on coelenterazine-h and preparation thereof, can solve the problems of short bioluminescence emission wavelength, low bioluminescence intensity, short duration and the like

Active Publication Date: 2021-11-23
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are some problems in the bioluminescence system, such as low bioluminescence intensity, short duration, short emission wavelength of bioluminescence, and greater damage to tissues, etc.

Method used

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  • Coelenterazine-h-based deuterated compound as well as preparation method and application thereof
  • Coelenterazine-h-based deuterated compound as well as preparation method and application thereof
  • Coelenterazine-h-based deuterated compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: 2-(1,1-dideuterium-1-phenylmethyl)-5-deuterium-6-(4-hydroxyphenyl)-8-(1,1-dideuterium-1-(2 , Preparation of 3,4,5,6-pentadeuteriophenyl)methyl)imidazol[1,2-a]pyrazin-3(7H)-one (C1).

[0067] Preparation of 1,1-dideuterium-1-(2,3,4,5,6-pentadeuteriophenyl)-1-bromomethane:

[0068] Deuterated toluene (1g, 9.98mmol, toluene-d 8 ) and N-bromosuccinimide (1.78g, 9.98mmol) were dissolved in 50mL of carbon tetrachloride, and then tert-butyl peroxybenzoate (581mg, 2.99mmol) was added. React at 90°C for 2 hours, use TLC to monitor the reaction, the reaction is complete, stop the reaction, filter, remove the succinimide in the reaction solution, collect the filtrate, spin dry, add 100-200 mesh silica gel to mix the sample, and mix with 200 -300 mesh silica gel column, with petroleum ether as eluent, to obtain intermediate compound 1, R f About 0.5, developer: petroleum ether, 1.1 g of colorless oily compound, yield 62%. 13 C NMR(101MHz,DMSO)δ138.22,129.56,129.32,12...

Embodiment 2

[0080] Example 2: 2-benzyl-6-(4-hydroxyphenyl)-8-((2,3,4,5,6-pentadeuteriophenyl)methyl)imidazo[1,2-a]pyridine Preparation of azin-3(7H)-ones (C2).

[0081] 2-benzyl-6-(4-hydroxyphenyl)-8-((2,3,4,5,6-pentadeuteriophenyl)methyl)imidazo[1,2-a]pyrazine-3( Preparation of 7H)-ketone:

[0082] 2-amino-3-(1,1-dideuterium-1-(2,3,4,5,6-pentadeuteriophenyl)methyl)-5-(4-hydroxyphenyl) prepared in Example 1 -pyrazine (100mg, 0.35mmol) and 1,1-diethoxy-3-phenylpropan-2-one (156mg, 0.73mmol) prepared in Example 1 were dissolved in 10mL of dehydrated ethanol, under nitrogen Under protection, after stirring at room temperature for 2 hours, concentrated hydrochloric acid (366mg, 3.5mmol) was added, the reaction solution was transferred to 80°C, reacted for 8 hours, cooled to room temperature, spin-dried, and thin-layer chromatography was performed. : Methanol = 15: 1 as the chromatographic solution, the target color band is obtained, and the target color band is washed with dichloromethane:...

Embodiment 3

[0085] Example 3: 5-deuterium-6-(4-hydroxyphenyl)-2,8-bis(1,1-dideuterium-1-phenylmethyl)imidazo[1,2-a]pyrazine-3 Preparation of (7H)-ketones (C3).

[0086] Preparation of 2-amino-3-benzyl-5-bromo-pyrazine:

[0087] Activated zinc powder (3.06g, 46.77mmol) was added to a 50mL double-necked flask, and under nitrogen protection at room temperature, a solution of iodine element (356mg, 1.4mmol) was added (iodine element was dissolved in ultra-dry tetrahydrofuran and ultra-dry N,N -Dimethylformamide, ultra-dry tetrahydrofuran:N,N-dimethylformamide=5:1), stirring, the color of the iodine element fades. Benzyl bromide (4 g, 23.39 mmol) was added to the above solution using a syringe and refluxed at 85°C. After 3 h, the reaction solution (uniform gray solution) was cooled to room temperature. Dissolve 2-amino-3,5-dibromopyrazine (3.94 g, 15.59 mmol) and bistriphenylphosphine palladium dichloride (328 mg, 467.67 μmol) in ultra-dry N,N-dimethylformamide solution , which was added d...

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Abstract

The invention discloses a coelenterazine-h-based deuterated compound and a preparation method and application thereof, the chemical structural formula is as follows, wherein R1 is phenyl or deuterated phenyl, R2 is hydrogen or deuterium, R3 is hydrogen or deuterium, R4 is hydrogen or deuterium, R5 is hydrogen or deuterium, R6 is hydrogen or deuterium, and at least one of R1-R6 is a deuterated group. According to the application of the deuterated compound as a bioluminescent substrate, the in-vivo and in-vitro distribution condition of luciferase can be monitored. The bioluminescence intensity of the deuterated substance of coelenterazine-h is superior to that ofthe coelenterazine-h at the enzyme level, the cell level and the animal level . Meanwhile, the preparation method of the deuterated compound of coelenterazine-h, provided by the invention, is simple, classical in reaction steps, high in operability and low in cost, and has a good practical value.

Description

technical field [0001] The invention belongs to the technical field of medicines and relates to the preparation of luciferase substrates, in particular to a deuterated compound based on coelenterazine-h and its preparation method and application. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Bioluminescence (Bioluminescene) is a special phenomenon of luminescence on living organisms, which is caused by the interaction between luciferase and its substrate luciferin. Luciferase catalyzes the oxidation of luciferin by molecular oxygen to excite The state is transformed into oxyluciferin molecules, and oxyluciferin emits visible light and returns to the ground state. All k...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07B59/00C09K11/06G01N21/64G01N21/76C12Q1/66
CPCC07D487/04C07B59/002C09K11/06G01N21/6428G01N21/763C12Q1/66C07B2200/05C09K2211/1059
Inventor 李敏勇杜吕佩杨月利
Owner SHANDONG UNIV
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