CN114394970B - Ester Furimazine derivative and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the field of bioluminescence, in particular to a method for preparing a fluorescent dyeEsters Furimazine derivatives, and preparation method and application thereof are provided. The chemical structure of the ester Furimazine derivative is shown as a formula I:
wherein R is 1 Selected from tert-butyl, phenyl, furyl, tert-butoxymethyl, 2-phenyl-2-methylethyl, 2- (benzoyloxy) -2-methylethyl, 1-methoxyethyl, propoxy. The substance can be used as a bioluminescent substrate, and compared with sulfur-containing Furinazine, part of the compounds have the advantages that the bioluminescent time at the cellular level and the animal level is prolonged, the bioluminescent substrate can continuously emit light for 3 hours, and the light signal can be detected at 24 hours.
Description
Technical Field
The invention belongs to the field of bioluminescence, and particularly relates to an ester Furimazine derivative, a preparation method and application thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Bioluminescence (BL) refers to visible light emitted by organisms, and can be emitted by chemical substances extracted from organisms such as bacteria, fireflies, renilla, and the like. Thirty or more bioluminescent systems have been discovered and currently the bioluminescent systems commonly employed are firefly bioluminescent systems, coelenterazine bioluminescent systems, the current state of the art NanoLuc-furimazine bioluminescent systems, and bacterial bioluminescent systems. Bioluminescence imaging techniques (Bioluminescent imaging, BLI) derived using bioluminescence properties are widely used for real-time monitoring of biological activity processes.
Bioluminescence imaging technology (BLI) is applied to three key elements of in vivo imaging: firstly, constructing a reporter gene containing a luciferase gene and expressing the reporter gene in virus, bacteria, plant or animal cells or whole animals; secondly, injecting a luciferin substrate into the animal subjected to the transgene or the animal expressing the luciferase; third, an imaging system (e.g., a CCD camera) is used to capture and convert the optical signals. The reason why in vivo imaging can be widely used is that the method is easy to operate and low in cost, and the real advantage is thatIts high sensitivity and specificity. The NanoLuc system is the currently newly discovered bioluminescent system. The NanoLuc luciferase is derived from a natural luciferase present in deep sea shrimp Oplophorus gracilirostris and is optimized to produce a luciferase subunit with improved luminescence and stability. The luminous intensity of the NanoLuc-furimazine bioluminescence system can reach 10 10 This gives a number of convenience to in vivo imaging, making the optical signal more easily captured, and is widely used for research and monitoring of various biological processes.
However, the inventors have found that, although the NanoLuc-furimazine bioluminescence system has significant luminescence advantages, the following disadvantages still remain: (1) The biological luminescence duration is short, which is unfavorable for long-time detection imaging; (2) The substrate Furimazine has poor stability, is easy to oxidize and deteriorate, and brings trouble to real-time monitoring.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides the ester Furimazine derivative, the preparation method and the application thereof, and the invention prolongs the bioluminescence time and improves the stability of the bioluminescence substrate by modifying and reforming the C3 and C8 positions of the Furimazine substrate.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
in a first aspect of the invention, there is provided an ester Furimazine derivative having a chemical structure represented by formula I:
wherein R is 1 Selected from tert-butyl, phenyl, furyl, tert-butoxymethyl, 2-phenyl-2-methylethyl, 2- (benzoyloxy) -2-methylethyl, 1-methoxyethyl, propoxy.
The second aspect of the invention provides a preparation method of the ester Furimazine derivative, which comprises the following steps: in an inert atmosphere, taking 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one (sulfur-containing Furimazine analogue B0) as a raw material, and reacting with chloromethyl ester compounds under the action of potassium carbonate and potassium iodide to obtain a compound shown in a formula I;
in a third aspect the invention provides the following uses of the above ester Furimazine derivatives:
(1) As luminescent substrate of NanoLuc bioluminescence system;
(2) Bioluminescence imaging studies;
(3) Research of protein-protein/ligand interactions and/or as bioluminescence resonance energy transfer biosensor technology;
(4) Monitoring pharmacological actions of the medicines.
One or more embodiments of the present invention have at least the following beneficial effects:
(1) The ester Furimazine derivative with the structure shown in the formula I can be used as a bioluminescence substrate, and compared with sulfur-containing furamazine, the bioluminescence time of partial compounds at the cellular level and the animal level is prolonged, the bioluminescence can be continued for 3 hours, and the optical signal can be detected at 24 hours.
(2) Compared with sulfur-containing Furimazine, the compound of the ester Furimazine derivative with the structure shown in the formula I has the characteristics of enhanced bioluminescence intensity, longer bioluminescence half-life, improved stability and the like in the same environment, and the bioluminescence intensity at the cellular level and the animal level is enhanced.
(3) The ester Furimazine derivative compounds with the structure shown in the formula I can be used as substrates of the NanoLuc-Furimazine bioluminescence system, so that the range of Furimazine analogues is widened, and the application range of the NanoLuc-Furimazine bioluminescence system is widened.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a diagram of Compound B1 1 H NMR spectrum;
FIG. 2 is a diagram of Compound B1 13 C NMR spectrum;
FIG. 3 is an ESI-HRMS spectra of Compound B1;
FIG. 4 is a diagram of Compound B2 1 H NMR spectrum;
FIG. 5 is a diagram of Compound B2 13 C NMR spectrum;
FIG. 6 is an ESI-HRMS spectra of Compound B2;
FIG. 7 is a diagram of Compound B3 1 H NMR spectrum;
FIG. 8 is a diagram of Compound B3 13 C NMR spectrum;
FIG. 9 is an ESI-HRMS spectra of Compound B3;
FIG. 10 is a diagram of Compound B4 1 H NMR spectrum;
FIG. 11 is a diagram of Compound B4 13 C NMR spectrum;
FIG. 12 is an ESI-HRMS spectra of Compound B4;
FIG. 13 is a diagram of Compound B5 1 H NMR spectrum;
FIG. 14 is a diagram of Compound B5 13 C NMR spectrum;
FIG. 15 is an ESI-HRMS spectra of Compound B5;
FIG. 16 is a diagram of Compound B6 1 H NMR spectrum;
FIG. 17 is a diagram of Compound B6 13 C NMR spectrum;
FIG. 18 is an ESI-HRMS spectra of Compound B6;
FIG. 19 is a diagram of Compound B7 1 H NMR spectrum;
FIG. 20 is a diagram of Compound B7 13 C NMR spectrum;
FIG. 21 is an ESI-HRMS spectra of Compound B7;
FIG. 22 is a diagram of Compound B8 1 H NMR spectrum;
FIG. 23 is a diagram of Compound B8 13 C NMR spectrum;
FIG. 24 is an ESI-HRMS spectrum of Compound B8.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
As described in the background art, the NanoLuc-Furimazine bioluminescence system in the prior art has the problems that the luminescence duration is short, long-time detection imaging is not facilitated, the stability of the substrate Furimazine is poor, the substrate is easy to oxidize and deteriorate, and real-time monitoring is not facilitated.
In order to solve the technical problems, the first aspect of the invention provides an ester Furimazine derivative, the chemical structure of which is shown as a formula I:
wherein R is 1 Selected from tert-butyl, phenyl, furyl, tert-butoxymethyl, 2-phenyl-2-methylethyl, 2- (benzoyloxy) -2-methylethyl, 1-methoxyethyl, propoxy.
The ester Furimazine derivatives comprise the following compounds:
b1: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) pivalic acid methyl ester
B2: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) benzoic acid methyl ester
B3: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) furan-2-carboxylic acid methyl ester
B4: ((2- (Furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) 2- (tert-butoxy) acetic acid methyl ester
B5: ((2- (Furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) 2-methyl-2-phenylpropionic acid methyl ester
B6:1- (((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) methoxy) -2-methyl-1-oxypropane benzoic acid 2-yl ester
B7: ((2- (Furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) 2-methoxypropionic acid methyl ester
B8: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) methylpropyl carbonate
The eight ester Furimazine derivatives are subjected to bioluminescence imaging tests at the cellular level and the in-vivo level, and the results show that the ester Furimazine derivatives with different structures have different effects, wherein the two compounds B3 and B8 show obvious advantages at the cellular level and the in-vivo level and can become novel substrates of a NanoLuc bioluminescence system. Thus, as a preferred embodiment, the ester Furimazine derivative is B3: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) furan-2-carboxylic acid methyl ester or B8: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3-yl) oxy) methylpropyl carbonate.
The second aspect of the invention provides a preparation method of the ester Furimazine derivative, which comprises the following steps: in an inert atmosphere, 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one (sulfur-containing Furimazine analogue B0) is taken as a raw material, and reacts with chloromethyl ester compounds under the action of potassium carbonate and potassium iodide to obtain a compound shown in a formula I;
2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] pyrazin-3 (7H) -one (sulfur-containing Furimazine analog B0) has the chemical formula:
the chemical structural formula of the chloromethyl ester compound is as follows:
further, the molar ratio of 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one to potassium carbonate is 1:1-3.
Further, the molar ratio of 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one to potassium iodide is 1:1-3.
Further, the molar ratio of the 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one to the chloromethyl ester compound is 1:1-5.
Further, 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one and chloromethyl ester compound are dissolved in DMF solution under inert atmosphere, and reacted under room temperature condition. The reaction temperature is 25-30 ℃. The inert atmosphere in the invention can be nitrogen atmosphere, argon atmosphere, neon atmosphere and the like.
In a third aspect, the present invention provides the following uses of the above ester Furimazine derivatives:
(1) As luminescent substrate of NanoLuc bioluminescence system;
(2) Bioluminescence imaging studies; the compound can realize stable and long-term in-vivo real-time monitoring;
(3) Research of protein-protein/ligand interactions and/or as bioluminescence resonance energy transfer biosensor technology;
(4) Monitoring pharmacological actions of the medicines. The compounds can be used as reporter molecules to detect pharmacological actions of drugs at enzyme level, cell level and in vivo level under the action of NanoLuc luciferase.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
Example 1: in vitro kinetic studies (HPLC) of ester Furimazine derivatives.
In vitro kinetics research is carried out on the ester derivative by utilizing an HPLC method so as to research the stability of the C-3 protected compound in aqueous solution. Tris-HC buffer (ph=7.40): methanol=2:3 (v/v) compound concentrate was diluted to a concentration of 100 μm, and incubation was performed at room temperature with sample injection measurements every 2h, with a detection signal of 276nm. Parameter setting: the sample volume was 20. Mu.L, the flow rate was 0.8mL/min, and the column used was C-8 column. The results are shown in the following table:
TABLE 1 in vitro kinetic studies (HPLC) of Furimazine derivatives of esters
It can be seen from the table that the derivatives B3, B4, B7 and B8 are poorly stable in aqueous solution and all decompose at room temperature for 8 hours. Of these, compound B4 had the worst stability, and as can be seen from HPLC kinetic data analysis, this compound decomposed about 70% of B4 in 8 hours, followed by compound B7, and about 30% of compound decomposed in 8 hours. Whereas the HPLC in vitro kinetic data showed that compounds B1, B2, B5 and B6 were very stable in aqueous solution with little hydrolysis reaction occurring within 8 hours.
Example 2: cell level imaging time study of ester Furimazine derivatives.
Cells expressing NanoLuc luciferase were cultured in 96-well plates. Fresh concentrated stock solutions were diluted to 0, 0.25, 0.5, 1.0, 2.0, 4.0, 5.0, 8.0, 10.0 and 25.0. Mu.M with serum-free medium, 100. Mu.L of the diluted compound solution was added to each well, and light signals were immediately collected using a small animal in vivo imager. The exposure time was set to 10 s, the first 60 minutes recorded the optical signal every 5 minutes, and then every 15 minutes shot until the optical signal disappeared, and the shooting time was continued for 2 hours, with the following table:
TABLE 2 time of cellular level imaging studies of Furimazine derivatives of esters
The results show that the bioluminescence time of partial ester Furimazine derivative is prolonged, wherein the change trend of the luminous intensity of the compounds B4 and B7 along with time is approximately similar, the luminous intensity reaches a peak value at 5 minutes, the luminous intensity drops rapidly, the luminous intensity is reduced by one order of magnitude at 60 minutes, and the luminous intensity is still stronger than that of the prototype compound B0. The compounds B3, B8 present a plateau for luminescence, in particular the compound B3 remains substantially at this luminescence intensity at 2 hours.
Example 3: in vivo horizontal imaging time study of mice of ester Furimazine derivatives.
And selecting an ester derivative with better bioluminescence performance at a cell level and a prototype substrate for in-vivo imaging experiment. The concentrated stock solution was diluted to a concentration of 2mM with physiological saline (10% ethanol). Mice were anesthetized with isoflurane and administered by intratumoral injection, each mouse being injected with a volume of 50 μl of compound solution. Immediately acquiring optical signals by using a living animal imager to obtain the following results:
TABLE 3 in vivo horizontal imaging time study of mice of ester Furimazine derivatives (bioluminescence intensity)
TABLE 4 in vivo horizontal imaging time study (relative intensity) of mice on ester Furimazine derivatives
The results show that the luminous intensity and the luminous time of the compound in the body level of the mice are higher than those of the sulfur-containing Furimazine analogue B0, wherein the bioluminescence intensity of the compounds B3 and B8 can be maintained at a higher level in two hours, and the luminous duration is longer. Taken together, compounds B3, B8 have the potential to become long-acting bioluminescent substrates.
In conclusion, the compounds B3 and B8 show obvious advantages at the cellular level and the in-vivo level, and can become novel substrates of the NanoLuc bioluminescence system.
In the invention, the chemical structural formula of the B1-B8 compounds and the sulfur-containing Furimazine analogue B0 is as follows:
the above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. An ester Furimazine derivative, characterized in that: the chemical structure is shown as formula I:
the ester Furimazine derivative is selected from the following compounds:
b3: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [1,2-a ] ] pyrazin-3-yl) oxy) furan-2-carboxylic acid methyl ester or B8: ((2- (furan-2-ylmethyl) -6-phenyl-8- (phenylsulfanyl) imidazo [ [1,2-a ] pyrazin-3-yl) oxy) methylpropyl carbonate.
2. The process for producing an ester Furimazine derivative according to claim 1, wherein: in an inert atmosphere, 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -ketone is taken as a raw material, and reacts with chloromethyl ester compounds under the action of potassium carbonate and potassium iodide to obtain a compound shown in a formula I;
3. the method of manufacturing as claimed in claim 2, wherein: the chemical structural formula of the 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one is as follows:
4. the method of manufacturing as claimed in claim 2, wherein: the chemical structural formula of the chloromethyl ester compound is as follows:
5. the method of manufacturing as claimed in claim 2, wherein: the molar ratio of the 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one to the potassium carbonate is 1:1-3.
6. The method of manufacturing as claimed in claim 2, wherein: the molar ratio of 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one to potassium iodide is 1:1-3.
7. The method of manufacturing as claimed in claim 2, wherein: the molar ratio of the 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one to the chloromethyl ester compound is 1:1-5.
8. The method of manufacturing as claimed in claim 2, wherein: 2- (furan-2-ylmethyl) -6-phenyl-8- (phenylthio) imidazo [1,2-a ] pyrazin-3 (7H) -one and chloromethyl ester compound are dissolved in DMF solution under inert atmosphere and react under room temperature.
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