A hydrogen sulfide-responsive carbon monoxide donor molecule, its preparation method and application

Abstract

The application discloses a hydrogen sulfide responsive carbon monoxide donor molecule, a preparation method and application thereof. The hydrogen sulfide responsive carbon monoxide donor molecule has the structure shown in the following formula: wherein R1, R2, R3 and R4 are independently selected from an electron-withdrawing group, an electron-donating group or a hydrogen atom, and X is selected from O or the application provides a hydrogen sulfide responsive carbon monoxide donor molecule, which is designed in structure, acyloxy diene-Fe(CO)3 is selected as a carbon monoxide releasing unit, and an azido group is selected as a hydrogen sulfide responsive unit; the donor molecule formed by the two units has hydrogen sulfide responsiveness, can release carbon monoxide in the presence of hydrogen sulfide, can adjust the hydrogen sulfide response rate of the donor material and the release rate of carbon monoxide, and can further realize the treatment of colon inflammation and the inhibition of colorectal cancer.

Description

Technical Field

[0001] This invention belongs to the field of gaseous neurotransmitter donor technology, specifically relating to a hydrogen sulfide-responsive carbon monoxide donor molecule, its preparation method, and its application. Background Technology

[0002] Gaseous neurotransmitters, as important endogenous molecules, have been extensively studied. Carbon monoxide, as a gaseous neurotransmitter, has been found to have therapeutic potential in inflammation, bacterial infections, cardiovascular diseases, and cancer-related diseases. However, direct gas inhalation needs to overcome the toxicity problems of high-pressure storage, inaccurate drug delivery, and non-specific distribution. A key issue to consider is how to achieve controlled release of gaseous neurotransmitters into deep lesion tissues to realize biological effects. Furthermore, the physiological functions of gaseous neurotransmitters are highly concentration-dependent; high concentrations exhibit biotoxicity, while low concentrations fail to achieve biological effects. Therefore, in designing gaseous neurotransmitter molecule donors, factors such as stimulation mode, tissue penetration, controlled release, and biosafety should be fully considered.

[0003] Hydrogen sulfide, as a gaseous signaling molecule, plays a crucial role in many physiological processes. In the pathological conditions of inflammatory bowel disease (IBD) and colorectal cancer, its concentration is selectively upregulated, making it a potential target for IBD and cancer treatment. Carbon monoxide is also an important gaseous signaling molecule, playing significant roles in anti-inflammation, anti-apoptosis, and anti-cancer activity. Leveraging the high hydrogen sulfide concentration in the pathological environment of IBD or colorectal cancer, carbon monoxide release can be triggered by the responsiveness of hydrogen sulfide, simultaneously downregulating hydrogen sulfide concentration and releasing carbon monoxide to exert its anti-inflammatory or anti-cancer effects.

[0004] Therefore, finding a carbon monoxide donor molecule that can achieve hydrogen sulfide responsiveness has been a long-term goal for researchers in the industry. Summary of the Invention

[0005] The main objective of this invention is to provide a hydrogen sulfide-responsive carbon monoxide donor molecule and its preparation method, so as to overcome the shortcomings of the prior art.

[0006] Another object of the present invention is to provide the application of the hydrogen sulfide-responsive carbon monoxide donor molecule.

[0007] To achieve the aforementioned objectives, the technical solution adopted by this invention includes:

[0008] This invention provides a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I):

[0009]

[0010] Wherein, R1, R2, R3, and R4 are independently selected from electron-withdrawing groups, electron-donating groups, or hydrogen atoms, and X is selected from O or

[0011] In some implementations, R1, R2, R3, and R4 are selected from any one of fluorine, nitro, trifluoromethyl, methoxy, and hydrogen atoms, respectively.

[0012] This invention also provides a method for preparing a hydrogen sulfide-responsive carbon monoxide donor molecule, comprising:

[0013] A first reaction is carried out on a first mixed reaction system containing the compound of formula (II), dimethylaminoborane and a first solvent to obtain the compound of formula (II);

[0014] In a protective atmosphere, a second mixed reaction system containing the compound of formula (II), a bromine source, and a second solvent is subjected to a second reaction to obtain the compound of formula (IV);

[0015] In a protective atmosphere, a third mixed reaction system comprising the compound shown in formula (V), sodium hydride, tetrabutylamine fluoride, and a third solvent is subjected to a third reaction, and then the compound shown in formula (IV) is added to carry out a fourth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I); wherein, X is O.

[0016] Alternatively, the preparation method includes:

[0017] A first reaction is carried out on a first mixed reaction system containing the compound of formula (II), dimethylaminoborane and a first solvent to obtain the compound of formula (II);

[0018] In a protective atmosphere, a fifth reaction is carried out in a fifth mixed reaction system comprising the compound of formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine, the compound of formula (VI), and a third solvent to prepare a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I), wherein X is...

[0019]

[0020]

[0021] This invention also provides the application of the hydrogen sulfide-responsive carbon monoxide donor molecule in the preparation of drugs with anti-inflammatory or anticancer functions.

[0022] Compared with the prior art, the beneficial effects of the present invention are at least as follows:

[0023] 1) The hydrogen sulfide-responsive carbon monoxide donor molecule provided by this invention is designed with acyloxydiene-Fe(CO)3 as the carbon monoxide-releasing unit and azide group as the hydrogen sulfide-responsive unit. The resulting donor molecule is hydrogen sulfide-responsive and can release carbon monoxide in the presence of hydrogen sulfide. The hydrogen sulfide response rate and carbon monoxide release rate of the donor material can be regulated, thereby achieving the treatment of colon inflammation and the inhibition of colorectal cancer.

[0024] 2) The hydrogen sulfide-responsive carbon monoxide donor molecule provided by this invention targets the characteristics of increased hydrogen sulfide concentration in lesions such as inflammatory bowel disease and colorectal cancer. Under the condition of high concentration of hydrogen sulfide, it responsively releases CO to inhibit the growth of inflammation or cancer cells. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 The 1H NMR spectrum of the N3-FeCO molecule in Example 1 is shown.

[0027] Figure 2 The 1H NMR spectrum of the N3-F-FeCO molecule in Example 2 is shown.

[0028] Figure 3 The nuclear magnetic resonance fluorine spectrum of the N3-F-FeCO molecule in Example 2 is shown.

[0029] Figure 4 The 1H NMR spectrum of the N3-2F-FeCO molecule in Example 3 is shown.

[0030] Figure 5 The nuclear magnetic resonance fluorine spectrum of the N3-2F-FeCO molecule in Example 3 is shown;

[0031] Figure 6 The 1H NMR spectrum of the N3-4F-FeCO molecule in Example 4 is shown.

[0032] Figure 7 The nuclear magnetic resonance fluorine spectrum of the N3-4F-FeCO molecule in Example 4 is shown.

[0033] Figure 8 The 1H NMR spectrum of the N3-OCO-FeCO molecule in Example 8 is shown.

[0034] Figure 9 The HPLC chromatogram of the degradation of N3-FeCO molecules in the presence of hydrogen sulfide in Example 1 is shown.

[0035] Figure 10 The HPLC chromatogram of the degradation of N3-F-FeCO molecules in the presence of hydrogen sulfide in Example 2 is shown.

[0036] Figure 11 The HPLC chromatogram of the degradation of N3-2F-FeCO molecules in the presence of hydrogen sulfide in Example 3 is shown.

[0037] Figure 12 The HPLC chromatogram of the degradation of N3-4F-FeCO molecules in the presence of hydrogen sulfide in Example 4 is shown.

[0038] Figure 13 A schematic diagram comparing the reaction rates of N3-FeCO, N3-2F-FeCO, and N3-4F-FeCO molecules with hydrogen sulfide at the same hydrogen sulfide concentration is shown in Examples 1-3.

[0039] Figure 14 A qualitative curve of CO release from N3-FeCO molecules in Example 1 is shown;

[0040] Figure 15 A quantitative curve of CO release from N3-FeCO molecules in Example 1 is shown. Detailed Implementation

[0041] In view of the problems existing in the prior art, after long-term research and a large number of experiments, and targeting the characteristics of increased hydrogen sulfide concentration in lesions such as inflammatory bowel disease and colorectal cancer, the inventors of this case propose a method for preparing a hydrogen sulfide-responsive carbon monoxide donor molecule. Through structural design, the hydrogen sulfide response rate and carbon monoxide release rate of the donor material can be adjusted, thereby achieving the treatment of colonic inflammation and the inhibition of colorectal cancer.

[0042] To facilitate understanding of the present invention, it will be described in more detail below. However, it should be understood that the present invention can be implemented in many different forms and is not limited to the embodiments or examples described herein. Rather, these embodiments or examples are provided to make the disclosure of the present invention more thorough and complete.

[0043] As one aspect of the technical solution of the present invention, a hydrogen sulfide-responsive carbon monoxide donor molecule has the structure shown in formula (I):

[0044]

[0045] Among them, R1, R2, R3, and R4 can be independently selected from electron-withdrawing groups such as fluorine (F), nitro (-NO2), and trifluoromethyl (-CF3), or electron-donating groups such as methoxy (-OCH3) or hydrogen atoms (H), and X is selected from O or That is, X can be an ether bond or a carbonate bond.

[0046] In some embodiments, the hydrogen sulfide-responsive carbon monoxide donor molecule has any of the following structural formulas:

[0047]

[0048] X is selected from O or

[0049] In some embodiments, the hydrogen sulfide-responsive carbon monoxide donor molecules have different hydrogen sulfide response rates, and electron-donating groups such as methoxy groups can reduce the hydrogen sulfide response rate, while electron-withdrawing groups such as fluorine, nitro, or trifluoromethyl groups can increase the hydrogen sulfide response rate.

[0050] In some embodiments, the hydrogen sulfide-responsive carbon monoxide donor molecules have different 1,6-rearrangement degradation rates, and electron-donating groups such as methoxy groups can increase the 1,6-rearrangement degradation rate, while electron-withdrawing groups such as fluorine, nitro, or trifluoromethyl groups can decrease the hydrogen sulfide response rate.

[0051] In some embodiments, the present invention selects acyloxydiene-Fe(CO)3 as the basic unit for releasing gaseous mediators (such as carbon monoxide) through structural design, and azide group as the hydrogen sulfide responsive basic unit. The resulting hydrogen sulfide responsive carbon monoxide donor molecule has hydrogen sulfide responsiveness and can release carbon monoxide (CO) in the presence of hydrogen sulfide. The time for releasing carbon monoxide is from 20 min to 72 h.

[0052] In some implementations, the hydrogen sulfide-responsive carbon monoxide donor molecule can release carbon monoxide in response to hydrogen sulfide. By changing different functional groups on the benzene ring, different hydrogen sulfide response rates and carbon monoxide release rates can be achieved. The mechanism by which the hydrogen sulfide-responsive carbon monoxide donor molecule releases carbon monoxide is as follows:

[0053]

[0054] As another aspect of the technical solution of the present invention, it relates to a method for preparing the hydrogen sulfide-responsive carbon monoxide donor molecule, which includes:

[0055] A first reaction is carried out on a first mixed reaction system containing the compound of formula (II), dimethylaminoborane and a first solvent to obtain the compound of formula (II);

[0056] In a protective atmosphere, a second mixed reaction system containing the compound of formula (II), a bromine source, and a second solvent is subjected to a second reaction to obtain the compound of formula (IV);

[0057] In a protective atmosphere, a third mixed reaction system comprising the compound shown in formula (V), sodium hydride, tetrabutylamine fluoride, and a third solvent is subjected to a third reaction, and then the compound shown in formula (IV) is added to carry out a fourth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I); wherein, X is O.

[0058]

[0059] In some embodiments, the preparation method specifically includes: dissolving the compound represented by formula (II) in a first solvent, adding dimethylaminoborane to form the first mixed reaction system, and carrying out the first reaction at room temperature for 4 to 12 hours to obtain the compound represented by formula (II).

[0060] Furthermore, the first solvent can be acetic acid, p-toluenesulfonic acid, etc., but is not limited to these.

[0061] In some embodiments, the molar ratio of the compound represented by formula (II), dimethylaminoborane, and acetic acid is in the range of 1:(1-2):(2-4).

[0062] In some embodiments, the preparation method specifically includes: dissolving the compound represented by formula (III) in a second solvent, adding a bromine source and a second solvent under a protective atmosphere to form the second mixed reaction system, and carrying out a second reaction at room temperature for 4 to 8 hours to obtain the compound represented by formula (IV).

[0063] Furthermore, the bromine source can be phosphorus tribromide, but is not limited to this.

[0064] Furthermore, the second solvent may include any one or a combination of two or more of dichloromethane, chloroform, ethyl acetate, etc., but is not limited to this.

[0065] In some embodiments, the molar ratio of the compound represented by formula (III), the bromine source and the second solvent is 1:(0.4-1):(2-4).

[0066] In some implementation schemes, the preparation method specifically includes:

[0067] The compound shown in formula (V) and sodium hydride are added to the third solvent and protected with an inert gas. Tetrabutylamine fluoride is added dropwise at 0–10 °C to form the third mixed reaction system. The third reaction is carried out at 0–10 °C for 0.5–2 hours.

[0068] The solution containing the compound shown in formula (IV) and the third solvent was then added dropwise, and the fourth reaction was carried out at room temperature for 12 to 24 hours to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule with the structure shown in formula (I), where X is O.

[0069] Furthermore, the third solvent may include any one or a combination of two or more of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, etc., but is not limited to this.

[0070] In some embodiments, the molar ratio of the compound represented by formula (V), sodium hydride, tetrabutylamine fluoride and the compound represented by formula (IV) is in the range of 1:(1 to 1.5):(1 to 1.5):(1 to 1.5).

[0071] In some more preferred embodiments, the method for preparing the hydrogen sulfide-responsive carbon monoxide donor molecule includes the following steps:

[0072]

[0073] (1) The compound shown in formula (II) was dissolved in the first solvent, and dimethylaminoborane was added to the reaction system. The reaction was carried out at room temperature, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure, the ethyl acetate was redissolved, and the mixture was washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the compound shown in formula (II).

[0074] (2) Dissolve the compound shown in formula (III) in the second solvent, slowly add the bromine source (such as phosphorus tribromide) and the solution of the second solvent under nitrogen protection, react at room temperature, monitor the degree of reaction by thin layer chromatography, after the reaction is complete, remove the solvent by vacuum evaporation, redissolve the compound in ethyl acetate, wash twice with water, wash with saturated brine, dry with anhydrous sodium sulfate, and purify by column chromatography (petroleum ether / ethyl acetate) to obtain the compound shown in formula (IV).

[0075] (3) The raw material acyloxydiene-Fe(CO)3 (FeCO-OTIPS) (i.e., the compound shown in formula (V)) was prepared according to previous reports (Organometallics, 2013, 32(13): 3587-3594).

[0076] FeCO-OTIPS (0.33 g, 1.0 eq) and sodium hydride were added to the third solvent under nitrogen protection. Tetrabutylamine fluoride was added dropwise to the reaction system at 0–10 °C and reacted for 0.5–2 hours. Then, the compound shown in formula (III) and the solution of the third solvent were added dropwise to the reaction system and reacted at room temperature. The reaction extent was monitored by thin-layer chromatography. After the reaction was complete, tetrahydrofuran was removed by rotary evaporation, and the product was redissolved in ethyl acetate. The organic phase was washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the product shown in formula (I).

[0077] As another aspect of the technical solution of the present invention, it relates to a method for preparing another hydrogen sulfide-responsive carbon monoxide donor molecule, which includes:

[0078] A first reaction is carried out on a first mixed reaction system containing the compound of formula (II), dimethylaminoborane and a first solvent to obtain the compound of formula (II);

[0079] In a protective atmosphere, a fifth reaction is carried out in a fifth mixed reaction system comprising the compound of formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine, the compound of formula (VI), and a third solvent to prepare a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I), wherein X is...

[0080]

[0081] In some embodiments, the preparation method specifically includes: dissolving the compound represented by formula (II) in a first solvent, adding dimethylaminoborane to form the first mixed reaction system, and carrying out a first reaction at room temperature for 4 to 12 hours to obtain the compound represented by formula (II).

[0082] In some embodiments, the molar ratio of the compound represented by formula (II), dimethylaminoborane, and the first solvent is in the range of 1:(1-2):(2-4).

[0083] In some embodiments, the preparation method specifically includes: dissolving the compound shown in formula (III) in a third solvent under a protective atmosphere, then adding N,N-diisopropylethylamine, 4-dimethylaminopyridine, and the compound shown in formula (VI) to form the fifth reaction system, and carrying out the fifth reaction at room temperature for 12 to 24 hours to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I).

[0084] In some embodiments, the molar ratio of the compound represented by formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine and the compound represented by formula (VI) is in the range of (1 to 1.5):(1 to 1.5):(0.2 to 0.4):1.

[0085] In some more preferred embodiments, the method for preparing the hydrogen sulfide-responsive carbon monoxide donor molecule includes the following steps:

[0086]

[0087] (A) The compound shown in formula (II) was dissolved in the first solvent, and dimethylaminoborane was added to the reaction system. The reaction was carried out at room temperature, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure, the ethyl acetate was redissolved, and the mixture was washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the compound shown in formula (II).

[0088] (B) Under nitrogen protection, the compound shown in formula (II) was dissolved in a third solvent. Then, N,N-diisopropylethylamine, 4-dimethylaminopyridine and FeCO active ester (the compound shown in formula (VI)) and the solution of the third solvent were added to the reaction system. The reaction was carried out at room temperature for 12 to 24 hours. The solvent was removed by vacuum evaporation and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the product shown in formula (I).

[0089] As one aspect of the technical solution of the present invention, it relates to the application of the hydrogen sulfide-responsive carbon monoxide donor molecule in the preparation of drugs with anti-inflammatory or anti-cancer functions.

[0090] Furthermore, the drug has the function of treating inflammatory bowel disease or colorectal cancer.

[0091] The technical solutions in the embodiments of the present invention will be clearly and completely described below. The described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0092] To further understand this application, the preparation of the hydrogen sulfide-responsive carbon monoxide donor molecule, the comparison of hydrogen sulfide response rates, and the carbon monoxide release rate provided by this invention are described in detail below with reference to the embodiments.

[0093] Unless otherwise specified, the raw materials and reagents used in the materials of this invention are all obtained commercially.

[0094] Example 1: Preparation of N3-FeCO donor molecules

[0095] The specific preparation route of the N3-FeCO donor molecule in this embodiment is as follows:

[0096]

[0097] 1) Preparation of 4-azidobenzyl bromide

[0098] 4-Fluorobenzaldehyde (1.0 g, 1.0 eq) was dissolved in dimethyl sulfoxide, and sodium azide (0.58 g, 1.5 eq) was added to the reaction system. The reaction was carried out at 70 °C, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, deionized water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azidobenzaldehyde.

[0099] 4-Azidoxane (0.6 g, 1.0 eq) was dissolved in acetic acid (2 eq), and dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system. The reaction was carried out at room temperature for 4 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the ethyl acetate was redissolved. The solution was washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azidoxane.

[0100] 4-Azide-benzyl alcohol (0.3 g, 1.0 eq) was dissolved in anhydrous dichloromethane. Under nitrogen protection, a dichloromethane solution of phosphorus tribromide (1.0 eq) was added dropwise to the reaction system. The dichloromethane solution was 2.0 eq. The reaction was carried out at room temperature for 4 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The solution was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azidobenzyl bromide.

[0101] 2) Preparation of N3-FeCO

[0102] The raw material, acyloxydiene-Fe(CO)3 (FeCO-OTIPS), was prepared according to previous reports (Organometallics, 2013, 32(13): 3587-3594).

[0103] For the preparation of N3-FeCO, FeCO-OTIPS (0.33 g, 1.0 eq) and sodium hydride (1.3 eq) were added to anhydrous tetrahydrofuran under nitrogen protection. Tetrabutylamine fluoride (0.23 g, 1.1 eq) was added dropwise to the reaction system at 0 °C and the reaction was carried out for 30 minutes. Then, a tetrahydrofuran solution of 4-azidobenzyl bromide (1.0 eq) was added dropwise to the reaction system and the reaction was carried out at room temperature for 12 h. The degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, the tetrahydrofuran was removed by rotary evaporation, the product was redissolved in ethyl acetate, the organic phase was washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the product N3-FeCO.

[0104] The 1H NMR spectrum of the N3-FeCO molecule produced in this embodiment is shown below. Figure 1 As shown.

[0105] Example 2: Preparation of N3-F-FeCO donor molecules

[0106] The specific preparation route of the N3-F-FeCO donor molecule in this embodiment is as follows:

[0107]

[0108] 1) Preparation of 4-azido-3-fluorobenzyl bromide

[0109] 3,4-Difluorobenzaldehyde (1.0 g, 1.0 eq) was dissolved in dimethyl sulfoxide, and sodium azide (0.64 g, 1.5 eq) was added to the reaction system. The reaction was carried out at 70 °C, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, deionized water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-fluorobenzaldehyde.

[0110] 0.6 g (1.0 eq) of 4-azido-3-fluorobenzaldehyde was dissolved in acetic acid (2.5 eq), and 0.26 g (1.2 eq) of dimethylaminoborane was added to the reaction system. The reaction was carried out at room temperature for 8 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the ethyl acetate was redissolved. The solution was washed with water and saturated sodium bicarbonate solution, respectively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-fluorobenzyl alcohol.

[0111] 4-Azide-3-fluorobenzyl alcohol (0.2 g, 1.0 eq) was dissolved in anhydrous dichloromethane. Under nitrogen protection, a dichloromethane solution of phosphorus tribromide (1.0 eq) was slowly added. The dichloromethane solution was 2.0 eq. The reaction was carried out at room temperature for 6 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The solution was redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-fluorobenzyl bromide.

[0112] 2) Preparation of N3-F-FeCO

[0113] FeCO-OTIPS (0.2 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran, and sodium hydride (1.3 eq) was added to the reaction system under nitrogen protection. Tetrabutylammonium fluoride (0.23 g, 1.1 eq) was added dropwise at 0 °C, and the reaction was continued for 30 minutes. Then, a tetrahydrofuran solution of 4-azido-3-fluorobenzyl bromide (1.1 eq) was added dropwise to the reaction system, and the reaction was carried out at room temperature for 15 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-F-FeCO.

[0114] The 1H NMR spectrum of the N3-F-FeCO molecule produced in this embodiment is shown below. Figure 2 As shown, the nuclear magnetic resonance fluorine spectrum is as follows: Figure 3 As shown.

[0115] Example 3: Preparation of N3-2F-FeCO donor molecules

[0116] The specific preparation route of the N3-2F-FeCO donor molecule in this embodiment is as follows:

[0117]

[0118] 1) Preparation of 4-azido-3,5-difluorobenzyl bromide

[0119] 3,4,5-trifluorobenzaldehyde (1.0 g, 1.0 eq) was dissolved in dimethyl sulfoxide, and sodium azide (0.57 g, 1.5 eq) was added to the reaction system. The reaction was carried out at 70 °C, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, deionized water was added, ethyl acetate was extracted, saturated brine was washed, anhydrous sodium sulfate was dried, and column chromatography (petroleum ether / ethyl acetate) was used to purify the product to obtain 4-azido-3,5-difluorobenzaldehyde.

[0120] 4-Azide-3,5-difluorobenzaldehyde (0.6 g, 1.0 eq) was dissolved in acetic acid (3.0 eq), and dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system. The reaction was carried out at room temperature for 10 h. The extent of reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by evaporation under reduced pressure. The ethyl acetate was redissolved, washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3,5-difluorobenzyl alcohol.

[0121] 4-Azide-3,5-difluorobenzyl alcohol (0.2 g, 1.0 eq) was dissolved in anhydrous dichloromethane. Under nitrogen protection, a dichloromethane solution of phosphorus tribromide (1.0 eq) was slowly added. The dichloromethane concentration was 3.0 eq. The reaction was carried out at room temperature for 4 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The solution was redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3,5-difluorobenzyl bromide.

[0122] 2) Preparation of N3-2F-FeCO

[0123] FeCO-OTIPS (0.17 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran, and sodium hydride (1.3 eq) was added to the reaction system under nitrogen protection. Tetrabutylammonium fluoride (0.12 g, 1.1 eq) was added dropwise at 0 °C, and the reaction was continued for 30 minutes. Then, a tetrahydrofuran solution of 4-azido-3,5-difluorobenzyl bromide (1.1 eq) was added dropwise to the reaction system, and the reaction was carried out at room temperature for 18 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-2F-FeCO.

[0124] The 1H NMR spectrum of the product N3-2F-FeCO molecule in this embodiment is shown below. Figure 4 As shown, the nuclear magnetic resonance fluorine spectrum is as follows: Figure 5 As shown.

[0125] Example 4: Preparation of N3-4F-FeCO donor molecules

[0126] The specific preparation route of the N3-4F-FeCO donor molecule in this embodiment is as follows:

[0127]

[0128] 1) Preparation of 4-azido-2,3,5,6-tetrafluorobenzyl bromide

[0129] Pentafluorobenzaldehyde (1.0 g, 1.0 eq) and sodium azide (0.4 g, 1.2 eq) were dissolved in a mixed solvent of acetone and water, and the mixture was microwaved at 70 °C for 15 minutes. After the reaction was completed, the reaction system was poured into ice water, extracted with diethyl ether, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to give 4-azido-2,3,5,6-tetrafluorobenzaldehyde.

[0130] 4-Azide-2,3,5,6-tetrafluorobenzaldehyde (0.6 g, 1.0 eq) was dissolved in acetic acid (4.0 eq), and dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system. The reaction was carried out at room temperature for 12 h. The extent of reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the ethyl acetate was redissolved. The solution was washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-2,3,5,6-tetrafluorobenzaldehyde.

[0131] 4-Azide-2,3,5,6-tetrafluorobenzyl alcohol (0.3 g, 1.0 eq) was dissolved in anhydrous dichloromethane. Under nitrogen protection, a dichloromethane solution of phosphorus tribromide (0.8 eq) was slowly added. The dichloromethane concentration was 2.0 eq. The reaction was carried out at room temperature for 8 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The solution was redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3,5-difluorobenzyl bromide.

[0132] 2) Preparation of N3-4F-FeCO

[0133] FeCO-OTIPS (0.3 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran, and sodium hydride (1.0 eq) was added to the reaction system under nitrogen protection. Tetrabutylammonium fluoride (0.2 g, 1.1 eq) was added dropwise at 5 °C, and the reaction was continued for 60 minutes. Then, a tetrahydrofuran solution of 4-azido-2,3,4,5-tetrafluorobenzyl bromide (1.2 eq) was added dropwise to the reaction system, and the reaction was carried out at room temperature for 20 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-4F-FeCO.

[0134] The 1H NMR spectrum of the product N3-4F-FeCO molecule in this embodiment is shown below. Figure 6 As shown, the nuclear magnetic resonance fluorine spectrum is as follows: Figure 7 As shown.

[0135] Example 5: Preparation of N3-OCH3-FeCO donor molecules

[0136] The specific preparation route of the N3-OCH3-FeCO donor molecule in this embodiment is as follows:

[0137]

[0138] 1) Preparation of 4-azido-3-methoxy-benzyl bromide

[0139] 4-Fluoro-3-methoxybenzaldehyde (0.8 g, 1.0 eq) was dissolved in dimethyl sulfoxide, and sodium azide (0.51 g, 1.5 eq) was added to the reaction system. The reaction was carried out at 70 °C, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, deionized water was added, ethyl acetate was extracted, saturated brine was washed, anhydrous sodium sulfate was dried, and column chromatography (petroleum ether / ethyl acetate) was used to purify the product to obtain 4-azido-3-methoxybenzaldehyde.

[0140] 4-Azide-3-methoxybenzaldehyde (0.5 g, 1.0 eq) was dissolved in acetic acid (2.0 eq), and dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system. The reaction was carried out at room temperature for 6 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by evaporation under reduced pressure. The ethyl acetate was redissolved, washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-methoxybenzyl alcohol.

[0141] 4-Azide-3-methoxybenzyl alcohol (0.3 g, 1.0 eq) was dissolved in anhydrous dichloromethane. Under nitrogen protection, a dichloromethane solution of phosphorus tribromide (0.4 eq) was slowly added. The dichloromethane concentration was 4.0 eq. The reaction was carried out at room temperature for 8 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The solution was redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-methoxybenzyl bromide.

[0142] 2) Preparation of N3-OCH3-FeCO

[0143] FeCO-OTIPS (0.15 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran, and sodium hydride (1.1 eq) was added to the reaction system under nitrogen protection. Tetrabutylammonium fluoride (0.11 g, 1.1 eq) was added dropwise at 10 °C, and the reaction was continued for 2 hours. Then, a tetrahydrofuran solution of 4-azido-3-methoxybenzyl bromide (1.3 eq) was added dropwise to the reaction system, and the reaction was carried out at room temperature. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-OCH3-FeCO.

[0144] Example 6: Preparation of N3-CF3-FeCO donor molecules

[0145] The specific preparation route of the N3-CF3-FeCO donor molecule in this embodiment is as follows:

[0146]

[0147] 1) Preparation of 4-azido-3-trifluoromethyl-benzyl bromide

[0148] 4-fluoro-3-trifluoromethylbenzaldehyde (1.0 g, 1.0 eq) was dissolved in dimethyl sulfoxide, and sodium azide (0.50 g, 1.5 eq) was added to the reaction system. The reaction was carried out at 70 °C, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, deionized water was added, ethyl acetate was extracted, saturated brine was washed, anhydrous sodium sulfate was dried, and column chromatography (petroleum ether / ethyl acetate) was used to purify the product to obtain 4-azido-3-trifluoromethylbenzaldehyde.

[0149] 4-Azide-3-trifluoromethylbenzaldehyde (0.4 g, 1.0 eq) was dissolved in acetic acid (3.0 eq), and dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system. The reaction was carried out at room temperature for 5 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by evaporation under reduced pressure. The ethyl acetate was redissolved, washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-trifluoromethylbenzyl alcohol.

[0150] 0.25 g (1.0 eq) of 4-azido-3-trifluoromethylbenzyl alcohol was dissolved in ethyl acetate. Under nitrogen protection, a solution of 1.0 eq of phosphorus tribromide in ethyl acetate was slowly added. The total ethyl acetate concentration was 2.0 eq. The reaction was carried out at room temperature for 4 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The ethyl acetate was redissolved, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-trifluoromethylbenzyl bromide.

[0151] 2) Preparation of N3-CF3-FeCO

[0152] FeCO-OTIPS (0.2 g, 1.0 eq) was dissolved in ethyl acetate, and sodium hydride (1.2 eq) was added to the reaction system under nitrogen protection. Tetrabutylammonium fluoride (1 eq) was added dropwise at 8 °C, and the reaction was continued for 100 min. Then, an ethyl acetate solution of 4-azido-3-trifluoromethylbenzyl bromide (1.5 eq) was added dropwise to the reaction system, and the reaction was carried out at room temperature for 24 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, and the solution was redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-CF3-FeCO.

[0153] Example 7: Preparation of N3-NO2-FeCO donor molecules

[0154] The specific preparation route of the N3-NO2-FeCO donor molecule in this embodiment is as follows:

[0155]

[0156] 1) Preparation of 4-azido-3-nitro-benzyl bromide

[0157] 4-Fluoro-3-nitrobenzaldehyde (1.0 g, 1.0 eq) was dissolved in dimethyl sulfoxide, and sodium azide (0.52 g, 1.5 eq) was added to the reaction system. The reaction was carried out at 70 °C, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, deionized water was added, ethyl acetate was extracted, saturated brine was washed, anhydrous sodium sulfate was dried, and column chromatography (petroleum ether / ethyl acetate) was used to purify the product to obtain 4-azido-3-nitrobenzaldehyde.

[0158] 4-Azide-3-nitrobenzaldehyde (0.5 g, 1.0 eq) was dissolved in acetic acid (2.0 eq), and dimethylaminoborane (1.0 eq) was added to the reaction system. The reaction was carried out at room temperature for 8 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by evaporation under reduced pressure. The ethyl acetate was redissolved, washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-nitrobenzaldehyde.

[0159] 4-Azide-3-nitrobenzyl alcohol (0.3 g, 1.0 eq) was dissolved in chloroform, and a chloroform solution of phosphorus tribromide (0.5 eq) was slowly added under nitrogen protection. The total amount of chloroform was 4.0 eq. The reaction was carried out at room temperature for 6 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the product was redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-nitrobenzyl bromide.

[0160] 2) Preparation of N3-NO2-FeCO

[0161] FeCO-OTIPS (0.2 g, 1.0 eq) was dissolved in anhydrous tetrahydrofuran, and sodium hydride (1.5 eq) was added to the reaction system under nitrogen protection. Tetrabutylammonium fluoride (1.5 eq) was added dropwise at 0 °C, and the reaction was continued for 30 minutes. Then, a tetrahydrofuran solution of 4-azido-3-nitrobenzyl bromide (1.1 eq) was added dropwise to the reaction system, and the reaction was carried out at room temperature for 12 h. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, redissolved in ethyl acetate, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-NO2-FeCO.

[0162] Example 8: Preparation of N3-OCO-FeCO donor molecules

[0163] The specific preparation route of the N3-OCO-FeCO donor molecule in this embodiment is as follows:

[0164]

[0165] FeCO active ester was synthesized and prepared according to the reference (Organometallics, 2013, 32(13): 3587-3594).

[0166] 1) Preparation of 4-azidobenzyl alcohol

[0167] 4-Fluorobenzaldehyde (1.0 g, 1.0 eq) was dissolved in dimethyl sulfoxide, and sodium azide (0.58 g, 1.5 eq) was added to the reaction system. The reaction was carried out at 70 °C, and the degree of reaction was monitored by thin-layer chromatography. After the reaction was complete, deionized water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azidobenzaldehyde.

[0168] 4-Azidobenzaldehyde (0.6 g, 1.0 eq) was dissolved in p-toluenesulfonic acid (4.0 eq), and dimethylaminoborane (2 eq) was added to the reaction system. The reaction was carried out at room temperature for 10 h. The extent of the reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the ethyl acetate was redissolved. The solution was washed with water and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azidobenzaldehyde.

[0169] 2) Preparation of N3-OCO-FeCO

[0170] Under nitrogen protection, 4-azidobenzyl alcohol (0.27 g, 1.5 eq) was dissolved in anhydrous tetrahydrofuran. Then, a tetrahydrofuran solution of N,N-diisopropylethylamine (1.5 eq), 4-dimethylaminopyridine (0.4 eq), and FeCO active ester (0.5 g, 1.0 eq) was added to the reaction system. The reaction was carried out at room temperature for 12 hours. The solvent was removed by evaporation under reduced pressure, and the solution was purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-OCO-FeCO.

[0171] The 1H NMR spectrum of the N3-OCO-FeCO molecule produced in this embodiment is shown below. Figure 8 As shown.

[0172] Example 9: Degradation of N3-FeCO in the presence of hydrogen sulfide using HPLC

[0173] First, a mixed solution of N3-FeCO (Example 1) (1 mM) and Na2S (5 mM) (acetonitrile:water = 1:1) was prepared and incubated at 37°C. At different time points, 100 μL of the solution was diluted to 1 mL with the acetonitrile and water mixture. The sample was tested through a 220 nm organic membrane. Based on the HPLC results and the predicted hydrogen sulfide response process, possible degradation processes and products were analyzed. Specific analyses are as follows: Figures 9-12 As shown.

[0174] Figure 9 The HPLC test results of the degradation of N3-FeCO molecules in the presence of hydrogen sulfide in Example 1 are shown.

[0175] Figure 10 The HPLC test results of the degradation of N3-F-FeCO molecules in the presence of hydrogen sulfide in Example 2 are shown.

[0176] Figure 11 The HPLC test results of the degradation of N3-2F-FeCO molecules in the presence of hydrogen sulfide in Example 3 are shown.

[0177] Figure 12The HPLC test results of the degradation of N3-4F-FeCO molecules in the presence of hydrogen sulfide in Example 4 are shown.

[0178] like Figure 9 As shown, with the increase of hydrogen sulfide reaction time, the peak area of ​​the raw material N3-FeCO at 41 minutes gradually decreased, indicating that the N3-FeCO molecule gradually degraded. At the same time, a new product peak appeared at 36 minutes, and the area of ​​the new peak also gradually decreased with the increase of time. It is speculated that the azide unit of the N3-FeCO molecule was reduced to an amino intermediate. At about 1 hour, a third peak appeared at 31 minutes, which is speculated to be an intermediate produced after the 1,6-elimination of p-aminobenzyl alcohol.

[0179] like Figures 10-12 As shown, the rate of decrease in the raw material peak area accelerates with increasing F atoms, proving that the responsiveness of the azide group to hydrogen sulfide can be modulated by changing the number of fluorine atoms. More fluorine atoms result in stronger electron-withdrawing properties, and a faster response of the azide unit to hydrogen sulfide. Simultaneously with... Figure 9 compared to, Figures 10-12 The slower rate of the third peak indicates that the increase in the number of fluorine atoms slowed down the rate of 1,6-rearrangement, thus affecting the CO release rate.

[0180]

[0181] The above is a schematic diagram of the degradation mechanism of the N3-FeCO donor molecule under hydrogen sulfide conditions in Example 1. It can be seen that in the presence of hydrogen sulfide, the sulfide anion reduces the azide group to an amino group, followed by a 1,6-rearrangement reaction, exposing the intermediate FeCO, which spontaneously releases CO under oxidative conditions.

[0182] HPLC test data show that as the number of fluorine atoms increases, the response rate of the azide group to hydrogen sulfide increases significantly. At the same time, the increase in the number of fluorine atoms leads to a decrease in the rate of 1,6-rearrangement of p-aminobenzyl alcohol, thus affecting the CO release rate.

[0183] Example 10: Comparison of hydrogen sulfide removal rates of N3-FeCO, N3-2F-FeCO, and N3-4F-FeCO

[0184] The hydrogen sulfide removal experiment was performed by ultraviolet spectrophotometry, and the hydrogen sulfide was quantified using MBA reagent.

[0185] Hydrogen sulfide detection: H2S release was detected using the methylene blue method. Different concentrations (100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 0 μM) of Na2S in PBS standard solutions were prepared. 1 mL of each standard solution was mixed with 0.2 mL of Zn(OAc)2 (1% w / v) aqueous solution, followed by the addition of 0.4 mL of FeCl3 (30 mM, 1.2 M HCl solution) and 0.4 mL of N,N-dimethyl-1,4-phenylenediamine sulfate (20 mM, 7.2 M HCl). The mixture was reacted in a 37°C water bath for 30 minutes. The absorption spectrum was then scanned using UV-Vis absorption spectroscopy, and the absorption at 670 nm was recorded.

[0186] Specifically, mixed solutions (95:5) of PBS / acetonitrile with different donor molecules (100 μM) and Na2S (500 μM) were prepared and co-cultured at 37°C for a period of time. The hydrogen sulfide content was then measured after different time periods. The specific results are as follows: Figure 13 As shown, the N3-4F-FeCO molecule has the largest and fastest rate of downregulation of hydrogen sulfide concentration, which is consistent with the HPLC test results. The increase in the number of fluorine atoms improves electron-withdrawing properties and accelerates the response rate between the azide unit and hydrogen sulfide.

[0187] Example 11: CO release in the presence of hydrogen sulfide

[0188] Carbon monoxide (CO) was detected by gas chromatography-FID (GC-FID) and a commercially available carbon monoxide detector. For CO release detection by GC, N3-FeCO was dissolved in an aqueous solution containing 5% dimethyl sulfoxide, added to a 10 mL glass sample vial, sealed with a rubber stopper, and incubated at 37°C for 24 hours. Afterward, headspace gas was aspirated using a syringe for GC detection.

[0189] Test results are as follows Figure 14 As shown, the CO signal peak is at 2 minutes, indicating that N3-FeCO can release CO in the presence of hydrogen sulfide.

[0190] Simultaneously, a commercially available CO detector (Drager Pac6500) was used for detection. The detector and a sample vial containing 200 μM of CO-emitting molecules (an aqueous solution containing 5% dimethyl sulfoxide) were placed in a transparent container. A stir bar was placed inside the sample vial for stirring during testing, and the container was sealed with a rubber stopper. The mixture was stirred at 37°C, and the detector readings were recorded at regular intervals. The results are as follows: Figure 15 As shown, 100 μM N3-FeCO molecules released 80 ppm CO within 24 hours.

[0191] All aspects, embodiments, features, and examples of this invention are to be regarded as illustrative in all respects and are not intended to limit the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will become apparent to those skilled in the art without departing from the spirit and scope of the invention as claimed.

[0192] In addition, the inventors of this case also conducted experiments with other raw materials, process operations, and process conditions described in this specification, referring to the aforementioned embodiments, and obtained relatively ideal results in all cases.

[0193] Although the invention has been described with reference to illustrative embodiments, those skilled in the art will understand that various other changes, omissions, and / or additions can be made without departing from the spirit and scope of the invention, and that elements of the embodiments can be substituted with substantially equivalents. Furthermore, many modifications can be made without departing from the scope of the invention to adapt particular situations or materials to the teachings of the invention. Therefore, this invention is not intended to be limited to the specific embodiments disclosed for carrying out the invention, but rather is intended to encompass all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated otherwise, any use of the terms first, second, etc., does not indicate any order or importance, but is used to distinguish one element from another.

Claims

1. A hydrogen sulfide-responsive carbon monoxide donor molecule, characterized in that, The hydrogen sulfide-responsive carbon monoxide donor molecule has the structure shown in formula (I): ； Equation (I); Wherein, R1, R2, R3, and R4 are independently selected from fluorine, nitro, trifluoromethyl, or hydrogen atoms, and X is selected from O or... .

2. The hydrogen sulfide-responsive carbon monoxide donor molecule according to claim 1, characterized in that, The hydrogen sulfide-responsive carbon monoxide donor molecule has any of the following structural formulas: ； ； ； ； X is selected from O or .

3. The hydrogen sulfide-responsive carbon monoxide donor molecule according to claim 1, characterized in that, The hydrogen sulfide-responsive carbon monoxide donor molecule can release carbon monoxide in the presence of hydrogen sulfide, and the time for releasing carbon monoxide is 20 min to 72 h.

4. A method for preparing the hydrogen sulfide-responsive carbon monoxide donor molecule according to any one of claims 1-3, characterized in that, include: A first reaction is carried out on a first mixed reaction system containing the compound of formula (II), dimethylaminoborane and a first solvent to obtain the compound of formula (III); In a protective atmosphere, a second mixed reaction system containing the compound of formula (III), a bromine source, and a second solvent is subjected to a second reaction to obtain the compound of formula (IV); In a protective atmosphere, a third mixed reaction system comprising the compound shown in formula (V), sodium hydride, tetrabutylamine fluoride, and a third solvent is subjected to a third reaction, and then the compound shown in formula (IV) is added to carry out a fourth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I); wherein, X is O. Alternatively, the preparation method includes: A first reaction is carried out on a first mixed reaction system containing the compound of formula (II), dimethylaminoborane and a first solvent to obtain the compound of formula (III); In a protective atmosphere, a fifth reaction is carried out in a fifth mixed reaction system comprising the compound of formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine, the compound of formula (VI), and a third solvent to prepare a hydrogen sulfide-responsive carbon monoxide donor molecule having the structure shown in formula (I), wherein X is... ; ； Formula (II) Formula (III) Formula (IV) Formula (V); ； Formula (VI).

5. The preparation method according to claim 4, characterized in that, include: The compound shown in formula (II) was dissolved in a first solvent and dimethylaminoborane was added to form the first mixed reaction system. The first reaction was carried out at room temperature for 4 to 12 hours to obtain the compound shown in formula (III).

6. The preparation method according to claim 5, characterized in that: The first solvent includes acetic acid and / or p-toluenesulfonic acid.

7. The preparation method according to claim 5, characterized in that: The molar ratio of the compound represented by formula (II), dimethylaminoborane, and the first solvent is 1:(1~2):(2~4).

8. The preparation method according to claim 4, characterized in that, include: The compound shown in formula (III) was dissolved in a second solvent, and a bromine source and a second solvent were added under a protective atmosphere to form the second mixed reaction system. The second reaction was carried out at room temperature for 4-8 hours to obtain the compound shown in formula (IV).

9. The preparation method according to claim 8, characterized in that: The bromine source includes phosphorus tribromide.

10. The preparation method according to claim 8, characterized in that: The second solvent includes any one or a combination of two or more of dichloromethane, chloroform, and ethyl acetate.

11. The preparation method according to claim 8, characterized in that: The molar ratio of the compound shown in formula (Ⅲ), the bromine source, and the second solvent is 1:(0.4~1):(2~4).

12. The preparation method according to claim 4, characterized in that, include: The compound shown in formula (V) and sodium hydride were added to the third solvent and protected with an inert gas. Tetrabutylamine fluoride was added dropwise at 0-10 °C to form the third mixed reaction system. The third reaction was carried out at 0-10 °C for 0.5-2 h. Then, a solution containing the compound shown in formula (IV) and the third solvent was added dropwise and the fourth reaction was carried out at room temperature for 12-24 h to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule with the structure shown in formula (I).

13. The preparation method according to claim 12, characterized in that: The third solvent includes any one or a combination of two or more of tetrahydrofuran, dichloromethane, trichloromethane, and ethyl acetate.

14. The preparation method according to claim 12, characterized in that: The molar ratio of the compound shown in formula (V), sodium hydride, tetrabutylamine fluoride and the compound shown in formula (IV) is 1:(1~1.5):(1~1.5):(1~1.5).

15. The preparation method according to claim 4, characterized in that, include: In a protective atmosphere, the compound shown in formula (III) is dissolved in a third solvent, and then N,N-diisopropylethylamine, 4-dimethylaminopyridine, and the compound shown in formula (VI) are added to form the fifth reaction system. The fifth reaction is carried out at room temperature for 12-24 h to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule with the structure shown in formula (I).

16. The preparation method according to claim 15, characterized in that: The molar ratio of the compound shown in formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine and the compound shown in formula (VI) is (1~1.5):(1~1.5):(0.2~0.4):

1.

17. The use of the hydrogen sulfide-responsive carbon monoxide donor molecule according to any one of claims 1-3 in the preparation of a medicament with anti-inflammatory or anticancer functions.

18. The application according to claim 17, characterized in that: The drug has the function of treating inflammatory bowel disease or colorectal cancer.

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