Hydrogen sulfide responsive carbon monoxide donor molecule as well as preparation method and application thereof

Abstract

The invention discloses a hydrogen sulfide responsive carbon monoxide donor molecule as well as a preparation method and application thereof. The hydrogen sulfide responsive carbon monoxide donor molecule has the following structure: # imgabs 0 #, R1, R2, R3 and R4 are respectively and independently selected from groups with electron withdrawing property, groups with electron donating property or hydrogen atoms, and X is selected from O or # imgabs 1 #. Acyloxydiene-Fe (CO) 3 is selected as an element for releasing carbon monoxide and an azido group is selected as a hydrogen sulfide response element, so that the formed donor molecule has hydrogen sulfide responsiveness and can release carbon monoxide in the presence of hydrogen sulfide, and the hydrogen sulfide response rate and the release rate of carbon monoxide of the donor material can be adjusted; therefore, the treatment on the colitis and the inhibition on the colorectal cancer can be realized.

Description

Technical Field

[0001] The invention belongs to the technical field of gaseous transmitter donors, and in particular relates to a hydrogen sulfide-responsive carbon monoxide donor molecule and a preparation method and application thereof. Background Art

[0002] Gasotransmitters, as important endogenous molecules, have been widely studied. Carbon monoxide as a gasotransmitter has been found to have therapeutic potential in inflammation, bacterial infection, cardiovascular disease and cancer-related diseases. However, direct gas inhalation needs to overcome the toxicity problems of high-pressure storage, inability to accurately administer the drug and non-specific distribution. How to achieve the controlled release of gasotransmitters in deep lesion tissues and thus achieve biological effects is a key issue that needs to be considered; in addition, the physiological functions of gasotransmitters are highly concentration-dependent, and they are biologically toxic at high concentrations and cannot achieve biological effects at low concentrations. In summary, in the design of gasotransmitter molecule donors, the stimulation mode, tissue penetration, controlled release and biosafety should be fully considered.

[0003] As a gas signaling molecule, hydrogen sulfide plays an important role in many physiological processes. In the pathological conditions of inflammatory bowel disease and colorectal cancer, the concentration of hydrogen sulfide is selectively upregulated, which can be used as a target for the treatment of inflammatory bowel disease and cancer. Carbon monoxide is also an important gas signaling molecule, playing a huge role in anti-inflammatory, anti-apoptotic and anti-cancer. By taking advantage of the high concentration of hydrogen sulfide in the pathological environment of inflammatory bowel disease or colorectal cancer, the release of carbon monoxide is triggered by hydrogen sulfide responsiveness, and carbon monoxide is released while the concentration of hydrogen sulfide is lowered, thereby exerting its anti-inflammatory or anti-cancer effects.

[0004] Therefore, how to find a carbon monoxide donor molecule that can achieve hydrogen sulfide responsiveness has become a direction that industry researchers have been working towards for a long time. Summary of the invention

[0005] The main purpose of the present invention is to provide a hydrogen sulfide responsive carbon monoxide donor molecule and a preparation method to overcome the deficiencies in the prior art.

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

[0007] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes:

[0008] The embodiment of the present invention provides a hydrogen sulfide-responsive carbon monoxide donor molecule having a structure as 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 embodiments, R1, R2, R3, and R4 are each selected from any one of fluorine, nitro, trifluoromethyl, methoxy, and hydrogen.

[0012] The embodiment of the present invention also provides a method for preparing a hydrogen sulfide-responsive carbon monoxide donor molecule, which comprises:

[0013] A first mixed reaction system comprising a compound represented by formula (II), dimethylaminoborane and a first solvent is subjected to a first reaction to obtain a compound represented by formula (II);

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

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

[0016] Alternatively, the preparation method comprises:

[0017] A first mixed reaction system comprising a compound represented by formula (II), dimethylaminoborane and a first solvent is subjected to a first reaction to obtain a compound represented by formula (II);

[0018] In a protective atmosphere, a fifth mixed reaction system comprising a compound represented by formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine, a compound represented by formula (VI), and a third solvent is subjected to a fifth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having a structure represented by formula (I), wherein X is

[0019]

[0020]

[0021] The embodiment of the present invention also provides the use of the hydrogen sulfide-responsive carbon monoxide donor molecule in the preparation of drugs with anti-inflammatory or anti-cancer functions.

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

[0023] 1) The hydrogen sulfide-responsive carbon monoxide donor molecule provided by the present invention is structurally designed, and acyloxydiene-Fe(CO)3 is selected as the moiety for releasing carbon monoxide, and an azide group is used as the hydrogen sulfide-responsive moiety. The donor molecule thus constructed has hydrogen sulfide responsiveness 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 adjusted, 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 the present invention responds to the increased concentration of hydrogen sulfide in lesions such as inflammatory bowel disease and colorectal cancer by releasing CO in the presence of high concentrations of hydrogen sulfide, thereby inhibiting the growth of inflammatory or cancer cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0026] Figure 1 shows the hydrogen nuclear magnetic resonance spectrum of the N3-FeCO molecule in Example 1;

[0027] Figure 2 shows the hydrogen nuclear magnetic resonance spectrum of the N3-F-FeCO molecule in Example 2;

[0028] Figure 3 The NMR fluorine spectrum of the N3-F-FeCO molecule in Example 2 is shown;

[0029] Figure 4 shows the hydrogen nuclear magnetic resonance spectrum of the N3-2F-FeCO molecule in Example 3;

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

[0031] Figure 6 shows the hydrogen nuclear magnetic resonance spectrum of the N3-4F-FeCO molecule in Example 4;

[0032] Figure 7 The NMR fluorine spectrum of the N3-4F-FeCO molecule in Example 4 is shown;

[0033] Figure 8 shows the hydrogen nuclear magnetic resonance spectrum of the N3-OCO-FeCO molecule in Example 8;

[0034] Fig. 9 The HPLC test chart of the degradation of N3-FeCO molecules in the presence of hydrogen sulfide in Example 1 is shown;

[0035] Fig.10 The HPLC test chart of the degradation of N3-F-FeCO molecules in the presence of hydrogen sulfide in Example 2 is shown;

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

[0037] Fig.12 The HPLC test chart of the degradation of N3-4F-FeCO molecules in the presence of hydrogen sulfide in Example 4 is shown;

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

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

[0040] Fig.15 A quantitative curve diagram of CO release from N3-FeCO molecules in Example 1 is shown. DETAILED DESCRIPTION

[0041] In view of the problems existing in the above-mentioned prior art, after long-term research and a large number of experiments, the inventors of this case proposed a method for preparing a hydrogen sulfide-responsive carbon monoxide donor molecule, targeting the characteristics of increased hydrogen sulfide concentration in lesions such as inflammatory bowel disease and colorectal cancer, and responsively releasing CO in the presence of high concentrations of hydrogen sulfide to inhibit the growth of inflammatory or cancer cells. 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 colon inflammation and the inhibition of colorectal cancer.

[0042] For ease of understanding of the present invention, the present invention 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. On the contrary, the purpose of providing these embodiments or examples is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

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

[0044]

[0045] Wherein, 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 atom (H), and X is selected from O or That is, X may be an ether bond or a carbonate bond.

[0046] In some embodiments, the structural formula of the hydrogen sulfide responsive carbon monoxide donor molecule is any one of the following structures:

[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 can reduce the hydrogen sulfide response rate, while electron withdrawing groups such as fluorine, nitro or trifluoromethyl 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 can increase the 1,6-rearrangement degradation rate, and electron-withdrawing groups such as fluorine, nitro or trifluoromethyl can reduce the hydrogen sulfide response rate.

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

[0052] In some embodiments, the hydrogen sulfide-responsive carbon monoxide donor molecule can release carbon monoxide under the action of hydrogen sulfide, and different hydrogen sulfide response rates and carbon monoxide release rates can be achieved by changing different functional groups on the benzene ring. The mechanism of the release of carbon monoxide by the hydrogen sulfide-responsive carbon monoxide donor molecule 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 comprises:

[0055] A first mixed reaction system comprising a compound represented by formula (II), dimethylaminoborane and a first solvent is subjected to a first reaction to obtain a compound represented by formula (II);

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

[0057] In a protective atmosphere, a third mixed reaction system comprising a compound represented by formula (V), sodium hydride, tetrabutylammonium fluoride, and a third solvent is subjected to a third reaction, and then a compound represented by formula (IV) is added to carry out a fourth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having a structure represented by 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 performing a first reaction at room temperature for 4 to 12 hours to obtain the compound represented by formula (IⅡ).

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

[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 the second solvent in a protective atmosphere to form the second mixed reaction system, and performing a second reaction at room temperature for 4 to 8 hours to obtain the compound represented by formula (IV).

[0063] Furthermore, the bromine source may be phosphorus tribromide, but is not limited thereto.

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

[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 embodiments, the preparation method specifically comprises:

[0067] Add the compound represented by formula (V) and sodium hydride to a third solvent, and under the protection of an inert gas, add tetrabutylammonium fluoride dropwise at 0 to 10° C. to form the third mixed reaction system, and carry out the third reaction at 0 to 10° C. for 0.5 to 2 hours;

[0068] Then, a solution containing the compound represented by formula (IV) and the third solvent is added dropwise, and a fourth reaction is carried out at room temperature for 12 to 24 hours to obtain a hydrogen sulfide responsive carbon monoxide donor molecule having a structure represented by formula (I), wherein 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 thereto.

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

[0071] Among them, in some more preferred embodiments, the method for preparing the hydrogen sulfide responsive carbon monoxide donor molecule comprises the following steps:

[0072]

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

[0074] (2) The compound represented by formula (III) is dissolved in a second solvent, and a bromine source (such as phosphorus tribromide) and a solution of the second solvent are slowly added under nitrogen protection, and the reaction is carried out at room temperature. The degree of reaction is monitored by thin layer chromatography. After the reaction is completed, the solvent is removed by evaporation under reduced pressure, and the mixture is 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 a compound represented by formula (IV).

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

[0076] FeCO-OTIPS (0.33 g, 1.0 eq) and sodium hydride are added to a third solvent under nitrogen protection; tetrabutylammonium fluoride is added dropwise to the reaction system at 0-10° C. and reacted for 0.5-2 hours; then the compound represented by formula (III) and the solution of the third solvent are added dropwise to the reaction system and reacted at room temperature. The degree of reaction is monitored by thin layer chromatography. After the reaction is complete, tetrahydrofuran is removed by rotation and redissolved in ethyl acetate. The organic phase is 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 represented by formula (I).

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

[0078] A first mixed reaction system comprising a compound represented by formula (II), dimethylaminoborane and a first solvent is subjected to a first reaction to obtain a compound represented by formula (II);

[0079] In a protective atmosphere, a fifth mixed reaction system comprising a compound represented by formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine, a compound represented by formula (VI), and a third solvent is subjected to a fifth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having a structure represented by 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 performing a first reaction at room temperature for 4 to 12 hours to obtain the compound represented by formula (IⅡ).

[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: in a protective atmosphere, dissolving the compound represented by formula (III) in a third solvent, then adding N,N-diisopropylethylamine, 4-dimethylaminopyridine, and the compound represented by formula (VI) to form the fifth reaction system, and conducting the fifth reaction at room temperature for 12 to 24 hours to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having a structure represented by 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 (1-1.5):(1-1.5):(0.2-0.4):1.

[0085] Among them, in some more preferred embodiments, the method for preparing the hydrogen sulfide responsive carbon monoxide donor molecule comprises the following steps:

[0086]

[0087] (A) Dissolve the compound represented by formula (II) in a first solvent, add dimethylaminoborane to the reaction system, react at room temperature, and monitor the degree of reaction by thin layer chromatography. After the reaction is complete, remove the solvent under reduced pressure, redissolve in ethyl acetate, wash with water and saturated sodium bicarbonate aqueous solution, respectively, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether / ethyl acetate) to obtain the compound represented by formula (II).

[0088] (B) Under nitrogen protection, the compound represented by formula (II) is dissolved in a third solvent, and then N, N-diisopropylethylamine, 4-dimethylaminopyridine and FeCO active ester (compound represented by formula (VI)) and a solution of the third solvent are added to the reaction system, reacted at room temperature for 12 to 24 hours, evaporated under reduced pressure to remove the solvent, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the product represented by formula (I).

[0089] As one aspect of the technical solution of the present invention, it involves the use 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 are described clearly and completely below. The described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0092] In order to further understand the present application, the preparation of the hydrogen sulfide responsive carbon monoxide donor molecules provided by the present invention, the comparison of hydrogen sulfide response rates and the carbon monoxide release rate are specifically described below in conjunction with the examples.

[0093] Unless otherwise specified, the raw materials and reagents of the materials of the present invention are all commercially available.

[0094] Example 1 Preparation of N3-FeCO Donor Molecule

[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, sodium azide (0.58 g, 1.5 eq) was added to the reaction system, and the mixture was reacted at 70°C. 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-azidobenzaldehyde (0.6 g, 1.0 eq) was dissolved in acetic acid (2 eq), dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system, and the reaction was carried out at room temperature for 4 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure, the mixture was redissolved in ethyl acetate, 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-azidobenzyl alcohol.

[0100] 4-azidobenzyl alcohol (0.3 g, 1.0 eq) was dissolved in anhydrous dichloromethane, and a dichloromethane solution of phosphorus tribromide (1.0 eq) was added dropwise to the reaction system under nitrogen protection, with dichloromethane being 2.0 eq. The reaction was carried out at room temperature for 4 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the mixture 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 a previous report (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; tetrabutylammonium fluoride (0.23 g, 1.1 eq) was added dropwise to the reaction system at 0°C and reacted for 30 minutes; then a tetrahydrofuran solution of 4-azidobenzyl bromide (1.0 eq) was added dropwise to the reaction system and reacted at room temperature for 12 hours. The degree of reaction was monitored by thin layer chromatography. After the reaction was complete, tetrahydrofuran was removed by rotation and redissolved with 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 nuclear magnetic resonance hydrogen spectrum of the product N3-FeCO molecule in this example is as follows Figure 1 shown.

[0105] Example 2 Preparation of N3-F-FeCO Donor Molecule

[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, sodium azide (0.64 g, 1.5 eq) was added to the reaction system, and the reaction was carried out at 70°C. 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] 4-azido-3-fluorobenzaldehyde (0.6 g, 1.0 eq) was dissolved in acetic acid (2.5 eq), dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system, and the reaction was carried out at room temperature for 8 h. 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 a saturated sodium bicarbonate aqueous 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-azido-3-fluorobenzyl alcohol (0.2 g, 1.0 eq) was dissolved in anhydrous dichloromethane, and a dichloromethane solution of phosphorus tribromide (1.0 eq) was slowly added under nitrogen protection, with dichloromethane being 2.0 eq. The reaction was carried out at room temperature for 6 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, 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-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 hours. The reaction was monitored by thin layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, and the mixture was redissolved with 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 nuclear magnetic resonance hydrogen spectrum of the product N3-F-FeCO molecule in this example is as follows Figure 2 As shown, the NMR fluorine spectrum is as Figure 3 shown.

[0115] Example 3 Preparation of N3-2F-FeCO Donor Molecule

[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, sodium azide (0.57 g, 1.5 eq) was added to the reaction system, and the mixture was reacted at 70°C. The degree of reaction was monitored by thin layer chromatography. After the reaction was complete, deionized water was added, 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-3,5-difluorobenzaldehyde;

[0120] 4-azido-3,5-difluorobenzaldehyde (0.6 g, 1.0 eq) was dissolved in acetic acid (3.0 eq), dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system, and the mixture was reacted at room temperature for 10 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was complete, the solvent was evaporated under reduced pressure and the mixture was redissolved in ethyl acetate, 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-azido-3,5-difluorobenzyl alcohol (0.2 g, 1.0 eq) was dissolved in anhydrous dichloromethane, and a dichloromethane solution of phosphorus tribromide (1.0 eq) was slowly added under nitrogen protection, with 3.0 eq of dichloromethane. The reaction was carried out at room temperature for 4 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent 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 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 hours. The reaction was monitored by thin layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, and the mixture 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 N3-2F-FeCO.

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

[0125] Example 4 Preparation of N3-4F-FeCO Donor Molecule

[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 subjected to microwave reaction at 70°C for 15 minutes. After completion of the reaction, the reaction system was poured into ice water, extracted with ether, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-2,3,5,6-tetrafluorobenzaldehyde;

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

[0131] 4-azido-2,3,5,6-tetrafluorobenzyl alcohol (0.3 g, 1.0 eq) was dissolved in anhydrous dichloromethane, and a dichloromethane solution of phosphorus tribromide (0.8 eq) was slowly added under nitrogen protection, with dichloromethane being 2.0 eq. The reaction was carried out at room temperature for 8 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, 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-3,5-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 hours. The reaction was monitored by thin layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, and the mixture was redissolved with 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 hydrogen nuclear magnetic resonance spectrum of the product N3-4F-FeCO molecule in this example is as follows Figure 6 As shown, the NMR fluorine spectrum is as Figure 7 shown.

[0135] Example 5 Preparation of N3-OCH3-FeCO Donor Molecule

[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, sodium azide (0.51 g, 1.5 eq) was added to the reaction system, and the mixture was reacted at 70°C. 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. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-methoxybenzaldehyde.

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

[0141] 4-azido-3-methoxybenzyl alcohol (0.3 g, 1.0 eq) was dissolved in anhydrous dichloromethane, and a dichloromethane solution of phosphorus tribromide (0.4 eq) was slowly added under nitrogen protection, with dichloromethane being 4.0 eq. The reaction was carried out at room temperature for 8 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, 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-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 was monitored by thin layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, and the mixture 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-OCH3-FeCO.

[0144] Example 6 Preparation of N3-CF3-FeCO Donor Molecule

[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, sodium azide (0.50 g, 1.5 eq) was added to the reaction system, and the mixture was reacted at 70°C. 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. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-trifluoromethylbenzaldehyde.

[0149] 4-azido-3-trifluoromethylbenzaldehyde (0.4 g, 1.0 eq) was dissolved in acetic acid (3.0 eq), dimethylaminoborane (0.26 g, 1.2 eq) was added to the reaction system, and the mixture was reacted at room temperature for 5 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was complete, the solvent was evaporated under reduced pressure and the mixture was redissolved in ethyl acetate, 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] 4-azido-3-trifluoromethylbenzyl alcohol (0.25 g, 1.0 eq) was dissolved in ethyl acetate, and a solution of phosphorus tribromide (1.0 eq) in ethyl acetate was slowly added under nitrogen protection, with ethyl acetate being 2.0 eq. The reaction was carried out at room temperature for 4 h. The degree of 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 minutes; 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 hours. The degree of the reaction was monitored by thin layer chromatography. After the reaction was complete, tetrahydrofuran was removed by evaporation under reduced pressure, and the mixture 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 Molecule

[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, sodium azide (0.52 g, 1.5 eq) was added to the reaction system, and the reaction was carried out at 70°C. The degree of reaction was monitored by thin layer chromatography. After the reaction was completed, deionized water was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azido-3-nitrobenzaldehyde.

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

[0159] 4-azido-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, with chloroform being 4.0 eq. The reaction was carried out at room temperature for 6 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the mixture 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 hours. The progress of the reaction was monitored by thin layer chromatography. After the reaction was complete, tetrahydrofuran 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 N3-NO2-FeCO.

[0162] Example 8 Preparation of N3-OCO-FeCO Donor Molecule

[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 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, sodium azide (0.58 g, 1.5 eq) was added to the reaction system, and the mixture was reacted at 70°C. 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), dimethylaminoborane (2 eq) was added to the reaction system, and the reaction was carried out at room temperature for 10 h. The degree of reaction was monitored by thin layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure, the mixture was redissolved in ethyl acetate, washed with water and saturated sodium bicarbonate aqueous solution, respectively, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate) to obtain 4-azidobenzyl alcohol.

[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, and then N, N-diisopropylethylamine (1.5 eq), 4-dimethylaminopyridine (0.4 eq) and FeCO active ester (0.5 g, 1.0 eq) in tetrahydrofuran were added to the reaction system. The reaction was carried out at room temperature for 12 hours, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain N3-OCO-FeCO.

[0171] The nuclear magnetic resonance hydrogen spectrum of the product N3-OCO-FeCO molecule in this example is as follows Figure 8 shown.

[0172] Example 9 Study on the Degradation of N3-FeCO in the Presence of Hydrogen Sulfide by 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. 100 μL of the solution was diluted to 1 mL with a mixed solution of acetonitrile and water at different time periods. The samples were tested on an organic film of 220 nm. Based on the HPLC results, the possible degradation process and products were analyzed in combination with the predicted hydrogen sulfide response process. The specific analysis is as follows: Figure 9-12 shown.

[0174] Fig. 9 HPLC test of the degradation of N3-FeCO molecules in the presence of hydrogen sulfide in Example 1 is shown.

[0175] Fig.10 HPLC test of the degradation of N3-F-FeCO molecules in the presence of hydrogen sulfide in Example 2 is shown.

[0176] Fig.11 HPLC test of the degradation of N3-2F-FeCO molecules in the presence of hydrogen sulfide in Example 3 is shown.

[0177] Fig.12HPLC test of the degradation of N3-4F-FeCO molecules in the presence of hydrogen sulfide in Example 4 is shown.

[0178] like Fig. 9 As shown in the figure, with the increase of hydrogen sulfide action time, the raw material peak area of ​​N3-FeCO with a peak time of 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 is reduced to an intermediate of the amino group. The third peak began to appear at 31 minutes after about 1 hour, which is speculated to be the intermediate produced after the 1,6-elimination of p-aminobenzyl alcohol.

[0179] like Figure 10-12 As shown in the figure, as the number of F atoms increases, the rate of decrease of the raw material peak area accelerates, proving that the responsiveness of the azide group to hydrogen sulfide can be regulated by changing the number of fluorine atoms. The more fluorine atoms there are, the stronger the electron-withdrawing property is, and the faster the azide unit responds to hydrogen sulfide. Fig. 9 compared to, Figure 10-12 The rate at which the third peak appears slows down, indicating that the increase in the number of fluorine atoms slows down the rate of 1,6-rearrangement, thereby affecting the release rate of CO.

[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 sulfur anion reduces the azide group to the amino group, and then a 1,6-rearrangement reaction occurs to expose the intermediate FeCO, which spontaneously releases CO under oxidative conditions.

[0182] It can be seen from the HPLC test data that with the increase in the number of fluorine atoms, the response rate of the azide group to hydrogen sulfide significantly increases. At the same time, the increase in the number of fluorine atoms will lead to a decrease in the rate of 1,6-rearrangement of aminobenzene alcohol, thereby affecting the release rate of CO.

[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 determined by UV spectrophotometry, and hydrogen sulfide was quantified by MBA reagent.

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

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

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

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

[0189] Test results such as Fig.14 As shown, the CO signal peak is at 2 minutes. It can be seen that in the presence of hydrogen sulfide, N3-FeCO can release CO.

[0190] At the same time, a commercial CO detector (Drager Pac6500) was used for detection. The detector and a sample bottle containing 200 μM CO release molecules (containing 5% dimethyl sulfoxide in water) were placed in a transparent container. A stirring bar was placed in the sample bottle to stir during the test, and the container was sealed with a rubber stopper. Stirring at 37°C, the detector reading changes were recorded at regular intervals. The results are shown in Fig.15 As shown, 100 μM N3-FeCO molecules released 80 ppm of CO within 24 hours.

[0191] The various aspects, embodiments, features and examples of the present invention should be considered as illustrative in all aspects and are not intended to limit the present invention, the scope of the present invention is defined only by the claims. Other embodiments, modifications and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.

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

[0193] Although the present invention has been described with reference to illustrative embodiments, it will be appreciated by those skilled in the art that various other changes, omissions and / or additions may be made without departing from the spirit and scope of the present invention and that the elements of the embodiments may be replaced by substantial equivalents. In addition, many modifications may be made without departing from the scope of the present invention to adapt specific circumstances or materials to the teachings of the present invention. Therefore, it is not intended herein to limit the present invention to the disclosed specific embodiments for performing the present invention, but it is intended that the present invention will include all embodiments within the scope of the appended claims. In addition, unless specifically stated, any use of the terms first, second, etc. does not indicate any order or importance, but rather uses the terms first, second, etc. 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 a structure as shown in formula (I): 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 2. The hydrogen sulfide responsive carbon monoxide donor molecule according to claim 1, characterized in that: R1, R2, R3, and R4 are each selected from any one of fluorine, nitro, trifluoromethyl, methoxy, and hydrogen atoms.

3. The hydrogen sulfide responsive carbon monoxide donor molecule according to claim 1, characterized in that: The structural formula of the hydrogen sulfide responsive carbon monoxide donor molecule is any one of the following structures: X is selected from O or 4. 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 minutes to 72 hours.

5. The method for preparing the hydrogen sulfide responsive carbon monoxide donor molecule according to any one of claims 1 to 4, characterized in that: include: A first mixed reaction system comprising a compound represented by formula (II), dimethylaminoborane and a first solvent is subjected to a first reaction to obtain a compound represented by formula (II); In a protective atmosphere, a second mixed reaction system comprising a compound represented by formula (II), a bromine source, and a second solvent is subjected to a second reaction to obtain a compound represented by formula (IV); In a protective atmosphere, a third mixed reaction system comprising a compound represented by formula (V), sodium hydride, tetrabutylammonium fluoride, and a third solvent is subjected to a third reaction, and then a compound represented by formula (IV) is added to carry out a fourth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having a structure represented by formula (I); wherein X is O; Alternatively, the preparation method comprises: A first mixed reaction system comprising a compound represented by formula (II), dimethylaminoborane and a first solvent is subjected to a first reaction to obtain a compound represented by formula (II); In a protective atmosphere, a fifth mixed reaction system comprising a compound represented by formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine, a compound represented by formula (VI), and a third solvent is subjected to a fifth reaction to obtain a hydrogen sulfide-responsive carbon monoxide donor molecule having a structure represented by formula (I), wherein X is 6. The preparation method according to claim 5, characterized in that: include: The compound represented by formula (II) is dissolved in a first solvent, and dimethylaminoborane is added to form the first mixed reaction system, and the first reaction is carried out at room temperature for 4 to 12 hours to obtain the compound represented by formula (III); and / or, the first solvent comprises acetic acid and / or p-toluenesulfonic acid; And / or, the molar ratio of the compound represented by formula (II), dimethylaminoborane and the first solvent is 1:(1-2):(2-4).

7. The preparation method according to claim 5, characterized in that: include: The compound represented by formula (III) is dissolved in a second solvent, a bromine source and the second solvent are added in a protective atmosphere to form the second mixed reaction system, and a second reaction is carried out at room temperature for 4 to 8 hours to obtain a compound represented by formula (IV); and / or, the bromine source comprises phosphorus tribromide; And / or, the second solvent includes any one of dichloromethane, chloroform, and ethyl acetate, or a combination of two or more thereof; And / or, the molar ratio of the compound represented by formula (III), the bromine source and the second solvent is 1:(0.4-1):(2-4).

8. The preparation method according to claim 5, characterized in that: include: The compound represented by formula (V) and sodium hydride are added to a third solvent, and tetrabutylammonium fluoride is added dropwise at 0 to 10° C. under inert gas protection to form the third mixed reaction system, and the third reaction is carried out at 0 to 10° C. for 0.5 to 2 hours; then, a solution containing the compound represented by formula (IV) and the third solvent is added dropwise, and a fourth reaction is carried out at room temperature for 12 to 24 hours to obtain a hydrogen sulfide responsive carbon monoxide donor molecule having a structure as represented by formula (I); And / or, the third solvent includes any one or a combination of two or more of tetrahydrofuran, dichloromethane, chloroform, and ethyl acetate; And / or, the molar ratio of the compound represented by formula (V), sodium hydride, tetrabutylammonium fluoride and the compound represented by formula (IV) is 1:(1-1.5):(1-1.5):(1-1.5).

9. The preparation method according to claim 5, characterized in that: include: In a protective atmosphere, the compound represented by formula (II) is dissolved in a third solvent, and then N, N-diisopropylethylamine, 4-dimethylaminopyridine, and the compound represented by formula (VI) are added to form the fifth reaction system, and the fifth reaction is carried out at room temperature for 12 to 24 hours to obtain a hydrogen sulfide responsive carbon monoxide donor molecule having a structure represented by formula (I); And / or, the molar ratio of the compound represented by formula (III), N,N-diisopropylethylamine, 4-dimethylaminopyridine and the compound represented by formula (VI) is (1-1.5):(1-1.5):(0.2-0.4):

1.

10. Use of the hydrogen sulfide-responsive carbon monoxide donor molecule according to any one of claims 1 to 4 in the preparation of a drug with anti-inflammatory or anti-cancer function; preferably, the drug has the function of treating inflammatory bowel disease or colorectal cancer.

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