CN112794865A - Bioactive oxygen response hydrogen sulfide donor and application thereof - Google Patents
Bioactive oxygen response hydrogen sulfide donor and application thereof Download PDFInfo
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- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 59
- 230000000975 bioactive effect Effects 0.000 title claims abstract description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000001301 oxygen Substances 0.000 title claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 13
- 230000004044 response Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000003480 eluent Substances 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007850 fluorescent dye Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 3
- 238000013270 controlled release Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 3
- 238000012800 visualization Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 2
- 230000019086 sulfide ion homeostasis Effects 0.000 claims 1
- 230000002459 sustained effect Effects 0.000 claims 1
- 241000252212 Danio rerio Species 0.000 description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 3
- CMFNMSMUKZHDEY-UHFFFAOYSA-N peroxynitrous acid Chemical compound OON=O CMFNMSMUKZHDEY-UHFFFAOYSA-N 0.000 description 3
- YZMHNNLDUWRZFW-UHFFFAOYSA-N (4-methoxyphenyl)-morpholin-4-yl-sulfanyl-sulfanylidene-$l^{5}-phosphane;morpholine Chemical compound C1COCC[NH2+]1.C1=CC(OC)=CC=C1P([S-])(=S)N1CCOCC1 YZMHNNLDUWRZFW-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical group N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
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- 230000001105 regulatory effect Effects 0.000 description 2
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- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000002153 sulfur containing inorganic group Chemical group 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 1
- JDLKFOPOAOFWQN-VIFPVBQESA-N Allicin Natural products C=CCS[S@](=O)CC=C JDLKFOPOAOFWQN-VIFPVBQESA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical compound [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 description 1
- FMMSEFNIWDFLKK-UHFFFAOYSA-N [O].OO Chemical compound [O].OO FMMSEFNIWDFLKK-UHFFFAOYSA-N 0.000 description 1
- JDLKFOPOAOFWQN-UHFFFAOYSA-N allicin Chemical compound C=CCSS(=O)CC=C JDLKFOPOAOFWQN-UHFFFAOYSA-N 0.000 description 1
- 235000010081 allicin Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000002158 endotoxin Substances 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- 229940079826 hydrogen sulfite Drugs 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
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- 210000000653 nervous system Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
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- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- -1 thiol-activated hydrogen sulfide Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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Abstract
The invention provides a bioactive oxygen-responsive hydrogen sulfide donor, which belongs to the technical field of molecular biology, and has a structural formula shown in an abstract figure.
Description
Technical Field
The invention relates to the technical field of molecular biology, in particular to a bioactive oxygen response hydrogen sulfide donor and application thereof.
Background
Hydrogen sulfide (H)2S) is a biological endogenous substance, believed to be third after Nitric Oxide (NO) and carbon monoxide (CO)A gaseous signal molecule. In vivo, L-cysteine and homocysteine are used as substrates and are catalytically produced under the action of enzymes widely existing in various organ tissues of a human body, so that hydrogen sulfide plays a wide and key role in a nervous system, a cardiovascular system, an immune system and a digestive system and is an important molecule in a biological oxidation-reduction process in an organism. Hydrogen sulfide also has physiological effects of regulating blood pressure, regulating cell proliferation and apoptosis, inhibiting insulin signal, relieving ischemic reperfusion injury, etc., and plays a key role in pathophysiological processes of central nervous diseases such as Alzheimer disease, Parkinson disease, Huntington disease, etc. Because of the key role of hydrogen sulfide in a plurality of physiological and pathological processes, the physiological and pathological mechanisms of hydrogen sulfide are deeply understood, and the method has important significance for preventing, diagnosing and treating diseases.
However, an ideal hydrogen sulfide donor is still lacked in hydrogen sulfide related research, and currently, the most commonly used hydrogen sulfide donors mainly comprise a slow-release hydrogen sulfide donor, including sulfur-containing inorganic salts (such as hydrogen sulfide and sodium hydrosulfide), lawson reagents (such as GYY4137), dimercaptothiones (such as DTTs) and the like, and have the most remarkable characteristic that the hydrogen sulfide donors are hydrolyzed after meeting water to release H at a certain rate2S gas; another type of donor is a thiol-activated hydrogen sulfide donor, common types include allicin, nitrogen sulfur, dimercapto, and thioamides, which release H under the action of a biological thiol2And (4) S gas.
The sulfur-containing inorganic salt can increase the hydrogen sulfide concentration in the body in a short time, but when a solution of these substances is prepared, H is added2S has been generated so that H is precisely controlled2The concentration of S becomes difficult, and the uncontrollable quick release of hydrogen sulfide causes great toxicity to the body, so that great inconvenience is caused to users in terms of the using amount; the use of GYY4137 in biological and medical research is widespread, but its sustained release pattern is fixed, the release rate cannot be controlled, it is impossible to satisfy all biological applications, and its by-products are uncertain, so it is controversial whether the physiological effect of the donor in a particular experiment is independently hydrogen sulfide. Thiol-activated donors are activated in vivo by biological thiolsThe hydrogen sulfide gas is released after the gasification, and has different structural characteristics, and the difference between the release kinetics and the release characteristics is very large, so that the common index is lacked. Thus, the use of such donors requires monitoring and quantifying the production of hydrogen sulfide in a number of additional ways.
Disclosure of Invention
In view of the above problems, it is an object of the present invention to provide a bioactive oxygen-responsive hydrogen sulfide donor that can release hydrogen sulfide in situ by stimulation of biological endogenous reactive oxygen species.
The purpose of the invention is realized by adopting the following technical scheme:
a bioactive oxygen-responsive hydrogen sulfide donor having the formula:
wherein R is alkyl, hydroxyalkyl or carboxyalkyl with 1-4 carbon atoms, the hydrogen sulfide donor can release hydrogen sulfide by two bioactive oxygens of hydrogen peroxide and peroxynitrite, and the efficiency of the hydrogen peroxide is 3-4 times higher than that of the peroxynitrite.
Preferably, R is n-butyl.
Another object of the present invention is to provide a method for synthesizing the hydrogen sulfide donor, which comprises the following steps:
s1, the compound (1) and equimolar n-butylamine are mixed in an ethanol solution, heated and refluxed for 10 hours, and after cooling, a solid is filtered out to obtain a compound (2);
s2, adding the compound (2) into an ethanol solution, fully stirring to obtain a suspension, adding 0.01-0.05 times of palladium-carbon in the molar weight of the compound (2), introducing hydrogen at room temperature to react for 3 hours, performing suction filtration by using kieselguhr to obtain a clear solution, and performing reduced pressure drying to obtain a compound (3);
s3, dissolving the compound (3) in dry dichloromethane, adding solid sodium bicarbonate with the molar amount equal to that of the compound (3), dropwise adding thiophosgene with the molar amount 1.5 times that of the compound (3) under the condition of ice-water bath while stirring, reacting for 3 hours, then spin-drying the liquid, and obtaining the compound (4) through column chromatography separation;
s4, mixing equimolar compounds (4) and (5) with sodium hydride in dry tetrahydrofuran, reacting at room temperature for 6h, spin-drying the liquid, and separating by column chromatography to obtain a compound (6);
the structural formulae of the compounds (1) to (6) are as follows:
preferably, the eluent for column chromatography separation in step S3 is a mixture of eluents in a volume ratio of 100: 1, a mixed solution of dichloromethane and ethanol; the eluent for column chromatography separation in the step S4 is a mixture of eluent with the volume ratio of 80: 1 of a mixed solution of dichloromethane and methanol.
It is a further object of the present invention to provide a use of the aforementioned hydrogen sulfide donor, comprising:
the application in preparing the in vitro or in vivo slow release or controlled release hydrogen sulfide medicine;
the application in preparing the medicine for generating hydrogen sulfide through in vitro or in vivo fluorescence visualization;
the application of the fluorescent probe as in-vitro or in-vivo hydrogen peroxide in the absence of peroxynitrite.
The invention has the beneficial effects that:
the hydrogen sulfide donor disclosed by the invention is based on biological endogenous hydrogen peroxide controlled release, has application values in different biological systems, can adjust the release speed through hydrogen peroxide, has better controllability, generates a fluorescence signal in situ in the process of releasing hydrogen sulfide, realizes the visualization of hydrogen sulfide release kinetics, and greatly simplifies the operation of a donor user.
Drawings
The invention is further illustrated by means of the attached drawings, but the embodiments in the drawings do not constitute any limitation to the invention, and for a person skilled in the art, other drawings can be obtained on the basis of the following drawings without inventive effort.
FIG. 1 is a structural formula of a bioactive oxygen-responsive hydrogen sulfide donor according to the present invention;
FIG. 2 is a synthetic scheme of a hydrogen sulfide donor according to example 1 of the present invention;
FIG. 3 is a schematic representation of the hydrogen sulfide donor route to hydrogen sulfide in accordance with example 1 of the present invention;
FIG. 4 is an image of a confocal laser microscopy of HepG2 cells from Experimental example (1);
a bright field image of the cell and a 488nm excited green light image are sequentially formed from left to right; synthetic diagrams of bright and fluorescent fields;
FIG. 5 is an image of a confocal laser microscopy of HepG2 cells from Experimental example (2);
from left to right, a bright field image of the cell, a 488nm excited green light image, a 488nm excited red fluorescence image, a bright field and fluorescence field synthesis image are sequentially shown;
FIG. 6 is an image of a confocal laser scanning microscope of zebra fish according to example (3);
from left to right, a light field imaging graph of the zebra fish, a 488nm excited green light imaging graph, a 488nm excited red fluorescence imaging graph and a synthesis graph of a light field and a fluorescence field are sequentially shown.
Detailed Description
The invention is further described with reference to the following examples.
Example 1
Embodiments of the present invention relate to a bioactive oxygen-responsive hydrogen sulfide donor having the following structural formula:
wherein R is n-butyl;
the hydrogen sulfide donor is synthesized by the following steps:
s1, the compound (1) and equimolar n-butylamine are mixed in an ethanol solution, heated, boiled and refluxed for 10 hours, and a solid is filtered after cooling to obtain a compound (2);
wherein the mixing ratio of the compound (1) to the ethanol solution is 30-40 ml/g;
s2, adding the compound (2) into an ethanol solution, fully stirring to obtain a suspension, adding 0.01-0.05 times of palladium-carbon in the molar weight of the compound (2), introducing hydrogen at room temperature to react for 3 hours, performing suction filtration by using kieselguhr to obtain a clear solution, and performing reduced pressure drying to obtain a compound (3);
wherein the mixing ratio of the compound (2) to the ethanol solution is 30-40 ml/g;
s3, dissolving the compound (3) in dry dichloromethane, adding solid sodium bicarbonate with the molar amount equal to that of the compound (3), dropwise adding thiophosgene with the molar amount 1.5 times that of the compound (3) under the condition of ice-water bath while stirring, reacting for 3h, then spin-drying the liquid, and separating by a 300-400-mesh silica gel chromatographic column to obtain the compound (4), wherein the eluent is 100: 1, a mixed solution of dichloromethane and ethanol;
s4, mixing equimolar amounts of the compound (4), the compound (5) and sodium hydride in dry tetrahydrofuran, reacting for 6h at room temperature, then spin-drying the liquid, and separating by using a 300-400-mesh silica gel chromatographic column to obtain the compound (6), wherein the eluent is a mixture of the following components in a volume ratio of 80: 1, a mixed solution of dichloromethane and methanol;
the compound (1) is easy to obtain and relatively cheap, and meanwhile, the nitro group is easy to directly reduce, the compound (1) is used as an initiator, so that the raw materials are easy to obtain, the length of the synthesis step can be taken into consideration, and the synthesis economy of the hydrogen sulfide donor is improved.
Examples of the experiments
(1) mu.M of the hydrogen sulfide donor described in example 1 was added to HepG2 cells, incubated for 15min, washed, and 50. mu.M of H was added2O2After stimulating for 10min, washing, and observing by laser confocal microscope imaging to observe green fluorescence signal generated in cells.
(2) HepG2 cells were supplemented with 5. mu.M of the hydrogen sulfide donor described in example 1 and H2S Probe, after 15min incubation, washedAdding 50 μ M of H2O2After stimulation for 10min, cleaning, observing by using a laser confocal microscope, and observing that the green fluorescence and the red fluorescence generated in the cell are highly coincided, thereby proving that the hydrogen sulfide donor can be formed by H in the cell2O2Stimulation of H2S；
Said H2The S probe is a red fluorescent probe, and is specifically referred to Yi Zheng, et al, early-associated fluorescent probe for hydrogen sulfite in living cells, dyes and primers, 98(2013), 367 and 371.
(3) The zebrafish roe verification model was created by stimulating 24H zebrafish roe with 2 μ g/ml lipopolysaccharide (lps), and 5 μ M hydrogen sulfide donor, H as described in example 1, was added 72H after spawning was completed2The S probe (same as Experimental example 2) was co-cultured in 72H of zebrafish juvenile fish for 15min with 50. mu.M of H2O2After the stimulation is carried out for 15min, the high coincidence of the green fluorescence and the red fluorescence generated in the zebra fish body can be observed by utilizing the imaging observation of a laser confocal microscope, and the result proves that the hydrogen sulfide donor can be expressed by H in a living model2O2Stimulation of H2S。
The hydrogen sulfide donor can release hydrogen sulfide gas under the stimulation of biological endogenous hydrogen peroxide, simultaneously generates green fluorescence signal response, can carry out in-situ tracing on the release of the hydrogen sulfide, and can be used as the basis of the hydrogen sulfide release kinetics; meanwhile, the fluorescence signal represents the existence of bioactive oxygen hydrogen peroxide, so the hydrogen sulfide donor can also be used as a hydrogen peroxide fluorescent probe in a cell.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (7)
1. A bioactive oxygen-responsive hydrogen sulfide donor having the formula:
wherein R is alkyl, hydroxyalkyl or carboxyalkyl having 1 to 4 carbon atoms.
2. The bioactive oxygen-responsive hydrogen sulfide donor of claim 1, wherein R is n-butyl.
3. The method of claim 2, wherein the method comprises the steps of:
s1, the compound (1) and equimolar n-butylamine are mixed in an ethanol solution, heated and refluxed for 10 hours, and after cooling, a solid is filtered out to obtain a compound (2);
s2, adding the compound (2) into an ethanol solution, fully stirring to obtain a suspension, adding 0.01-0.05 times of palladium-carbon in the molar weight of the compound (2), introducing hydrogen at room temperature to react for 3 hours, performing suction filtration by using kieselguhr to obtain a clear solution, and performing reduced pressure drying to obtain a compound (3);
s3, dissolving the compound (3) in dry dichloromethane, adding solid sodium bicarbonate with the molar amount equal to that of the compound (3), dropwise adding thiophosgene with the molar amount 1.5 times that of the compound (3) under the condition of ice-water bath while stirring, reacting for 3 hours, then spin-drying the liquid, and obtaining the compound (4) through column chromatography separation;
s4, mixing equimolar compounds (4) and (5) with sodium hydride in dry tetrahydrofuran, reacting at room temperature for 6h, spin-drying the liquid, and separating by column chromatography to obtain a compound (6);
the structural formulae of the compounds (1) to (6) are as follows:
4. the method as claimed in claim 3, wherein the step S3 is performed by column chromatography using eluent with a volume ratio of 100: 1, a mixed solution of dichloromethane and ethanol; the eluent for column chromatography separation in the step S4 is a mixture of eluent with the volume ratio of 80: 1 of a mixed solution of dichloromethane and methanol.
5. Use of a biologically active oxygen-responsive hydrogen sulfide donor according to claim 1 in the preparation of a medicament for the sustained or controlled release of hydrogen sulfide in vitro or in vivo.
6. Use of the bioactive oxygen-responsive hydrogen sulfide donor of claim 1 in the preparation of a medicament for fluorescence visualization of hydrogen sulfide production in vitro or in vivo.
7. Use of the bioactive oxygen-responsive hydrogen sulfide donor of claim 1 as a hydrogen peroxide fluorescent probe in vitro or in vivo.
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