CN112661740B - Light-responsive donor molecule capable of cooperatively releasing carbon monoxide and nitric oxide and derivatives, preparation method and application thereof - Google Patents
Light-responsive donor molecule capable of cooperatively releasing carbon monoxide and nitric oxide and derivatives, preparation method and application thereof Download PDFInfo
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- CN112661740B CN112661740B CN202011593036.7A CN202011593036A CN112661740B CN 112661740 B CN112661740 B CN 112661740B CN 202011593036 A CN202011593036 A CN 202011593036A CN 112661740 B CN112661740 B CN 112661740B
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- nitric oxide
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title claims abstract description 130
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 229910002091 carbon monoxide Inorganic materials 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims description 22
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- 229940002612 prodrug Drugs 0.000 claims abstract description 20
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- 229940079593 drug Drugs 0.000 claims abstract description 7
- 229920000642 polymer Polymers 0.000 claims description 43
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 28
- 239000001301 oxygen Substances 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 21
- 239000007789 gas Substances 0.000 claims description 17
- 239000000178 monomer Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 4
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002262 Schiff base Substances 0.000 claims description 3
- 150000004753 Schiff bases Chemical class 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 claims description 3
- 230000009935 nitrosation Effects 0.000 claims description 3
- 238000007034 nitrosation reaction Methods 0.000 claims description 3
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 239000002840 nitric oxide donor Substances 0.000 abstract description 5
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- 238000005286 illumination Methods 0.000 description 24
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 16
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
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- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical group C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 8
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- 235000001671 coumarin Nutrition 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
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- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000693 micelle Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
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- 238000006116 polymerization reaction Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
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- MUMXDRRTIYLYMY-YJKCNMNRSA-N (Z)-[dodecyl-[6-(dodecylazaniumyl)hexyl]amino]-oxido-oxidoiminoazanium Chemical compound CCCCCCCCCCCC[NH2+]CCCCCCN(CCCCCCCCCCCC)[N+](\[O-])=N\[O-] MUMXDRRTIYLYMY-YJKCNMNRSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
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- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 2
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- HXBMIQJOSHZCFX-UHFFFAOYSA-N 1-(bromomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CBr HXBMIQJOSHZCFX-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- ZFHUHPNDGVGXMS-UHFFFAOYSA-N 4-(hydroxymethyl)benzaldehyde Chemical compound OCC1=CC=C(C=O)C=C1 ZFHUHPNDGVGXMS-UHFFFAOYSA-N 0.000 description 1
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- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 1
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- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 1
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention provides a donor molecule capable of cooperatively releasing carbon monoxide and nitric oxide in a light response mode, which has a structure shown in a formula (I). The carbon monoxide and nitric oxide donor molecule shown in the structure of the formula (I) can sensitively and rapidly release carbon monoxide and nitric oxide under low-intensity visible light response, can be further prepared into high-molecular prodrugs, can be assembled to obtain high-performance high-molecular drugs, and can kill gram-positive bacteria with high efficiency. The structural molecule does not relate to components with great harm to human bodies, such as metal ions, and the like, is completely dispersed and stable in aqueous solution, and has wide application prospect.
Description
Technical Field
The invention relates to the field of signal molecule carrier preparation and polymer polymerization precursor materials, in particular to a donor molecule for cooperatively releasing carbon monoxide and nitric oxide by light response, a derivative thereof, a preparation method and application thereof.
Background
Carbon monoxide (CO) has long been considered a toxic gas, and its knowledge is that competing with oxygen for hemoglobin causes hypoxia in the body, ultimately leading to asphyxia death. However, in recent years, carbon monoxide, similar to nitric oxide and hydrogen sulfide, is a gas signal molecule and plays an important role in signal transmission. The carbon monoxide produced in human body mainly comprises heme to generate biliverdin under the action of heme oxygenase, and ferrous ions and carbon monoxide are released. Carbon monoxide generally acts as a messenger molecule and has many physiological functions, such as anti-inflammatory, vasodilation, wound repair, etc. In addition, carbon monoxide at a slightly higher concentration (μm) can inhibit bacterial growth while killing bacteria, but because of its high toxicity, it is unsuitable for treatment as a gas inhalation, and various carbon monoxide releasing molecules have been developed that can release carbon monoxide under the triggering of different stimulation signals. The existing carbon monoxide release donors comprise metal coordination compounds, cyclohexamethylenetetramine carboxyborane, 3-hydroxyflavone derivatives and the like. The metal complex has the defects that the biocompatibility is poor, the release is uncontrollable and the metal complex is released immediately in water environment due to metal ions. While the cyclohexamethylenetetramine carboxyborane can generate hydrogen while releasing carbon monoxide, which can have adverse effects on the release of CO by organisms. The 3-hydroxyflavone derivative can realize the controllable release of light irradiation, has fluorescent property and can image at the cell level, but the 3-hydroxyflavone derivative also has the defects of poor solubility and the like, and a novel carbon monoxide donor needs to be developed so as to realize the controllable release, have good biocompatibility and can be applied to the biomedical field.
Nitric oxide is the first gas signaling molecule discovered first, and is recognized as an important gas signaling molecule in the cardiovascular and central nervous system, with many physiological roles including in platelet aggregation and adhesion, vasodilation, wound repair, immune response, and cancerous changes. Research shows that low concentration of nitric oxide can reverse the multidrug resistance of tumor or bacteria, and high concentration of nitric oxide can kill cancer cells or bacteria directly. NO is used as a signal molecule in a human body and can be generated endogenously in the human body. Nitric oxide synthase (Nitric Oxide Synthase, NOS) is present in vascular endothelial cells, and NOS is a family of proteases, mainly including neural nitric oxide synthase, inducible nitric oxide synthase and endothelial nitric oxide synthase. Endogenous NO is mainly derived from L-arginine, and under certain conditions, NOS can decompose L-arginine into NO and L-citrulline. Because NO is gas under room temperature, is easily oxidized in the air, and accurate control of the administration concentration and dosage is inconvenient for clinical operation, the application in clinic is greatly limited. The current clinical treatment of neonatal persistent pulmonary hypertension by inhalation of NO requires the use of a special flow control device. Typical NO donors include nitro compounds (e.g., nitroglycerin), metal nitrosyl complexes (e.g., sodium nitroprusside), diazeniumdiolate (NONOates), and sulfur nitrosyl compounds (RSNO), among others. These donor molecules are generally difficult to synthesize and purify and are stable in physiological environmentsInsufficient qualitative and uncontrollable release. For example, conventional diazeniumdiolate (DEA. NONOate) is prepared synthetically by long-term reaction (-3 days) under high pressure (5-10 atm) and strong alkali condition, and has a half-life of about 2.1min for spontaneous NO release under physiological condition; a large amount of byproducts are generated in the synthesis reaction process of the sulfur nitrosyl compound (RSNO), and the separation and the purification are difficult; and in mercapto group, transition metal ion (Cu + ) NO can be released under the conditions of illumination, etc. Therefore, the development of a novel nitric oxide prodrug release donor which can be precisely and controllably released and has good biocompatibility has important significance.
The photoresponse has the excellent characteristic of serving as a trigger release condition, and a molecule of flavone derivative can release a molecule of carbon monoxide under illumination; and N-N bond homolytic cleavage can be generated by the nitrosamine under low light intensity irradiation, and a molecule of nitric oxide free radical is released. Based on the above, nitric oxide and carbon monoxide release is made controllable. It is therefore of great importance to develop a donor with fluorescent properties that is capable of light-responsive co-release of nitric oxide and carbon monoxide.
Disclosure of Invention
In view of the above, the present invention aims to provide a donor molecule and its derivative capable of cooperatively releasing carbon monoxide and nitric oxide in a light response manner, a preparation method and an application thereof, and the obtained flavone derivative can cooperatively release carbon monoxide and nitric oxide at a low irradiation intensity, and the release process is accompanied with obvious fluorescence change, so that the flavone derivative can be used for biological imaging and monitoring in vivo release conditions.
In order to achieve the above object, the present invention provides a donor molecule for cooperatively releasing carbon monoxide and nitric oxide in a light response manner, which has a structure shown in formula (I):
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 The primitive is protected for light response.
Preferably, the R 1 Selected from the formula (R) 1 -1) to formula (R) 1 -14) any one of the structures:
wherein ,meaning attached to the nitrogen element and meaning attached to the methylene group.
Preferably, the R 2 Selected from (R) 2 -a), formula (R 2 -b)、(R 2 -c)、(R 2 -any one of the structures of d):
preferably, the donor molecule has any one structure of the formulas (I-1) to (I-7):
the invention provides a preparation method of the donor molecule, which comprises the following steps:
combining compound II with R 1 -NH 2 Reacting to generate Schiff base, reducing and nitrosation, and then reacting with methyl propylAlkene acyl chloride reacts to obtain a structure shown in a formula (I),
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 The primitive is protected for light response.
The invention provides an amphipathic prodrug polymer with fluorescent property for cooperatively releasing carbon monoxide and nitric oxide, which has a structure shown in a formula (III):
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 Protecting the primitive for light response;
n is 1-30;
said n 1 30 to 70.
The invention provides a preparation method of the amphipathic prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide, which comprises the following steps:
mixing a compound with a structure shown in a formula (IV) and a monomer molecule with a fluorescent property, wherein the monomer molecule is used for cooperatively releasing carbon monoxide and nitric oxide through a light response with a fluorescent property, and reacting in the presence of an initiator AIBN to obtain an amphiphilic carbon monoxide and nitric oxide prodrug polymer with a structure shown in a formula (III);
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 The primitive is protected for light response.
N is 1-30;
said n 1 30 to 70.
The invention provides an assembly, which is prepared from the amphipathic prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide by photo-response or prepared by the preparation method.
The invention provides application of the assembly as a signal molecule gas carrier in preparing high molecular medicines.
The invention provides application of the assembly as a signal molecule gas carrier in preparation of a medicament for killing gram-positive bacteria.
Compared with the prior art, the invention provides a donor molecule for cooperatively releasing carbon monoxide and nitric oxide in a light response manner, which has a structure shown in a formula (I). The carbon monoxide and nitric oxide donor molecule shown in the structure of the formula (I) can sensitively and rapidly release carbon monoxide and nitric oxide under low-intensity visible light response, can be further prepared into high-molecular prodrugs, can be assembled to obtain high-performance high-molecular drugs, and can kill gram-positive bacteria with high efficiency. The structural molecule does not relate to components with great harm to human bodies, such as metal ions, and the like, is completely dispersed and stable in aqueous solution, and has wide application prospect.
It should be noted that, in the prior art, there is no donor capable of cooperatively releasing carbon monoxide and nitric oxide in the field of releasing gas signal molecules, and the donor is capable of simultaneously releasing carbon monoxide and nitric oxide under irradiation of a light source with low intensity. The donor molecule provided by the invention has multiple functions, can cooperatively release two signal molecules and simultaneously has fluorescence change, and can generate strong red fluorescence under illumination, and the red fluorescence disappears after the gas molecules are released. The donor molecule can be used for preparing a polymer capable of releasing carbon monoxide and nitric oxide under the triggering of visible light through controllable polymerization, so that the stability of NO is improved, and the safety problem caused by premature release of NO is avoided.
Drawings
FIG. 1 shows the nuclear magnetic hydrogen and nuclear magnetic carbon spectra of the NCORM monomer obtained in example 1 of the present invention;
FIG. 2 is a high resolution mass spectrum and a high performance liquid chromatography of the NCORM monomer obtained in example 1 of the present invention;
FIG. 3 is an amphiphilic block polymer BP (PEG) obtained in example 1 of the present invention 45 -b-PCNORM 9 ) Nuclear magnetic resonance and gel chromatography curves of (2);
FIG. 4 BP (PEG) of example 1 of the present invention 45 -b-PCNORM 9 ) TEM photographs of micelle nano particles obtained by polymer self-assembly;
FIG. 5 shows BP (PEG) as provided in example 1 of the present invention 45 -b-PCNORM 9 ) Fluorescence change curve of the polymer prepared nano particles under 410nm illumination;
FIG. 6 shows BP (PEG) of example 3 of the present invention 45 -b-PCNORM 9 ) A curve of quantitative analysis of carbon monoxide release of polymer micelle nanoparticles in pure water and phosphate buffer under 410nm light;
FIG. 7 shows BP (PEG) of example 4 of the present invention 45 -b-PCNORM 9 ) A curve of quantitative analysis of nitric oxide release of the polymer micelle nanoparticles under 410nm light;
FIG. 8 shows BP (PEG) of example 2 of the present invention 45 -b-PCNORM 9 ) Detecting and quantifying states of nitric oxide and carbon monoxide released by the polymer micelle nano particles under different illumination conditions;
FIG. 9 shows BP (PEG) of example 2 of the present invention 45 -b-PCNORM 9 ) Histogram of polymer micelle nanoparticles killing gram positive bacteria, staphylococcus aureus, under 410nm light.
Detailed Description
The invention provides a donor molecule for cooperatively releasing carbon monoxide and nitric oxide in a light response manner, which has a structure shown in a formula (I):
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 The primitive is protected for light response.
According to the invention, X is preferably an oxygen element or a nitrogen element; the Y is preferably an oxygen element or a sulfur element.
According to the invention, said R 1 Selected from the formula (R) 1 -1) to formula (R) 1 -14) any one of the structures:
wherein ,meaning attached to the nitrogen element and meaning attached to the methylene group.
In the present invention,and represents the connection position; a single bond represents a methyl group.
According to the invention, said R 2 More specifically selected from (R 2 -a), formula (R 2 -b)、(R 2 -c)、(R 2 -any one of the structures of d):
in the invention, the light response synergistic release carbon monoxide and nitric oxide donor molecule with fluorescent property has any one structure of the formulas (I-1) to (I-7):
the invention provides a preparation method of the light-responsive co-release carbon monoxide and nitric oxide donor molecule with fluorescence property, which comprises the following steps:
combining compound II with R 1 -NH 2 Reacting to generate Schiff base, reacting with methacryloyl chloride after reduction and nitrosation steps to obtain a structure shown in formula (I),
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 The primitive is protected for light response.
Said X, Y, R 1 、R 2 The ranges of (2) are the same and are not described in detail herein.
The conditions of the above reaction are not particularly limited, and the reaction may be carried out by simple mixing, and a person skilled in the art may select an appropriate preparation process according to common general knowledge in the art.
The invention also provides an amphipathic light response prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide, which has a structure shown in a formula (III):
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 Protecting the primitive for light response;
n is 1-30;
said n 1 30 to 70.
Said X, Y, R 1 、R 2 The ranges of (2) are the same and are not described in detail herein.
The number n is preferably 5 to 20, more preferably 5 to 15.
Said n 1 Preferably is45 to 60, more preferably 50 to 55.
The invention provides a preparation method of the amphipathic prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide, which comprises the following steps:
mixing a compound with a structure shown in a formula (IV) and a monomer molecule with a fluorescent property, wherein the monomer molecule is used for cooperatively releasing carbon monoxide and nitric oxide through a light response with a fluorescent property, and reacting in the presence of an initiator AIBN to obtain an amphiphilic carbon monoxide and nitric oxide prodrug polymer with a structure shown in a formula (III);
wherein, X is oxygen element or nitrogen element;
y is oxygen or sulfur;
the R is 1 Is a substituted or unsubstituted phenylene, coumarin, benzofurazan group;
the substituent groups of the phenylene, coumarin and benzofurazan groups are selected from one or more of nitro and trifluoromethyl;
the R is 2 The primitive is protected for light response.
N is 1-30;
said n 1 30 to 70.
Said X, Y, R 1 、R 2 、n、n 1 The ranges of (2) are the same and are not described in detail herein.
The preparation method of the amphiphilic prodrug polymer capable of cooperatively releasing carbon monoxide and nitric oxide through light response with fluorescent property is not limited to reversible addition-fragmentation chain transfer polymerization (RAFT), and other suitable synthesis methods known to those skilled in the art can be used to obtain the structure disclosed by the invention.
Furthermore, the amphiphilic block polymer can form a nano assembly, and the polymer assembly can release nitric oxide and nitric oxide under the irradiation of 410nm visible light, compared with small molecules, the stability of NO is improved, the problem of safety caused by premature release of NO is avoided, and the NO can not be metabolized in a short time.
Based on the above, the invention provides an assembly, which is prepared from the amphipathic prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide by photo-response or the amphipathic prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide by self-assembly.
The method of self-assembly is not particularly limited, and may be a self-assembly method known to those skilled in the art. The embodiment of the invention adopts a cosolvent and then is assembled by slowly adding water, wherein the cosolvent comprises one or more of dimethyl sulfoxide, N-dimethylformamide, 1, 4-dioxane, tetrahydrofuran and the like as the cosolvent, so that a stable nanoscale polymer assembly can be obtained.
Specifically, the amphiphilic block polymer is dissolved in an organic solvent as a cosolvent, added into purified water (such as ultrapure water) under certain temperature and stirring conditions, and then removed by dialysis at certain temperature; specifically, the obtained polymer nano particles are placed in a dialysis bag at a certain temperature to dialyze and remove the organic solvent, so as to obtain the polymer nano particle aqueous dispersion.
According to the invention, the carbon monoxide and the nitric oxide can be controllably and accurately released in the water phase through selecting the amphipathic polymer with fluorescence property, wherein the amphipathic polymer is prepared by selecting proper structure and functional group and is capable of cooperatively releasing carbon monoxide and nitric oxide. The specific implementation method is that after stable nanoparticle dispersion liquid is obtained, a detection instrument or a detection reagent is used for testing the molecular quantification result of nitric oxide and carbon monoxide released from the assembled nanoparticle dispersion liquid under the illumination of 410 nm. In addition, under the illumination of 410nm, the fluorescence change of the test sample is sampled at different times, and meanwhile, the macroscopic fluorescence change of the nanoparticle dispersion liquid can be observed.
The self-assembled assembly can be used as a drug carrier and has good effect as a drug for killing gram-positive bacteria.
Based on the above, the invention provides the application of the assembly as a signal molecule gas carrier in the preparation of high polymer medicines.
The invention also provides application of the assembly as a signal molecule gas carrier in preparing medicines for killing gram-positive bacteria.
The technical solutions of the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments, but not all embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In order to further understand the light-responsive co-releasing carbon monoxide and nitric oxide donor molecules and derivatives thereof, as well as methods of preparation and use, described herein, reference will be made in detail to examples.
Example 1
1-1) synthetic light response synergistic release of nitric oxide and carbon monoxide donor molecules (R) 1 Is phenylene, R 2 Is O-nitrobenzyl, X is O, Y is O, and the left side is naphthalene ring structure)
The preparation method comprises the following steps: 1 (1 g,5.37 mmol) was weighed, 15mL of ethanol was added to form a suspension, aqueous sodium hydroxide solution (5.4 mL, 5M) was added, stirring was performed at room temperature for 30min, p-hydroxymethylbenzaldehyde (748 mg,5.5 mmol) was added to the reaction flask, stirring was performed at room temperature for 5h, after the reaction was completed, 2mL of 30% hydrogen peroxide was added dropwise to the reaction flask, the reaction was performed overnight, the pH was acidified to 6.5 with 0.5M HCl to form a yellow precipitate, and the product was obtained by suction filtration; the product (288 mg,1 mmol), potassium carbonate (140 mg,1.0 mmol), o-nitrobenzyl bromide (258 mg,1.2 mmol) were weighed and dissolved in 10mL DMF, the mixture was stirred at room temperature for 12h, after the reaction was completed, precipitated in water, and the product was obtained by suction filtration; weighing the product of the last step (457 mg,1 mmol) and pyridinium chlorochromate (620 mg,1.2 mmol), adding 55mL of anhydrous dichloromethane, dissolving and clarifying, reacting overnight at room temperature, filtering, washing with water for three times, and recrystallizing to obtain a yellow product; the aldehyde product (450 mg,1 mmol) obtained in the previous step is weighed, THF (20 mL) is added, ethanol (15 mL) is dissolved and clarified, p-aminobenzyl alcohol (563 mg,3.68 mmol) is added, the reaction is carried out at room temperature overnight, solid is separated out, the reaction solution is filtered to obtain 300mg of filter cake, the filter cake is dissolved in dichloromethane, 266mg of cyano sodium borohydride is added, the reaction solution is subjected to rotary evaporation for 2h to remove the solvent, THF (10 mL) is added for dissolution, 5mL of glacial acetic acid is added, 55mg of sodium nitrite is further added, the reaction is carried out overnight, and column chromatography is carried out to obtain a yellow product. The precursor product (293 mg,0.5 mmol) was weighed and dissolved in 30mL of anhydrous dichloromethane, anhydrous triethylamine (100 mg,1 mmol) was added, methacryloyl chloride (105 mg,1 mmol) was added, reacted at room temperature for 6h, and water-washed column chromatography gave 325mg of yellow solid.
The nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the obtained structure of the donor molecule NCORM for cooperatively releasing nitric oxide and carbon monoxide through the light response are represented as a result shown in a figure 1, wherein the upper graph is a hydrogen spectrum, and the lower graph is a carbon spectrum. Meanwhile, the obtained donor molecule NCORM is further characterized, and the result is shown in fig. 2, wherein the upper graph is a high-resolution mass spectrogram, and the lower graph is a high-performance liquid chromatogram. Fig. 1 and fig. 2 are a nuclear magnetic hydrogen spectrum, a carbon spectrum, a high resolution mass spectrum and a high performance liquid chromatogram of the light response co-release nitric oxide and carbon monoxide monomer molecules obtained in example 1 of the present invention. From the results, it can be seen that the molecular structure and purity of the obtained monomer are in accordance with the expected design.
1-2) Synthesis of prodrug Block Polymer BP with fluorescent Properties capable of light-responsive synergistic nitric oxide and carbon monoxide Release
Reaction characteristics: the photo-responsive co-releasing nitric oxide and carbon monoxide prodrug block polymer PCNORM is obtained by a reversible addition-fragmentation chain transfer polymerization (RAFT) method by adding PEO macroRAFT agent and the monomer with fluorescent property capable of photo-responsive co-releasing nitric oxide and carbon monoxide motifs. The degree of polymerization n of the hydrophobic segment can be effectively changed by changing the polymerization parameters and conditions, and preferably n=5 to 20. Those skilled in the art will appreciate that the degree of polymerization n is not critical to the present invention, so long as it has no detrimental effect on the present invention. In order to more clearly aid understanding, the following description will be given by taking a polymer with n=9 as an example.
The preparation method comprises the following steps: 300mg of NCORM monomer (0.4575 mmol), 103mg PEO macroRAFT agent ((0.1 mmol; synthetic method: macromolecules,2008,41,12) and 16.53mg of AIBN (0.045 mmol) were added to a lock tube, dissolved in 2mL of DMSO, fully degassed, finally degassed once, lock tube, placed in an oil bath at 70 ℃ C., polymerization was terminated after 10 hours, a small amount of methylene chloride was added to the resulting polymer solution, precipitated in dehydrated ether, repeated three times of precipitation, and dried in a vacuum oven to obtain a yellowish polymer BP 217mg (yield: 53.8%).
The structure of the obtained polymer BP is characterized by nuclear magnetic resonance hydrogen spectrum and GPC, and the result is shown in figure 3, wherein the upper graph is nuclear magnetic resonance hydrogen spectrum, and the lower graph is gel chromatographic curve. From the figures, it can be seen that the synthetic polymers of the present invention are as expected.
Example 2
The self-assembly preparation of the nano material is specifically described as follows:
1mg of BP polymer was dissolved in 1mL of N, N-dimethylformamide co-solvent, 9mL of ultrapure water was added thereto at a rate of 0.9mL/h under stirring at room temperature of 500r/min, and the resulting whitish suspension was placed in a MW14000 dialysis bag, dialyzed against ultrapure water, and the organic solvent was removed after dialysis for 12 hours. To obtain the nano-assembly.
The resulting nanomaterial assembly was tested and the test results are shown in fig. 4. Fig. 4 is a TEM image of the nanomaterial obtained in example 2, and it can be seen from the figure that the nanomaterial obtained is a micelle of about 200 nm.
Application example 1
Monitoring of the change in fluorescence properties of an assembly under 410nm illumination
Taking 2mL of the assembly aqueous solution, sampling at different times under the illumination of 410nm in a fluorescence cuvette with an optical path of 1cm, monitoring the fluorescence change of the nano material, adopting 405nm for excitation wavelength, and collecting fluorescence in the wavelength range of 415nm to 800 nm. While the fluorescence properties of the assembly are visually altered. The test results are shown in fig. 5, wherein the left graph is a fluorescence emission change graph of 5s before illumination, and the right graph is a fluorescence emission change graph of 5s after illumination.
From FIG. 5, it is possible to observe a clear change in fluorescence properties, in which the red fluorescence at 610nm is rapidly increased at the initial stage of illumination, while illumination is continued, the flavone structure is changed, carbon monoxide is released, and the red fluorescence is seen to disappear. The phenomenon is that the o-nitrobenzaldehyde serving as a light response protecting group falls off to expose hydroxyl, so that flavone generates ESIPT effect and generates strong red fluorescence. When one molecule of CO is released under the action of oxygen, the structure of flavone is changed, ESIPT effect disappears, and red fluorescence gradually disappears.
Application example 2
Light emission of carbon monoxide
The release of nanoparticles provided by example 2 in different solutions under quantitative 410nm illumination was detected using a degel gas detector. Specifically, 10mL of the assembly water dispersion solution and pH7.4 phosphate buffer dispersion solution were stirred and subjected to 410nm LED lamp illumination (28.1 mW/cm 2 ) The carbon monoxide release was quantified in a closed environment. The quantitative results are shown in FIG. 6, and it can be observed that only instrument readings fluctuate under dark conditions, and almost no carbon monoxide leaks, and the final release concentration is above 200 nmol/mg.
Application example 3
Light-emitting nitric oxide release
Nitric oxide release was quantified using Griess reagent. With a 410nm LED lamp (28.1 mW/cm) 2 ) The nano-assemblies obtained in example 2 were each irradiated with light. Specifically, the assembly body with different illumination times is taken to be mixed with the Griess reagent with equal volume, after the incubation for 10min in dark, the ultraviolet absorption spectrum is tested, and the content of nitric oxide release is quantified through the absorbance at 550 nm.
The result is shown in fig. 7, and fig. 7 is a graph of quantitative analysis of nitric oxide release under the condition of visible light illumination of micelle nanoparticles obtained by self-assembly of polymer BP; as can be seen from the figure, the nitric oxide release amount tended to be stable when the nano-assembly was illuminated for 60min, and the assembly released 32.8% of nitric oxide.
Application example 4
Nitric oxide release compared with carbon monoxide release under different illumination intensities
And detecting the quantitative condition of the quantitative assembly nanoparticle solution releasing nitric oxide and carbon monoxide by changing the illumination intensity from weak to strong under the illumination condition of 410 nm. The quantitative results are shown in FIG. 8, wherein the left graph shows the graph of carbon monoxide release as a function of illumination intensity, and the right graph shows the graph of nitric oxide release as a function of illumination intensity. As can be seen from the graph, the release amount of nitric oxide and carbon monoxide increases with the increase of illumination intensity, which indicates that the release behavior of two gas molecules is intensity dependent, and the more the energy of the received photons is, the more thorough the photochemical reaction occurs, so the more the release amount is.
Application example 5
Killing staphylococcus aureus, gram positive bacteria under illumination condition of assembly
Specifically, colonies on solid agar plates were cultured for 16-18 hours using 2.5mL of sterilized TSB broth, which was inoculated once, followed by 1:100, adding primary inoculation bacterial liquid into TSB liquid culture medium, culturing to logarithmic phase, centrifuging, washing and diluting to obtain final required bacterial concentration 5×10 5 CFU/mL. 100. Mu.L of each of the assembly solutions and 50. Mu.L of the bacterial liquid were added to a 96-well plate, and the mixture was irradiated with light at 410nm (28.1 mW/cm 2 15 min), culturing at 37 ℃ for 30min, diluting 100 times, taking 20 mu L for plating, culturing at 37 ℃ for 15h for colony counting, and obtaining a sterilization effect bar graph.
As shown in FIG. 9, it was found that 81% of the bacteria could be killed at 6.25. Mu.g/mL and more than 99% of the bacteria could be killed at 25. Mu.g/mL. From the results, the polymer nanoparticle assembly solution with fluorescent property and light response and co-release of carbon monoxide and nitric oxide can effectively kill gram-positive bacteria at a very low concentration. The polymer has wide application prospect in the aspect of antibiosis, and meanwhile, the gas signal molecules can kill bacteria and avoid the bacteria from generating drug resistance, thereby providing reliable and effective reference for the subsequent sterilization by using the gas signal molecules.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (9)
1. A donor molecule that is light responsive to co-release of carbon monoxide and nitric oxide, having the structure of formula (i):
wherein, X is oxygen element;
y is oxygen;
the R is 1 Is phenylene;
the R is 2 Is of the formula (R) 2 -a) a structure shown in:
2. the donor molecule of claim 1, wherein R 1 Selected from the formula (R) 1 -1) to formula (R) 1 -any one of the structures of 3):
wherein ,represents bonding to nitrogen, represents bonding to methylene。
3. The donor molecule of claim 1, having any of the structures of formulae (I-1) to (I-3):
4. a method of preparing a donor molecule according to any of claims 1 to 3, comprising the steps of:
combining compound II with R 1 -NH 2 Reacting to generate Schiff base, reacting with methacryloyl chloride after reduction and nitrosation steps to obtain a structure shown in formula (I),
wherein, X is oxygen element;
y is oxygen;
the R is 1 Is phenylene;
the R is 2 Is of the formula (R) 2 -a) a structure shown in:
5. an amphiphilic light-responsive prodrug polymer capable of cooperatively releasing carbon monoxide and nitric oxide with fluorescent property, which has a structure shown in a formula (III):
wherein, X is oxygen element;
y is oxygen;
the R is 1 Is phenylene;
the R is 2 Is of the formula (R) 2 -a) a structure shown in:
n is 1-30;
said n 1 30 to 70.
6. The method for preparing the amphiphilic prodrug polymer with fluorescent property and capable of cooperatively releasing carbon monoxide and nitric oxide through light response as claimed in claim 5, which comprises the following steps:
mixing a compound with a structure shown in a formula (IV) and a monomer molecule with a fluorescent property, wherein the monomer molecule is used for cooperatively releasing carbon monoxide and nitric oxide through a light response with a fluorescent property, and reacting in the presence of an initiator AIBN to obtain an amphiphilic carbon monoxide and nitric oxide prodrug polymer with a structure shown in a formula (III);
wherein, X is oxygen element;
y is oxygen;
the R is 1 Is phenylene;
the R is 2 Is of the formula (R) 2 -a) a structure shown in:
n is 1-30;
said n 1 30 to 70.
7. An assembly obtained by self-assembly from the amphiphilic prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide prepared by the preparation method of claim 5 or the amphiphilic prodrug polymer with fluorescence property for cooperatively releasing carbon monoxide and nitric oxide prepared by the preparation method of claim 6.
8. The use of the assembly of claim 7 as a carrier for signal molecule gases in the preparation of polymeric drugs.
9. Use of the assembly of claim 7 as a carrier for a signal molecule gas for the preparation of a medicament for killing gram positive bacteria.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016123141A1 (en) * | 2015-01-26 | 2016-08-04 | Berreau Lisa M | Carbon monoxide releasing molecules and associated methods |
| CN110128384A (en) * | 2019-06-19 | 2019-08-16 | 中国科学技术大学 | A kind of nitric oxide donors molecule of multifunctionality, polymer and its preparation method and application |
| CN110437150A (en) * | 2019-06-06 | 2019-11-12 | 中国科学技术大学 | Carbon monoxide donor molecule with photoluminescent property and its preparation method and application |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016123141A1 (en) * | 2015-01-26 | 2016-08-04 | Berreau Lisa M | Carbon monoxide releasing molecules and associated methods |
| CN110437150A (en) * | 2019-06-06 | 2019-11-12 | 中国科学技术大学 | Carbon monoxide donor molecule with photoluminescent property and its preparation method and application |
| CN110128384A (en) * | 2019-06-19 | 2019-08-16 | 中国科学技术大学 | A kind of nitric oxide donors molecule of multifunctionality, polymer and its preparation method and application |
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| Title |
|---|
| Lei Gao et al..Orchestrating Nitric Oxide and Carbon Monoxide Signaling Molecules for Synergistic Treatment of MRSA Infections.Angew. Chem. Int. Ed..2021,第61卷第1-9页. * |
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