CN111635389A - Hydrogen peroxide responsive compound for imaging and therapy and synthesis method thereof - Google Patents

Hydrogen peroxide responsive compound for imaging and therapy and synthesis method thereof Download PDF

Info

Publication number
CN111635389A
CN111635389A CN202010378023.1A CN202010378023A CN111635389A CN 111635389 A CN111635389 A CN 111635389A CN 202010378023 A CN202010378023 A CN 202010378023A CN 111635389 A CN111635389 A CN 111635389A
Authority
CN
China
Prior art keywords
hydrogen peroxide
compound
imaging
dichloromethane
responsive compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202010378023.1A
Other languages
Chinese (zh)
Other versions
CN111635389B (en
Inventor
张建祥
闫新豪
郭嘉伟
吴鹏
李兰兰
窦寅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Army Medical University
Original Assignee
Army Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Army Medical University filed Critical Army Medical University
Priority to CN202010378023.1A priority Critical patent/CN111635389B/en
Publication of CN111635389A publication Critical patent/CN111635389A/en
Application granted granted Critical
Publication of CN111635389B publication Critical patent/CN111635389B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
    • C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/36—Oxalic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/86—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Nanotechnology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a hydrogen peroxide responsive compound for imaging and therapy and a synthesis method thereof. The chemical structure of the responsive compound is shown in the following figure. The invention also provides a synthesis method of the hydrogen peroxide responsive compound, which comprises the following steps: reacting a monohydroxy compound with oxalyl chloride in an organic solvent containing an acid-binding agent to obtain the hydrogen peroxide responsive compound. The synthesis method of the responsive compound is simple and easy for large-scale synthesis; the nano particles can be prepared by different methods, and the auxiliary chemiluminescence property of the nano particles has hydrogen peroxide responsiveness; when the monohydroxy compound is a micromolecular drug, a hydrogen peroxide responsive prodrug can be obtained and used for preparing nano-drugs for treating inflammation, oxidative stress injury related diseases and hydrogen peroxide high-expression tumor prevention and treatment; the hydrogen peroxide responsive compound has good in-vivo safety.
Figure DDA0002480953080000011

Description

Hydrogen peroxide responsive compound for imaging and therapy and synthesis method thereof
Technical Field
The invention relates to the field of hydrogen peroxide responsive materials, in particular to a hydrogen peroxide responsive compound with auxiliary chemiluminescence imaging and treatment functions and a synthesis method thereof.
Background
When stimulated by growth factors or immune stimulation, cells produce endogenous hydrogen peroxide1. The hydrogen peroxide has lipophilicity, is easy to pass through cell membranes to realize intercellular diffusion, is used as a second chemical messenger in cells, and plays an important role in regulating physiological reactions such as cell proliferation, differentiation, migration and the like2-3. In addition, hydrogen peroxide is also involved in cellular redox signaling4Regulating the normal physiological functions of the body, and is closely related to the occurrence and development of various diseases, including angiogenesis, oxidative stress, aging, tumor and the like5. During the course of the disease, the expression and activity of hydrogen peroxide affect the pathophysiological changes of the disease, and therefore, studies on the diagnosis and treatment of diseases by means of hydrogen peroxide-responsive materials are receiving increasing attention6-11。
A peroxyoxalate ester chemiluminescence system is a chemiluminescence system mainly composed of diaryl oxalate, hydrogen peroxide, fluorescent agent and solvent12. The light-emitting mechanism is that chemical energy is transferred to fluorophore to transfer to excited state, and the excited state is transferred to ground state to emit light of certain wavelength13. The luminescent system is mainly applied in two aspects: detection application in analytical chemistry and development of chemical cold light source14. The peroxyoxalate ester compound is a small molecular substance sensitive to hydrogen peroxide, when the peroxyoxalate ester compound reacts with the hydrogen peroxide, an oxalate ester bond can be broken to generate intermediate and raw material molecules, and the intermediate can excite a dye to emit light for imaging15The responsiveness can be used for preparing a hydrogen peroxide responsive disease imaging diagnosis material or a hydrogen peroxide responsive drug release material16-18Thereby being applied to the treatment of inflammation, oxidative stress injury and tumor related diseases19-22. However, the in vivo safety of the products of hydrolysis of currently available peroxyoxalate compounds severely limits their use in disease imaging and therapy; meanwhile, the existing peroxy oxalate compounds can only be used for auxiliary chemiluminescence imaging and have no disease treatment function.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, it is a first object of the present invention to provide a hydrogen peroxide-responsive compound having a function of assisting in chemiluminescent imaging and therapy. Another object of the present invention is to provide a method for synthesizing the hydrogen peroxide-responsive compound.
In order to achieve the first object, the invention adopts the technical scheme that: a hydrogen peroxide responsive compound, the chemical structure general formula of which is as follows
Figure BDA0002480953060000021
Wherein:
Figure BDA0002480953060000022
in order to achieve the second object, the invention adopts the technical scheme that: the invention provides a synthesis method of a hydrogen peroxide responsive compound, which comprises the following steps: mixing a single hydroxyl compound and an acid-binding agent in an organic solvent, slowly dropwise adding oxalyl chloride into the solution under the ice bath condition under the protection of nitrogen, removing the ice bath after dropwise adding, reacting for 2-12h, adding methanol or ethanol after the raw materials completely react, and quenching the reaction to obtain a crude product of the hydrogen peroxide responsive compound.
In order to further purify the crude product to obtain a final product, the synthesis method of the invention further comprises the following steps: extracting the crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water, vacuum filtering, evaporating to remove dichloromethane, concentrating to obtain crude product, and separating and purifying with silica gel chromatographic column to obtain final product.
Further, the monohydroxy compound is selected from tocopherol, idebenone, camptothecin, zidovudine, 4-hydroxymethylphenylboronic acid pinacol ester, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine nitroxide, 3-methoxy-4-hydroxybenzaldehyde, 4-methoxymethylphenol, 4-ethoxymethylphenol, amyl salicylate, (E) -3, 5-dimethoxy-4' -hydroxystilbene or 2, 4-dinitrophenol.
Further, the acid-binding agent is selected from N, N-diisopropylethylamine or triethylamine.
Further, the organic solvent is dichloromethane.
Further, the concentration of the monohydroxy compound in the organic solvent is between 0.1mmol/ml and 0.4 mmol/ml.
Further, the molar ratio of the monohydroxy compound to the oxalyl chloride is between 1:0.5 and 1:1, and the molar ratio of the monohydroxy compound to the acid-binding agent is between 1:2 and 1: 5.
The technical scheme of the invention also comprises the application of the hydrogen peroxide responsive compound in preparing a medicament and/or an imaging probe for preventing and treating diseases related to inflammation and/or oxidative stress injury.
The inflammation includes allergic inflammation, non-specific inflammation, and infectious inflammation; the nonspecific inflammation comprises red swelling and pain caused by trauma or operation; infectious inflammation includes inflammation caused by bacteria, bacterial products or viruses; allergic inflammation includes inflammatory diseases such as peritonitis, inflammatory bowel disease, arthritis, asthma, atherosclerosis, and non-alcoholic fatty liver disease.
The oxidative stress injury comprises acute heart injury, acute lung injury, acute/chronic liver injury, acute/chronic kidney injury, and acute/chronic intestinal tract injury.
Wherein the hydrogen peroxide-responsive compound is administered by a route selected from the group consisting of oral, intravenous, subcutaneous, intramuscular, and any combination thereof.
By combining the technical scheme, the invention has the beneficial technical effects that:
(1) the responsive compound is simple and convenient in synthesis method, when the selected compound is the monohydroxy active compound, the reaction site is single, namely one equivalent of oxalyl chloride is combined with two equivalents of monohydroxy active compound, the target compound is obtained by room temperature reaction, the condition is mild, and the scale synthesis is easy.
(2) The responsive compounds have significant and sensitive hydrogen peroxide dependent hydrolysis characteristics.
(3) The responsive compounds can be hydrolyzed in the presence of physiological levels of reactive oxygen species to the corresponding starting compounds.
(4) The responsive compound can be prepared into hydrogen peroxide responsive nanoparticles by different methods, and can effectively load fluorescent dye, so that the luminescent imaging nanoprobes with different self-luminescent wavelengths can be conveniently obtained.
(5) The nanoparticles prepared from the responsive compound can effectively load hydrophobic nano-drugs and realize the responsive release of hydrogen peroxide loaded with the drugs.
(6) When the responsive compound is synthesized by selecting the hydroxyl-containing drug, the hydrogen peroxide responsive prodrug can be conveniently prepared, and hydrogen peroxide responsive prodrug nanoparticles are prepared by adopting different methods, so that hydrogen peroxide responsive activation and release of the corresponding drug are realized.
(7) The nanoparticles prepared from the responsive compound have good in-vivo safety.
(8) When the obtained responsive compound is a solid, recrystallization can be used for removing impurities in the purification process, so that the silica gel chromatographic column is not used for separation and purification, and the method is easy to realize industrial production.
Drawings
FIG. 1 is a reaction of tocopherol with hydrogen peroxide responsive tocopherol compounds in deuterated chloroform, obtained by reacting tocopherol with oxalyl chloride1And H NMR spectrum, and the structural correctness is confirmed according to the spectrum.
FIG. 2 is mass spectral data of a compound having a hydrogen peroxide-responsive tocopherol obtained by reacting tocopherol with oxalyl chloride.
FIG. 3 is a graph of light intensity measurements of 0.5mM hydrogen peroxide-responsive tocopherol compound and 0.5mM sulforhodamine 101 under stimulation with different concentrations of hydrogen peroxide; as can be seen, the luminous intensity increases as the hydrogen peroxide concentration increases.
FIG. 4 is a graph showing the luminous intensity test of 0.5mM hydrogen peroxide-responsive tocopherol compound and 0.5mM 1-chloro-9, 10-diphenylethynylanthracene under different concentrations of hydrogen peroxide, and it can be seen that the luminous intensity increases with increasing hydrogen peroxide concentration, and has concentration dependence.
Fig. 5 is a photograph of a sample, a particle size distribution diagram, and a transmission electron microscope photograph of nanoparticles prepared from the hydrogen peroxide-responsive tocopherol compound, the average particle size of which is 188 nm.
Fig. 6 is a graph showing that the sulforhodamine 101 nanoparticle encapsulated by the hydrogen peroxide-responsive tocopherol compound stimulates the light-responsive measurement to different types of active oxygen, and the nanoparticle has selective response to hydrogen peroxide.
Fig. 7 is an imaging diagram of a pore plate with the luminescent responsiveness of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles to hydrogen peroxide with different concentrations, and it can be seen from the graph that the luminescent intensity of the nanoparticles increases with the increase of the hydrogen peroxide concentration, and the nanoparticles have concentration dependence.
Fig. 8 is an imaging diagram of a pore plate of a hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle in mouse peritoneal neutrophils, wherein the luminous intensity of the nanoparticle is gradually enhanced along with the increase of the number of the neutrophils, and the imaging of the nanoparticle has neutrophil responsiveness.
FIG. 9 shows imaging functional verification of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles in thioglycollate-induced peritonitis in mice.
Fig. 10 shows imaging functional verification of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles in alcohol-induced liver injury in mice.
Fig. 11 is an imaging functional test of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles in subcutaneous tumors.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments. It is to be understood that the embodiments of the present invention are merely for illustrating the present invention and not for limiting the present invention, and that various substitutions and alterations made according to the common knowledge and conventional means in the art without departing from the technical idea of the present invention are included in the scope of the present invention.
Example 1
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials completely react to quench the reaction. The obtained crude product is extracted by a dichloromethane/water system for 3 times (namely 100mL of dichloromethane is used for dissolving the crude product, the crude product is transferred to a 250mL separating funnel, 15mL of distilled water is added for washing for 3 times), the solution in dichloromethane is collected, then saturated sodium chloride aqueous solution is used for extracting for 1 time, an organic phase is dried by anhydrous magnesium sulfate to remove excessive water in a sample, the organic phase obtained by suction filtration is removed by a rotary evaporator, and dichloromethane is concentrated to obtain the crude product. Concentrating the crude product, and subjecting to silica gel chromatographyThe product (M) was obtained by eluting with ethyl acetate/n-hexane (volume ratio 1/10)1)1.6 g, yield 86%.
Example 2
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of triethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 4mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the mixture reacts for 12 hours at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/10) to give the product (M)1)1.2 g, yield 66%.
Example 3
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 40mL of anhydrous dichloromethane, 3mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 3h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/10) to give the product (M)1)1.5 g, 83% yield.
Example 4
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 10mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dripped under the condition of ice bath, the ice bath is removed after the dripping is finished, the reaction is carried out for 2h at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and ethanol is added after the raw materials are completely reacted to quench the reaction. The crude product obtainedExtracting with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/10) to give the product (M)1)1.5 g, 83% yield.
Product M synthesized in examples 1-4 above1Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz，CDCl3)(ppm)2.64(t,J＝6.0Hz,4H,CH2),2.13(s,9H,CH3),2.08(s,9H,CH3),1.86-1.77(m,4H,CH2),1.62-1.49(m,8H,CH2),1.48-1.37(m,8H,CH2),1.34-1.17(m,24H),1.16-1.12(m,6H,CH2),1.11-1.05(m,6H,CH2),0.88(s,9H,CH3),0.86(s,9H,CH3),0.85(s,6H,CH3)；Ms(ESI)m/z:938.0[M+Na]+。
prepared M1The chemical structural formula is as follows:
Figure BDA0002480953060000061
example 5
Under the protection of nitrogen, 1mmol of idebenone and 2mmol of N, N-diisopropylethylamine are mixed in 5mL of anhydrous dichloromethane, 0.5mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 3h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)2)0.302 g, 83% yield. Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz，CDCl3)(ppm)4.27(t,J＝6.0Hz,2H,CH2),3.97(s,3H,CH3),2.44(t,J＝6.0Hz,2H,CH2),1.99(s,3H,CH3),1.72-1.70(t,J＝6.0Hz,2H,CH2),1.37-1.25(m,12H,CH2)；Ms(ESI)m/z:753.4[M+Na]+。
prepared M2The chemical structural formula is as follows:
Figure BDA0002480953060000062
example 6
Under the protection of nitrogen, 1mmol of camptothecin and 5mmol of N, N-diisopropylethylamine are mixed in 5mL of anhydrous dichloromethane, 0.5mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 4h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials are completely reacted to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)3)0.296 g, yield 79%. Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz，CDCl3)(ppm)8.66(s,1H,Ph),8.14(d,J＝12.0Hz,1H,Ph),8.10(d,J＝12.0Hz,1H,Ph),7.83(t,J＝6.0Hz,1H,Ph),7.69(t,J＝6.0Hz,1H,Ph),6.52(s,1H,Ph),5.39(s,2H,CH2),5.25(s,2H,CH2),1.87(m,2H,CH2),0.87(t,J＝6.0Hz,3H,CH3)；Ms(ESI)m/z:751.6[M+H]+。
prepared M3The chemical structural formula is as follows:
Figure BDA0002480953060000071
example 7
Under the protection of nitrogen, 1mmol of zidovudine and 4mmol of N, N-diAfter mixing isopropyl ethylamine in 5mL of anhydrous dichloromethane, slowly adding 0.5mmol of oxalyl chloride dropwise under the ice bath condition, removing the ice bath after the dropwise adding is finished, heating and refluxing at 40 ℃ for reaction for 4h, monitoring the reaction process by using a thin-layer chromatography plate, and adding methanol to quench the reaction after the raw materials completely react. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)4)0.212 g, yield 72%. Hydrogen nuclear magnetic resonance1H NMR data Ms (ESI) M/z 589.2[ M + H ]]+。
Prepared M4The chemical structural formula is as follows:
Figure BDA0002480953060000081
example 8
Under the protection of nitrogen, 4mmol of 4-hydroxymethylphenylboronic acid pinacol ester and 20mmol of N, N-diisopropylethylamine are mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped in the mixture under the condition of ice bath, the ice bath is removed after the dropping is finished, the mixture reacts for 2 hours at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)5)0.918 g, 88% yield. Hydrogen nuclear magnetic resonance1H NMR data:
1H NMR(600MHz，CDCl3)(ppm)7.92(d,J＝6.0Hz,2H,Ph),7.18(d,J＝6.0Hz,2H,Ph),4.66(s,2H,CH2),1.27(s,3H,CH3)；Ms(ESI)m/z:523.4[M+H]+。
prepared M5The chemical structural formula is as follows:
Figure BDA0002480953060000082
example 9
Under the protection of nitrogen, 4mmol of 4-hydroxy-2, 2,6, 6-tetramethylpiperidine oxynitride and 12mmol of N, N-diisopropylethylamine are mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)6)0.740 g, 93% yield. Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz，CDCl3)(ppm)3.82(m,1H,CH),2.23(m,2H,CH2),1.95(m,2H,CH2),1.50(s,12H,CH3)；Ms(ESI)m/z:422.4[M+Na]+。
prepared M6The chemical structural formula is as follows:
Figure BDA0002480953060000091
example 10
Under the protection of nitrogen, 4mmol of 3-methoxy-4-hydroxybenzaldehyde and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the mixture reacts for 12 hours at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and methanol is added to quench the reaction after the raw materials completely react. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Figure BDA0002480953060000092
Example 11
Under the protection of nitrogen, 4mmol of 4-hydroxybenzaldehyde and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Figure BDA0002480953060000093
Example 12
Under the protection of nitrogen, 4mmol of 4-methoxymethylphenol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Figure BDA0002480953060000101
Example 13
Under the protection of nitrogen, 4mmol of 4-ethoxymethylphenol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Figure BDA0002480953060000102
Example 14
Under the protection of nitrogen, 4mmol of amyl salicylate and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials are completely reacted to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Figure BDA0002480953060000103
Example 15
Under the protection of nitrogen, 4mmol of (E) -3, 5-dimethoxy-4' -hydroxystilbene (pterostilbene) and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dripped under the condition of ice bath, the ice bath is removed after the dripping, the reaction is carried out for 2h at 25 ℃, a thin layer chromatography plate is used for monitoring the reaction process, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Figure BDA0002480953060000111
Example 16
Under the protection of nitrogen, 4mmol of 2, 4-dinitrophenol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Figure BDA0002480953060000112
Preparation of nanoparticles based on hydrogen peroxide-responsive tocopherol compounds: 10mg of tocopherol oxalate and 4mg of DSPE-PEG2000Dissolving in 1.5mL dichloromethane solution, adding 9mL triple distilled water, performing intermittent ultrasound with an ultrasonic probe for 60s at 70% power, stirring at room temperature for 6h to obtain nanoparticles, evaporating dichloromethane with a rotary evaporator, and measuring DLS particle diameter, wherein the sample photograph, particle diameter distribution diagram and transmission electron microscope picture are shown in FIG. 5, and the average particle diameter is 188 nm.
Preparation of hydrogen peroxide-responsive tocopherol compound-encapsulated sulforhodamine 101 nanoparticles: 10mg of tocopherol oxalate, 4mg of DSPE-PEG2000And dissolving 1mg of sulforhodamine 101 in 1.5mL of dichloromethane solution, adding 9mL of triple distilled water, performing intermittent ultrasound for 60s by using an ultrasonic probe with the power of 70%, and then stirring at room temperature for 6h to obtain the sulforhodamine 101 loaded nanoparticle. The photo-responsiveness assay was excited for different types of reactive oxygen species, as can be seen in FIG. 6The nanoparticle has a selective response luminescence characteristic to hydrogen peroxide.
Preparation of hydrogen peroxide-responsive tocopherol compound-encapsulated 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles: 10mg of tocopherol oxalate, 4mg of DSPE-PEG2000And 1mg of 1-chloro-9, 10-diphenylethynyl anthracene is dissolved in 1.5mL of dichloromethane solution, 9mL of triple distilled water is added, intermittent ultrasonic treatment is carried out for 60s by using an ultrasonic probe with the power of 70 percent, and then stirring is carried out for 6h at room temperature to obtain the loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle.
An imaging graph of a pore plate with the light-emitting responsiveness of the hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles to different concentrations is shown in fig. 7, and the light-emitting intensity of the nanoparticles is increased along with the increase of the hydrogen peroxide concentration, so that the nanoparticles have concentration dependence.
As can be seen from fig. 8, the imaging of the pore plate of the hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle in the neutrophil in the abdominal cavity of the mouse shows that the luminescent intensity of the nanoparticle is gradually enhanced with the increase of the number of the neutrophil, and the imaging of the nanoparticle has the neutrophil responsiveness.
As can be seen from fig. 9, the hydrogen peroxide-responsive tocopherol compound loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle can be used for imaging peritonitis in mice. Wherein, the peritonitis model is successfully constructed by injecting thioglycolate into the abdominal cavity of a mouse9. After 300 mu L of nanoparticles (1mg/mL) are injected into the abdominal cavity, the imaging performance of the nanoparticles is verified in a living body imaging system. As a large amount of ROS is generated in abdominal inflammation, the hydrogen peroxide responsive nanoparticles are activated, and energy is transferred to the fluorescent dye to realize chemiluminescence imaging.
As can be seen from fig. 10, the hydrogen peroxide-responsive tocopherol compound loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle can be used for imaging of liver injury in mice. Wherein the liver injury of the mouse is induced and constructed by alcohol according to a literature method23(ii) a Then, 100 mu L of encapsulated 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles (1mg/mL) are injected into the tail vein of the alcoholic liver injury mouse, and the imaging performance of the nanoparticles is verified by a living body imaging system. The oxidative stress generates a large amount of ROS to activate the hydrogen peroxide responsive nanoparticles, and the energy is transferred to fluorescenceDye to realize chemiluminescence imaging.
As can be seen from fig. 11, the hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle can be used for imaging of breast tumors with high hydrogen peroxide expression of 4T1 in mice. Because the 4T1 tumor microenvironment contains a large amount of ROS, the hydrogen peroxide responsive nanoparticles are activated, energy is transferred to the fluorescent dye, and the chemiluminescence imaging of the hydrogen peroxide high-expression tumor is realized.
Reference to the literature
1.D'Autréaux,B.；Toledano,M.B.,ROS as signalling molecules:mechanismsthat generate specificity in ROS homeostasis.Nature Reviews Molecular CellBiology 2007,8(10),813-824.
2.Giorgio,M.；Trinei,M.；Migliaccio,E.；Pelicci,P.G.,Hydrogen peroxide:ametabolic by-product or a common mediator of ageing signals？Nature ReviewsMolecular Cell Biology 2007,8(9),722-728.
3.Kim,J.S.；Huang,T.Y.；Bokoch,G.M.,Reactive oxygen species regulate aslingshot-cofilin activation pathway.Molecular biology of the cell 2009,20(11),2650-60.
4.Niethammer,P.；Grabher,C.；Look,A.T.；Mitchison,T.J.,A tissue-scalegradient of hydrogen peroxide mediates rapid wound detection inzebrafish.Nature 2009,459(7249),996-9.
5.Finkel,T.；Holbrook,N.J.,Oxidants,oxidative stress and the biologyof ageing.Nature 2000,408(6809),239-247.
6.Wang,D.；Peng,F.；Li,J.；Qiao,Y.；Li,Q.；Liu,X.,Butyrate-inserted Ni–Tilayered double hydroxide film for H2O2-mediated tumor and bacteriakilling.Materials Today 2017,20(5),238-257.
7.Cheng,J.；Zhang,R.；Li,C.；Tao,H.；Dou,Y.；Wang,Y.；Hu,H.；Zhang,J.,ATargeting Nanotherapy for Abdominal Aortic Aneurysms.Journal of the AmericanCollege of Cardiology 2018,72(21),2591-2605.
8.Guo,J.；Li,D.；Tao,H.；Li,G.；Liu,R.；Dou,Y.；Jin,T.；Li,L.；Huang,J.；Hu,H.；Zhang,J.,Cyclodextrin-Derived Intrinsically Bioactive Nanoparticles forTreatment of Acute and Chronic Inflammatory Diseases.Advanced Materials 2019,31(46),e1904607.
9.Guo,J.；Tao,H.；Dou,Y.；Li,L.；Xu,X.；Zhang,Q.；Cheng,J.；Han,S.；Huang,J.；Li,X.；Li,X.；Zhang,J.,A myeloperoxidase-responsive and biodegradableluminescent material for real-time imaging of inflammatory diseases.MaterialsToday 2017,20(9),493-500.
10.Li,L.；Guo,J.；Wang,Y.；Xiong,X.；Tao,H.；Li,J.；Jia,Y.；Hu,H.；Zhang,J.,ABroad-Spectrum ROS-Eliminating Material for Prevention of Inflammation andDrug-Induced Organ Toxicity.Advanced Science 2018,5(10),1800781.
11.Zhang,Q.；Zhang,F.；Chen,Y.；Dou,Y.；Tao,H.；Zhang,D.；Wang,R.；Li,X.；Zhang,J.,Structure–Property Correlations of Reactive Oxygen Species-Responsive and Hydrogen Peroxide-Eliminating Materials with Anti-Oxidant andAnti-Inflammatory Activities.Chemistry of Materials 2017,29(19),8221-8238.
12.Delafresnaye,L.；Bloesser,F.R.；Kockler,K.B.；Schmitt,C.W.；Irshadeen,I.M.；Barner-Kowollik,C.,All Eyes on Visible-Light PeroxyoxalateChemiluminescence Read-Out Systems.Chemistry–A European Journal 2019,26(1),114-127.
13.Kazemi,S.Y.；Abedirad,S.M.,Effect of glutathione on peroxyoxalatechemiluminescence of hypericin as the fluorophore.Spectrochimica Acta.Part A,Molecular and Biomolecular Spectroscopy 2014,118,782-6.
14.de Paula Oliveira,L.C.；Gaubeur,I.；Dantoni,P.,Hydrazone as a newfluorophore in the peroxyoxalate chemiluminescence reaction.Journal ofLuminescence 2017,183,418-423.
15.Kockler,K.B.；Frisch,H.；Barner-Kowollik,C.,Making and BreakingChemical Bonds by Chemiluminescence.Macromolecular Rapid Communications 2018,39(21),e1800516.
16.Wu,Y.；Zhou,D.；Qi,Y.；Xie,Z.；Chen,X.；Jing,X.；Huang,Y.,Novel multi-sensitive pseudo-poly(amino acid)for effective intracellular drugdelivery.RSC Advances 2015,5(40),31972-31983.
17.Liu,C.；Zhu,X.；Wang,X.；Miao,D.；Liang,X.；Wang,C.；Pang,L.；Sun,H.；Kong,D.；Yang,J.,Hydrogen peroxide-responsive micelles self-assembled from aperoxalate ester-containing triblock copolymer.Biomaterials Science 2016,4(2),255-7.
18.Li,J.；Li,Y.；Wang,Y.；Ke,W.；Chen,W.；Wang,W.；Ge,Z.,Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy.Nano Letters 2017,17(11),6983-6990.
19.Romanyuk,A.V.；Grozdova,I.D.；Ezhov,A.A.；Melik-Nubarov,N.S.,Peroxyoxalate Chemiluminescent Reaction as a Tool for Elimination of TumourCells Under Oxidative Stress.Scientific Reports 2017,7(1),3410.
20.Jung,E.；Noh,J.；Kang,C.；Yoo,D.；Song,C.；Lee,D.,Ultrasound imagingand on-demand therapy of peripheral arterial diseases using H2O2-Activatedbubble generating anti-inflammatory polymer particles.Biomaterials 2018,179,175-185.
21.Lee,D.；Khaja,S.；Velasquez-Castano,J.C.；Dasari,M.；Sun,C.；Petros,J.；Taylor,W.R.；Murthy,N.,In vivo imaging of hydrogen peroxide withchemiluminescent nanoparticles.Nature Materials 2007,6(10),765-769.
22.Kang,C.；Cho,W.；Park,M.；Kim,J.；Park,S.；Shin,D.；Song,C.；Lee,D.,H2O2-triggered bubble generating antioxidant polymeric nanoparticles as ischemia/reperfusion targeted nanotheranostics.Biomaterials 2016,85,195-203.
23.Ramaiah,S.K.；Jaeschke,H.,Hepatic Neutrophil Infiltration in thePathogenesis of Alcohol-Induced Liver Injury.Toxicology Mechanisms andMethods 2007,17(7),431-440.

Claims (10)

1. A hydrogen peroxide responsive compound for use in imaging and therapy, characterized by: the chemical structural general formula is as follows
Figure FDA0002480953050000011
Wherein:
Figure FDA0002480953050000012
2. a method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy comprising the steps of: mixing a single hydroxyl compound and an acid-binding agent in an organic solvent, slowly dropwise adding oxalyl chloride into the solution under the ice bath condition under the protection of nitrogen, removing the ice bath after dropwise adding, reacting for 2-12h, adding methanol or ethanol after the raw materials completely react, and quenching the reaction to obtain a crude product of the hydrogen peroxide responsive compound.
3. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2, wherein: extracting the crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water, vacuum filtering, evaporating to remove dichloromethane, concentrating to obtain crude product, and separating and purifying with silica gel chromatographic column to obtain final product.
4. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the monohydroxy compound is selected from tocopherol, idebenone, camptothecin, zidovudine, 4-hydroxymethylphenylboronic acid pinacol ester, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine nitroxide, 3-methoxy-4-hydroxybenzaldehyde, 4-methoxymethylphenol, 4-ethoxymethylphenol, amyl salicylate, (E) -3, 5-dimethoxy-4' -hydroxystilbene or 2, 4-dinitrophenol.
5. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the acid-binding agent is selected from N, N-diisopropylethylamine or triethylamine.
6. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the organic solvent is dichloromethane.
7. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the concentration of the monohydroxy compound in the organic solvent is between 0.1mmol/ml and 0.4 mmol/ml.
8. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the molar ratio of the monohydroxy compound to the oxalyl chloride is between 1:0.5 and 1:1, and the molar ratio of the monohydroxy compound to the acid-binding agent is between 1:2 and 1: 5.
9. Use of the hydrogen peroxide-responsive compound of claim 1 for the preparation of a medicament and/or an imaging probe for the prevention and treatment of diseases associated with inflammation and/or oxidative stress injury.
10. Use according to claim 9, characterized in that: the inflammation includes allergic inflammation, non-specific inflammation, and infectious inflammation; the oxidative stress injury comprises acute heart injury, acute lung injury, acute/chronic liver injury, acute/chronic kidney injury, and acute/chronic intestinal tract injury.
CN202010378023.1A 2020-05-07 2020-05-07 Hydrogen peroxide responsive compound for imaging and therapy and method for synthesizing same Active CN111635389B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010378023.1A CN111635389B (en) 2020-05-07 2020-05-07 Hydrogen peroxide responsive compound for imaging and therapy and method for synthesizing same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010378023.1A CN111635389B (en) 2020-05-07 2020-05-07 Hydrogen peroxide responsive compound for imaging and therapy and method for synthesizing same

Publications (2)

Publication Number Publication Date
CN111635389A true CN111635389A (en) 2020-09-08
CN111635389B CN111635389B (en) 2023-06-27

Family

ID=72328353

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010378023.1A Active CN111635389B (en) 2020-05-07 2020-05-07 Hydrogen peroxide responsive compound for imaging and therapy and method for synthesizing same

Country Status (1)

Country Link
CN (1) CN111635389B (en)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6233481B1 (en) * 1997-10-09 2001-05-15 Spectra Science Corporation Diagnostic application of sono-chemical excitation of fluorescent photosensitizers
CN101205462A (en) * 2006-12-20 2008-06-25 天津天龙化学发光管有限公司 Solid chemistry luminescent composition
CN101240165A (en) * 2007-02-07 2008-08-13 天津天龙化学发光管有限公司 Excellent oxalic ester chemoluminescence system
KR20110061432A (en) * 2009-12-01 2011-06-09 한국과학기술연구원 Aqueous dispersion of chemiluminescent nanoparticles, and preparation method and use thereof
US20120016217A1 (en) * 2010-07-15 2012-01-19 Indian Institute Of Technology Bombay Biosensor for health monitoring and uses thereof
US20120039814A1 (en) * 2010-08-13 2012-02-16 Sample Jennifer L Topical Compositions and Methods of Detection and Treatment
CN102775984A (en) * 2011-05-13 2012-11-14 天津天龙化学发光管有限公司 Pasty chemiluminescent composition with low oxidizability and high stability
JPWO2015068725A1 (en) * 2013-11-07 2017-03-09 住友精化株式会社 Charge transport material for photoelectrochemical devices
US20180064832A1 (en) * 2016-09-08 2018-03-08 Korea Institute Of Science And Technology Oxamide nanogel, a preparation method of the same, and use thereof
WO2019178247A1 (en) * 2018-03-15 2019-09-19 Biolum Sciences Llc Sensor devices and systems for monitoring markers in breath

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6233481B1 (en) * 1997-10-09 2001-05-15 Spectra Science Corporation Diagnostic application of sono-chemical excitation of fluorescent photosensitizers
CN101205462A (en) * 2006-12-20 2008-06-25 天津天龙化学发光管有限公司 Solid chemistry luminescent composition
CN101240165A (en) * 2007-02-07 2008-08-13 天津天龙化学发光管有限公司 Excellent oxalic ester chemoluminescence system
KR20110061432A (en) * 2009-12-01 2011-06-09 한국과학기술연구원 Aqueous dispersion of chemiluminescent nanoparticles, and preparation method and use thereof
US20120016217A1 (en) * 2010-07-15 2012-01-19 Indian Institute Of Technology Bombay Biosensor for health monitoring and uses thereof
US20120039814A1 (en) * 2010-08-13 2012-02-16 Sample Jennifer L Topical Compositions and Methods of Detection and Treatment
CN102775984A (en) * 2011-05-13 2012-11-14 天津天龙化学发光管有限公司 Pasty chemiluminescent composition with low oxidizability and high stability
JPWO2015068725A1 (en) * 2013-11-07 2017-03-09 住友精化株式会社 Charge transport material for photoelectrochemical devices
US20180064832A1 (en) * 2016-09-08 2018-03-08 Korea Institute Of Science And Technology Oxamide nanogel, a preparation method of the same, and use thereof
WO2019178247A1 (en) * 2018-03-15 2019-09-19 Biolum Sciences Llc Sensor devices and systems for monitoring markers in breath

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
COLUMBUS, OHIO, US REGISTRY[ONLINE]: "STN检索报告", 《STN REGISTRY》 *
FABRIZIO RONCAGLIA: "Designing and Using a Safer, Greener Azole Oxamide for Chemiluminescence Demonstrations", 《J. CHEM. EDUC.》 *
吕玉光主编: "《仪器分析》", 31 January 2016, 中国医药科技出版社 *
唐嘉: "过氧草酸酯类化合物的合成及其发光体系的应用", 《化学工程与装备》 *
支正良等: "过氧草酸酯类化学发光体系的研究进展", 《化学世界》 *
胡文祥 等: "草酸二芳香酯类化合物的合成及其在药物超微量分析中的应用", 《中 国 药 物 化 学 杂 志》 *

Also Published As

Publication number Publication date
CN111635389B (en) 2023-06-27

Similar Documents

Publication Publication Date Title
CN108714222A (en) A kind of preparation and application of novel and multifunctional supermolecule vesica
CN111423423A (en) Application of ratiometric fluorescent probe in detecting peroxynitrite anion
CN113956265B (en) Near-infrared molecular probe based on malondialdehyde response, preparation method and application thereof
CN101475597A (en) Preparation and use of ruthenium and iridium metal complex singlet oxygen fluorescent probe
CN110078665A (en) A kind of hypochlorous fluorescence probe of detection of endoplasmic reticulum targeting and application
CN104529890A (en) Preparation method and application of water-soluble florescent probe for specifically identifying zinc ions
CN108285789A (en) A kind of hydrogen peroxide fluorescence probe and its preparation method and application
CN102258788B (en) Targeted transmission assembly of adriamycin anticancer medicine and preparation method thereof
CN104277061A (en) Boric acid fluorescence molecular probe as well as preparation method and application thereof
CN113801105A (en) Mitochondrion targeted peroxynitrite/bisulfite dual-response fluorescent probe
CN110194951B (en) Tetraphenyl ethylene derivative fluorescent probe and preparation method thereof
CN110373181B (en) Fluorescent probe for detecting fluorine ions
CN106543251B (en) Nitric oxide production water-soluble fluorescent probe and its application in a kind of detection liver cell
CN111635389B (en) Hydrogen peroxide responsive compound for imaging and therapy and method for synthesizing same
CN110437283B (en) Potassium ion fluorescent probe and preparation method and application thereof
CN101007821A (en) Fluorescent probe for detecting fluorinion and its synthesis method and uses
CN111196821B (en) Compounds, preparation method thereof and application thereof as near-infrared two-region fluorescent probe for detecting methylglyoxal
CN111072694B (en) Hydrogen sulfide identification detection fluorescent probe and preparation method and application thereof
CN113004258A (en) Preparation method and application of hydrogen sulfide ratio type fluorescent molecular probe based on ESIPT effect
CN115403475A (en) Preparation method and application of diagnostic reagent for specifically detecting copper ion concentration
CN113651840A (en) Fluorescent probe of-S-S-disulfide bond small molecule drug for inhibiting AD and preparation method thereof
WO2010027108A1 (en) Fluorescent sugar derivative compound and sensor using same
CN113666937A (en) Near-infrared fluorescent probe for detecting zinc ions and preparation method and application thereof
CN107501104B (en) Formaldehyde fluorescent nano probe intermediate with double-signal turn-on output and preparation and application thereof
CN118406174B (en) Mannose-containing polymer, method for preparing mannose-containing polymer by combining RAFT polymerization and click chemistry and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant