WO2019214691A1 - 主族金属配合物及其制备方法和应用 - Google Patents

主族金属配合物及其制备方法和应用 Download PDF

Info

Publication number
WO2019214691A1
WO2019214691A1 PCT/CN2019/086272 CN2019086272W WO2019214691A1 WO 2019214691 A1 WO2019214691 A1 WO 2019214691A1 CN 2019086272 W CN2019086272 W CN 2019086272W WO 2019214691 A1 WO2019214691 A1 WO 2019214691A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
group
alkyl
group metal
substituted
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.)
Ceased
Application number
PCT/CN2019/086272
Other languages
English (en)
French (fr)
Inventor
张俊龙
尹昊琰
王炳武
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.)
Peking University
Original Assignee
Peking 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 Peking University filed Critical Peking University
Priority to EP19799825.5A priority Critical patent/EP3792268A4/en
Priority to AU2019265404A priority patent/AU2019265404B2/en
Priority to US16/973,474 priority patent/US12018038B2/en
Publication of WO2019214691A1 publication Critical patent/WO2019214691A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • C07F5/06—Aluminium compounds
    • C07F5/069—Aluminium compounds without C-aluminium linkages
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/30—Germanium compounds

Definitions

  • the present invention relates to a series of main group metal complexes having cancer cell killing effects, a preparation method thereof and use for treating cancer.
  • Metal complex small molecule anticancer drugs are an important class of cancer chemotherapeutic drugs.
  • most of the existing researches focus on transition metal complexes such as platinum, rhodium and gold, and cooperate with the main group metals.
  • transition metal complexes such as platinum, rhodium and gold
  • the inventors conducted intensive studies and found that salicylaldehyde or a substituted salicylaldehyde, a diamine precursor, and a main group metal can react to obtain a main group metal complex having an antitumor effect;
  • the group metal complex also has fluorescent properties and thus can also be used as a photomarker, thereby completing the present invention.
  • the object of the present invention is to provide the following aspects:
  • the present invention provides a main group metal complex containing a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, solvate, non-covalent bond complex or prodrug thereof,
  • the main group metal complex including its positive ions, is composed of a Schiff base-like planar tetradentate ligand and a p-region main group metal ion, wherein
  • M represents a main group metal of the p region
  • X represents a diamine residue in which a nitrogen atom of an imine bond flanked by a substituted or unsubstituted C 1-12 alkyl group or a C 2-12 alkenyl group, or a substituted or unsubstituted aryl group or a hetero group a terminal substituent in a cyclic aryl group;
  • Y is hydrogen, C 1-12 alkyl, halogen, halogen substituted alkyl, cyano, amino, carbonyl, C 1-12 alkoxy or substituted amino;
  • Z is hydrogen, C 1-12 alkyl, halogen, nitro, hydroxy, decyl or carboxyl;
  • R 1 , R 2 , R 3 and R 4 are a substituent on the phenyl ring in the ligand skeleton, each independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, decyl, carboxyl, amino, cyano, C 1- 12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-8 alkoxy, C 2-8 alkenyloxy, C 2-8 alkynyloxy, C 1-8 alkanethio , C 3-8 heterocyclyl, aryl, C 1-8 alkanoyl, C 1-8 alkanoyl, C 1-8 alkylsulfonyl, arylsulfonyl, C 1-12 alkyl substituted amino Or halogen substituted C 1-12 alkyl;
  • R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 may form a ring.
  • the present invention provides a method for preparing the above-mentioned main group metal complex, which comprises placing a salicylaldehyde or a substituted salicylaldehyde represented by Formula V, a diamine precursor represented by Formula VI, and a main group metal salt MD.
  • the reaction is carried out at 50 to 150 ° C for 12 to 24 hours, that is,
  • the formula IV can be carried out according to the following reaction equation: the ligand represented by the formula VII and the main group metal salt MD are placed in the organic solvent L, and the reaction is carried out at 50 to 150 ° C for 12 to 24 hours, and the target complex molecule is obtained in one step. :
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned main group metal complex as an active ingredient, comprising a pharmaceutically acceptable adjuvant.
  • the present invention provides a pharmaceutical preparation of the above-mentioned main group metal complex, which comprises a gastrointestinal administration preparation and an injection administration preparation,
  • Formulations for parenteral administration include tablets, capsules, oral solutions, oral emulsions, suppositories, and granules;
  • Formulations for injection administration include injection solutions, injection emulsions, injection suspension solutions, and injection suspensions.
  • the present invention provides a main group metal complex, a pharmaceutically acceptable salt, a solvate, a non-covalent bond complex or a prodrug, or a pharmaceutical composition comprising the structure of Formula I or Formula II
  • a pharmaceutical composition comprising the structure of Formula I or Formula II
  • the application is preparation for treatment including breast cancer, liver cancer, lung cancer, melanoma, prostate cancer, colon cancer, colorectal cancer, glioblastoma, renal cancer, pancreatic cancer, gastric cancer, lymphoma, cervical cancer, ovarian cancer, esophagus Applications in cancer, nasal cancer, leukemia, ductal carcinoma of the breast, gallbladder cancer, testicular cancer, cardiac cancer, and thyroid cancer;
  • the dosage level of the drug is 0.01 to 200 mg/kg body weight per day, or 0.5 to 14 g per patient per day.
  • the present invention provides a use of a main group metal complex, salt, solvate, non-covalent bond complex or precursor material containing a structure of Formula I or Formula II, in photo-marking; Use in fluorescent labeling;
  • fluorescent imaging probes targeting formulations, materials, organic light emitting diodes, dye sensitized solar cells.
  • the present invention provides a main group metal complex consisting of a Schiff base-like planar tetradentate ligand and a p-region main group metal ion and an axial monodentate ligand, the structure of which is as follows:
  • M represents a main group metal of the p region
  • X represents a diamine residue, and the nitrogen atom of the imine bond on both sides is linked to each other by a fatty chain having 1 to 5 carbon atoms or a substituted aliphatic chain, or as an aromatic a terminal substituent of the ring
  • Y is hydrogen or an alkyl group
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, amino, substituted amino, alkyl, alkoxy, Halogen substituted alkyl, indenyl or alkylthio wherein the two adjacent substituents R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 may form a ring
  • L represents one or more axial directions
  • a monodentate ligand which is a halogen, an oxygen coordination small molecule or a nitrogen coordination small molecule
  • Z is hydrogen or an alkyl group.
  • M is aluminum, gallium, indium, antimony, bismuth, tin or lead.
  • the X represents a benzene, a substituted benzene or a pyridine ring, or a fatty chain having a main chain of C1-C3 or a substituted aliphatic chain.
  • the halogen is selected from one or more of F, Cl, Br and I; the alkyl group is a C1-C12 alkyl group; the substituted amino group is a C1-C12 alkyl-substituted amino group; a C1-C8 alkoxy group; the halogen-substituted alkyl group is one or more halogen-substituted C1-C12 alkyl groups; the alkylthio group is a C1-C8 alkyl-substituted fluorenyl group; and the oxygen coordination small molecule is selected from the group consisting of One or more of methanol, ethanol, acetone, dimethyl sulfoxide, tetrahydrofuran and water; the nitrogen coordination small molecule is one or more selected from the group consisting of pyridine, piperidine, n-propylamine, ethylenediamine and ethanolaminekind.
  • R1 and R2, R2 and R3 and/or R3 are ring-formed with R4, and the combination represents 1,3-butadiene-1,4-diyl or 1,4-dibutyl.
  • the main group metal complex is one of the following complexes:
  • the salicylaldehyde or substituted salicylaldehyde represented by the formula and the diamine precursor represented by the above formula and the main group metal salt ML are placed in an organic solvent, and reacted at 50 to 150 ° C for 12 to 24 hours, and one step is synthesized as shown in Formula I. a complex; wherein X, Y, M, L, R1, R2, R3 and R4 are as described in (1).
  • the ligand represented by the above formula and the main group metal salt ML are placed in an organic solvent, and the reaction is carried out at 50 to 150 ° C for 12 to 24 hours, and the complex represented by the formula II is synthesized in one step; wherein X, Y, Z, M, L R1, R2, R3 and R4 are as described in (1).
  • the organic solvent in (3) and (4) is methanol, ethanol or acetonitrile, and the reaction is followed by recrystallization from an acetonitrile/diethyl ether solvent system to precipitate a complex solid from the system.
  • the main group metal complex, the preparation method and the use thereof provided by the invention have the following beneficial effects:
  • the main group metal complex provided by the present invention exhibits high cytotoxicity against various cancer cell lines, and is selective for killing effect, and is more effective than the existing metal anticancer drug;
  • the main group metal complex provided by the invention has excellent fluorescence performance and can be used as a photo-marker for fluorescent labeling, especially single-two-photon fluorescent labeling, such as in vivo imaging tracking, targeted preparation, materials and the like;
  • FIG. 1 shows the median lethal concentration of the complex in Experimental Example 1 against different cancer cell lines
  • FIG. 2 shows the cytotoxicity curve of the complex in Experimental Example 1 against human cervical cancer cell line HeLa
  • FIG. 3 shows Experimental Example 3.
  • FIG. 4 shows the fluorescence image of the mouse in vivo experiment in Experimental Example 4
  • a and B respectively show the changes in the tumor volume and mass after the treatment in the living body tumor inhibition experiment in Experimental Example 5
  • the change in body weight after treatment in nude mice in the live tumor inhibition experiment in Experimental Example 5 is shown
  • in Figure 7 D shows the H&E staining map of the tumor tissue in the live tumor inhibition experiment in Experiment 5
  • E shows the nuclear magnetic field of the tumor site in each experimental group.
  • Resonance black and white map and color map F shows the standard deviation of tumor tissue changes in each group in E;
  • Fig. 8 shows the results of hematology analysis in the experimental example 5 in vivo tumor inhibition experiment;
  • Fig. 9 shows the experimental example 5 in vivo tumor inhibition experiment H&E staining map of the main organs.
  • the present invention provides a main group metal complex containing a structure of formula I or formula II, or a pharmaceutically acceptable salt, solvate, non-covalent bond complex or prodrug thereof,
  • the main group metal complex including its positive ions, is composed of a Schiff base-like planar tetradentate ligand and a p-region main group metal ion, wherein
  • M represents a main group metal of the p region
  • X represents a diamine residue in which a nitrogen atom of an imine bond flanked by a substituted or unsubstituted C 1-12 alkyl group or a C 2-12 alkenyl group, or a substituted or unsubstituted aryl group or a hetero group a terminal substituent in a cyclic aryl group;
  • Y is hydrogen, C 1-12 alkyl, halogen, halogen substituted alkyl, cyano, amino, carbonyl, C 1-12 alkoxy or substituted amino;
  • Z is hydrogen, C 1-12 alkyl, halogen, nitro, hydroxy, decyl or carboxyl;
  • R 1 , R 2 , R 3 and R 4 are a substituent on the phenyl ring in the ligand skeleton, each independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, decyl, carboxyl, amino, cyano, C 1- 12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-8 alkoxy, C 2-8 alkenyloxy, C 2-8 alkynyloxy, C 1-8 alkanethio , C 3-8 heterocyclyl, aryl, C 1-8 alkanoyl, C 1-8 alkanoyl, C 1-8 alkylsulfonyl, arylsulfonyl, C 1-12 alkyl substituted amino Or halogen substituted C 1-12 alkyl;
  • R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 may form a ring.
  • the p-group main group metal refers to a metal element in the p-group main group element according to the existing chemical element periodic table, and generally refers to a group 13 metal aluminum, gallium, indium in the periodic table of the chemical element. , bismuth and 14 metal bismuth, tin, lead.
  • the M in the formula I or the formula II is one of aluminum, gallium, indium, antimony, bismuth or tin; preferably, the M in the formula I or the formula II is in aluminum, gallium, indium, antimony or bismuth. Preferably, M in Formula I or Formula II is one of aluminum, gallium, indium or antimony.
  • the carbon atom in the cyclic aryl, alkanoyl, alkanoyl, alkylsulfonyl, arylsulfonyl, alkylamino and hydrocarbyl substituted amino groups may be halogen, nitro, hydroxy, thiol, carboxy, amino, cyano or carbonyl Replace or not replace.
  • the alkyl group is meant to include a linear, branched or cyclic saturated hydrocarbon group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclohexyl and 2-ethyl-4.
  • Propyl-cyclohexyl; C 1-12 means that the carbon atom in the hydrocarbon chain has a length of from 1 to 12.
  • the olefin group means a hydrocarbon group having an alkenyl group in a linear, branched or cyclic hydrocarbon chain, and the alkenyl carbon atom is bonded or not bonded to a carbon atom on the ligand phenyl group.
  • alkenyl carbon atom is bonded or not bonded to a carbon atom on the ligand phenyl group.
  • vinyl, 1-allyl, 1-phenyl-allyl, and 2-methylpropenyl Similarly, a C 2-12 olefin group means that the total number of carbon atoms in the olefin group is 2-12.
  • the alkynyl group means a straight-chain, branched or cyclic hydrocarbon group including an alkynyl group which is bonded or not bonded to a carbon atom on a ligand phenyl group.
  • an alkynyl group which is bonded or not bonded to a carbon atom on a ligand phenyl group.
  • propynyl, propargyl, 2-methylbutynyl Similarly, a C 2-12 alkynyl group means that the total number of carbon atoms in the alkynyl group is 2-12.
  • the alkoxy group means an oxygen ether group including the aforementioned alkyl group, such as a methoxy group, an ethoxy group, a propoxy group or the like; and a C 1-8 alkoxy group means that the total number of carbon atoms in the alkoxy group is 1-8. .
  • the alkenyloxy group means an oxygen ether group of a linear, branched or cyclic hydrocarbon group containing an alkenyl group; and the C 2-8 alkenyloxy group means that the total number of carbon atoms in the alkenyloxy group is 2-8.
  • the alkynyloxy group means an oxygen ether group of a linear, branched or cyclic hydrocarbon group containing an alkynyl group; and the C 2-8 alkynyloxy group means that the total number of carbon atoms in the alkyne group is 2-8.
  • the alkylthio group means a thioether group including the aforementioned alkyl group, such as a methylthio group, an ethylthio group, a propylthio group or the like; and a C 1-8 alkylthio group means that the total number of carbon atoms in the alkylthio group is 1-8. .
  • the heterocyclic group refers to a stable 3-8 membered saturated cyclic group containing a hetero atom which is bonded or not bonded to a benzene in the ligand, preferably linked.
  • Typical heteroatoms include oxygen, sulfur, and nitrogen.
  • the C 3-8 heterocyclic group means that the total number of carbon atoms in the heterocyclic group is 3-8.
  • the aryl group means an aromatic ring containing a phenyl group, and is generally benzene, naphthalene, anthracene or phenanthrene, and preferably benzene or naphthalene.
  • the heterocyclic aryl group means a mono- or poly-aryl ring group including a hetero atom, preferably a ring of 5-10 members.
  • the polycyclic aromatic group may be a bi-monoaromatic ring, a benzo-monoaryl ring or a fused aromatic ring group.
  • the aryl group may be furan, pyridine, thiophene, imidazole, pyrrole, pyridazine, pyrazine, benzopyrrole, benzofuran, benzisoquinoline or pyrazinopyridazine.
  • the alkanoyl group means an acyl group containing the aforementioned alkyl group, and the C 1-8 alkanoyl group means that the total number of carbon atoms contained therein is from 1 to 8.
  • the alkanoamide group means an alkanoamide group containing the aforementioned alkyl group, and the C 1-8 alkanoamide group means that the total number of carbon atoms contained therein is from 1 to 8.
  • the alkylsulfonyl group means an alkylsulfonyl group containing the aforementioned alkyl group, and the C 1-8 alkylsulfonyl group means that the total number of carbon atoms contained therein is from 1 to 8.
  • the arylsulfonyl group means a sulfonyl group containing the aforementioned aryl group.
  • the alkyl-substituted amino group means an amino group substituted with the aforementioned alkyl group, such as a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group or the like; and a C 1-12 alkylamino group means a carbon atom in the substituted alkyl group. The total is 1-12.
  • the nitrogen atoms on both sides of the X are linked to each other by an aliphatic chain or a substituted aliphatic chain having 1 to 5 carbon atoms, or as an ortho substituent of the aromatic ring.
  • the X in the formula I forms a conjugated structure with the two imino groups in the ligand.
  • X may be selected from the group consisting of ethylene, cyano substituted ethylene, 1,3-butadiene, cyano substituted 1,3-butadiene benzene, benzene, pyridine, benzopyridine, naphthalene, cyanide A substituted naphthyl group.
  • X of formula I or formula II is selected from the group consisting of ethylene, cyano substituted ethylene, 1,3-butadiene, benzene, benzene, cyano substituted benzene, pyridine or cyano substituted pyridine groups.
  • X is a phenyl group.
  • X is a 4-cyano substituted phenyl group.
  • X is a 4,5-dicyano substituted phenyl group.
  • X is
  • X in Formula I or Formula II is a substituted or unsubstituted saturated alkyl group, and in these embodiments, X is preferably selected from -CH 2 -, -CH 2 -CH 2 - , -CH 2 (Cl)-CH 2 -, -CH(CN)-CH(CN)-, -CH 2 (OH)-CH 2 - or -CH 2 (CH 3 )-CH 2 -; more preferably X Is -CH 2 -, -CH 2 -CH 2 -, -CH 2 (Cl)-CH 2 - or -CH 2 (CH 3 )-CH 2 -.
  • Y in the formula I or formula II is hydrogen, halogen, cyano, C 1-4 alkyl or C 1-4 alkoxy.
  • halogen includes F, Cl, Br and I.
  • Y in the formula I or formula II is an alkyl group, it is further preferably a C 1-3 alkyl group.
  • Y is hydrogen, halogen, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, halogen substituted C 1-3 alkyl or halogen substituted C 1-3 alkoxy.
  • the Y is hydrogen, halogen, cyano, methyl or methoxy.
  • the Z is hydrogen, C 1-10 alkyl, halogen, nitro, hydroxy, decyl or carboxyl; preferably Z is hydrogen, C 1-6 alkyl, halogen, nitro, hydroxy, decyl or carboxyl.
  • the Z is hydrogen
  • the R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, nitro, hydroxy, decyl, carboxyl, amino, cyano, C 1- 12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-8 alkoxy, C 2-8 alkenyloxy, C 2-8 alkynyloxy, C 1-8 alkanethio , C 3-8 heterocyclyl, aryl, C 1-8 alkanoyl, C 1-8 alkanoyl, C 1-8 alkanoyl, C 1-8 alkylsulfonyl, arylsulfonyl, N,N-di (C 1 -6 alkyl)amino, N-(C 1-6 alkyl)-N-(C 1-6 alkyl)amino, N-(C 1-6 alkyl)-NC 1-6 alkynyl)amino , N,N-diarylamino
  • R 1 , R 2 , R 3 and R 4 in formula I or formula II are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, nitro, hydroxy, thiol, amino, cyano, C 1-5 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, C 1-8 alkylamino, N,N-di(C 1-6 alkyl)amino, N-(C 1 -6 alkyl)-N-(C 1-6 alkyl)amino, N-(C 1-6 alkyl)-N-(C 3-6 alkynyl)amino, C 3-8 unsaturated heterocycle a C 3-8 saturated heterocyclic group, a halogen-substituted C 5-6 cyclic alkyl group or a halogen-substituted C 1-6 alkyl group.
  • R 1 , R 2 and R 4 in formula I or formula II are each independently hydrogen, cyano, decyl, C 2-4 alkylthio or C 1-5 alkyl;
  • R 1 in formula I or formula II is hydrogen
  • R 4 is hydrogen, cyano or C 1-5 alkyl
  • R 2 is hydrogen, decyl, C 2-4 alkylthio or C 1-5 alkyl.
  • R 1 and R 2 in formula I or formula II are both hydrogen and R 4 is a fluorenyl or C 2-4 alkylthio group;
  • R 1 and R 4 in formula I or formula II are both hydrogen and R 2 is fluorenyl or C 2-4 alkylthio;
  • R 1 , R 2 and R 4 in formula I or formula II are all hydrogen.
  • R 3 in formula I or formula II is selected from the group consisting of hydrogen, fluorine, chlorine, amino, C 1-8 alkylamino, C 1-4 alkoxy, N,N-di(C 1-5 alkyl)amino , N-(C 1-6 alkyl)-N-(C 1-4 alkyl)amino, N-(C 1-4 alkyl)-N-(C 3-5 alkynyl)amino, C 3 -8 unsaturated nitrogen heterocyclic group or C 3-8 saturated nitrogen heterocyclic group.
  • R 3 in formula I or formula II is selected from the group consisting of hydrogen, C 1-4 alkoxy, N,N-di(C 1-5 alkyl)amino, N-(C 1-4 alkyl)- N-(C 1-2 alkyl)amino, N-(C 1-4 alkyl)-N-(C 3-5 alkynyl)amino or C 3-5 saturated azamonocyclic.
  • R 3 in formula I or formula II is selected from the group consisting of hydrogen, methoxy, ethoxy, isopropoxy, N,N-dimethylamino, N,N-diethylamino, N, N-dipropylamino, N-(2-methyl-n-butyl)amino, N-n-butyl-N-methylamino, N-ethyl-N-methylamino, N-n-butyl-N Ethylamino, N-propargyl-N-methylamino, N-ynylbutyl-N-ethylamino, tetrahydropyrrole, hydrogenated pyridine or hydrogenated imidazole.
  • R 3 in Formula I or Formula II is N,N-dimethylamino, and R 4 is C 2-4 alkylthio;
  • R 3 in Formula I or Formula II is N,N-diethylamino, and R 4 is indenyl or C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 in formula I or formula II is hydrogen, methoxy, N,N-diethylamino, N,N-dimethylamino, N-methyl-N-positive Butylamino, N-methyl-N-propargylamino or tetrahydropyrrole is, R 4 is hydrogen;
  • R 1 , R 2 , R 3 and R 4 in formula I or formula II are all hydrogen.
  • R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 form a ring
  • the combination represents 1,3-butadiene-1,4-diyl, 1,4-dibutyl, etc.
  • the benzene ring is combined to form naphthalene or tetralin.
  • R 2 and R 3 or R 3 and R 4 in Formula I or Formula II are ring-formed, preferably formed
  • R 2 and R 3 and R 3 and R 4 in Formula I or Formula II are both cyclic, preferably formed
  • the main group metal complex containing the structure of Formula I or II provided by the present invention further carries a ligand, as shown in Formula III and Formula IV:
  • the L represents one or more axial monodentate ligands, including anionic ligands, neutral ligands; the L may also be a non-coordinating anion; preferably the anionic ligand comprises a halogen (eg, fluorine, chlorine, bromine) , iodine) ion, acetate ion; the neutral ligand is an oxygen coordination or nitrogen coordination ligand, preferably from a solvent molecule.
  • halogen eg, fluorine, chlorine, bromine
  • the oxygen coordinated solvent molecule is selected from the group consisting of methanol, ethanol, acetone, dimethyl sulfoxide, tetrahydrofuran, water, isopropanol, glycerol, formaldehyde, acetic acid, formic acid, diethyl ether and dimethyl sulfoxide or A plurality of;
  • the nitrogen-coordinating solvent molecules are one or more selected from the group consisting of pyridine, piperidine, n-propylamine, ethylenediamine, ethanolamine, dimethylformamide, acetonitrile, aqueous ammonia, and triethylamine.
  • the L is selected from the group consisting of fluoride ion, chloride ion, bromide ion, acetate ion, methanol, ethanol, isopropanol, acetone, dimethyl sulfoxide, dimethylformamide, pyridine or acetonitrile.
  • the main group metal complex provided by the present invention is composed of a Schiff base-like planar tetradentate ligand and a p-region main group metal ion and an axial monodentate ligand, and in Formula III and Formula IV,
  • M represents a main group metal of the p region
  • X represents a diamine residue, and the nitrogen atom of the imine bond on both sides is linked to each other by a fatty chain having 1 to 5 carbon atoms or a substituted aliphatic chain, or as a benzene, a substituted benzene, a pyridine, or the like.
  • R 1 , R 2 , R 3 and R 4 are substituents on the benzene ring in the ligand skeleton, each independently selected from the group consisting of hydrogen, halogen, nitro, Hydroxy, amino, substituted amino, alkyl, alkoxy, halogen substituted alkyl, fluorenyl or alkylthio, wherein two adjacent substituents (R 1 and R 2 , R 2 and R 3 and/or R 3 And R 4 ) may form a ring; L represents one or more axial monodentate ligands, which are halogen, oxygen coordination small molecules or nitrogen coordination small molecules; Z in formula II is hydrogen or alkyl.
  • the M is preferably one of a group 13 metal aluminum, gallium, indium, antimony or a group 14 metal antimony, tin or lead.
  • the X is an aromatic ring such as benzene, substituted benzene or pyridine, and an aliphatic chain or a substituted aliphatic chain having a main chain of C1-C3, wherein the substituent on the substituted aliphatic chain is, for example, a cyano group.
  • the halogen includes F, Cl, Br, and I.
  • the alkyl group is preferably a C1-C12 alkyl group, more preferably a C1-C6 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or the like.
  • the substituted amino group is preferably a C1-C12 alkyl-substituted amino group, more preferably a C1-C6 alkyl-substituted amino group such as a methylamino group, an ethylamino group, a dimethylamino group or a diethylamino group.
  • the alkoxy group is preferably a C1-C8 alkoxy group, more preferably a C1-C4 alkoxy group such as a methoxy group, an ethoxy group, a propoxy group or the like.
  • the halogen-substituted alkyl group is preferably one or more halogen-substituted C1-C12 alkyl groups, more preferably one or more halogen-substituted C1-C6 alkyl groups such as a trifluoromethyl group and the like.
  • the alkylthio group is preferably a C1-C8 alkyl-substituted fluorenyl group, more preferably a C1-C4 alkyl-substituted fluorenyl group, such as a methylthio group, an ethylthio group, a propylthio group or the like.
  • R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 form a ring
  • the combination represents 1,3-butadiene-1,4-diyl, 1,4-dibutyl, etc.
  • the benzene ring is combined to form naphthalene or tetralin.
  • the oxygen coordination small molecule such as methanol, ethanol, acetone, dimethyl sulfoxide, tetrahydrofuran, water or the like; the nitrogen coordination small molecule such as pyridine, piperidine, n-propylamine, ethylenediamine, ethanolamine or the like.
  • M is indium, L is chlorine, X is -CH 2 -CH 2 -, Y is hydrogen, and there is no modification on the benzene ring in the salicylaldehyde residue;
  • M gallium
  • L chlorine
  • X ortho-disubstituted benzene
  • Y hydrogen
  • the modification on the benzene ring in the salicylaldehyde residue is a diethylamino group at the R 3 position.
  • M is ⁇
  • L is two chlorine
  • Y is hydrogen
  • the modification on the benzene ring in the salicylaldehyde residue is methoxy at the R 3 position. base.
  • the main group metal complex containing the formula I or formula II provided by the present invention may also exist in the form of a pharmaceutically acceptable salt, as shown in the following formula V or formula VI:
  • the salt of the compound provided by the present invention means a non-toxic pharmaceutically acceptable salt, generally a mineral acid salt or an organic acid salt.
  • D- represents the acid group of the inorganic acid or organic acid forming the salt.
  • Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, acetic acid, sulfuric acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid. , citric acid, benzoic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, cyclohexylaminesulfonic acid, salicylic acid or trifluoroacetic acid.
  • the inorganic acid salt or organic acid of the main group metal complex is selected from the group consisting of hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, acetic acid, sulfuric acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid. , citric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid or salicylic acid.
  • the inorganic acid salt or organic acid of the main group metal complex is selected from the group consisting of hydrochloric acid, nitric acid, acetic acid, sulfuric acid, lactic acid, succinic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Trifluoromethanesulfonic acid or salicylic acid.
  • the pharmaceutically acceptable salt containing the main group metal complex of Formula I or Formula II is a hydrochloride, nitrate or trifluoromethanesulfonic acid.
  • the main group metal complex containing the structure of Formula I or Formula II provided by the present invention may also be present in the form of a pharmaceutically acceptable solvate, a non-covalent bond complex or a prodrug.
  • the invention also provides a preparation method of a main group metal complex containing a structure represented by formula I or formula II, in particular, a main group metal complex of the structure represented by formula III or formula IV:
  • the salicylaldehyde or substituted salicylaldehyde of the formula V, the diamine precursor of the formula VI and the main group metal salt MD are placed in the organic solvent L, and the reaction is carried out at 50 to 150 ° C for 12 to 24 hours, which is one step.
  • the target complex molecules are synthesized, as follows:
  • the salicylaldehyde or substituted salicylaldehyde of the following formula and the diamine precursor of the following formula and the main group metal salt ML are placed in an organic solvent, and the reaction is carried out at 50 to 150 ° C for 12 to 24 hours.
  • the target complex molecule is obtained in one step.
  • the optimum reaction conditions were 90 ° C for 24 h.
  • the organic solvent is methanol, ethanol or acetonitrile or the like.
  • the reaction equations involved are as follows:
  • Formula IV can be carried out according to the following reaction equation, and the ligand of the formula VII and the main group metal salt MD are placed in an organic solvent L, and the reaction is carried out at 50 to 150 ° C for 12 to 24 hours to obtain a target complex molecule in one step:
  • the ligand represented by the formula VII and the main group metal salt ML are placed in an organic solvent, and the reaction is carried out at 50 to 150 ° C for 12 to 24 hours to obtain a target complex molecule in one step.
  • the organic solvent is methanol, ethanol or acetonitrile or the like.
  • MD represents a metal salt.
  • L is a neutral ligand such as methanol, acetonitrile or the like;
  • the organic solvent is selected from the group consisting of acetone, dimethylformamide, dimethyl sulfoxide, pyridine, methanol, ethanol and acetonitrile; preferably, the reaction conditions are from 90 to 150 ° C for 12 to 24 hours.
  • the preparation method further includes post-treatment, and the typical post-treatment is to precipitate the product from the reaction system by a recrystallization operation.
  • the work-up is recrystallized from an acetonitrile/diethyl ether solvent system to precipitate the complex solids from the system.
  • the main group metal complex containing the structure of formula I or formula II provided by the invention has obvious killing effect on cancer cell lines, and has significant toxicity to various cancer cell lines, and the half-lethal concentration in 24 hours is generally below 2 ⁇ M. .
  • the difference in the median lethal concentration of such compounds against cancer cell lines can be up to 10 times, and thus has a certain killing selectivity for cancer cell lines.
  • the main group metal complex provided by the invention has obvious killing effect on cancer cell lines, wherein the representative complex 1 has significant toxicity to various cancer cell lines, and the half-lethal concentration in 24 hours is generally below 2 ⁇ M; 11 has the lowest median lethal concentration for human malignant melanoma cells and can reach 70 nM. Compared with normal cell lines, these compounds have certain killing selectivity for cancer cell lines, and the difference in median lethal concentration can be up to 10 times.
  • the main group metal complex portion provided by the present invention has strong fluorescence emission.
  • the mechanism of action of such complexes can be studied by confocal fluorescence imaging with experimental methods such as protein immunoblotting, mRNA gene chip and proteomics research.
  • this type of complex enters the cell by passive diffusion, inhibits the enzymatic activity of the protein disulfide isomerase family in the endoplasmic reticulum, impedes the normal protein folding process, and causes endoplasmic reticulum stress.
  • a series of unfolded protein reactions affect the state and function of mitochondria, causing mitochondria to swell and digest the membrane potential of the mitochondrial inner membrane, producing reactive oxygen species, ultimately destroying cell death caused by cell homeostasis. This is clearly different from the cancer cell killing mechanism of platinum-based anticancer drugs represented by cisplatin targeting nuclear DNA.
  • the main group metal Schiff base complex provided by the invention has obvious killing effect on cancer cells. It has been experimentally determined that this type of compound is significantly lower than the main group metal complex reported in the literature for 24 hours and half-killing of cancer cell lines, and even better than a part of transition metal complex containing anti-cancer activity including cisplatin. This means that this class of compounds is expected to be used as a small molecule anticancer drug in clinical treatment.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the main group metal complex of the structure represented by Formula I or Formula II as an active ingredient or the main group of the structure represented by Formula I or Formula II obtained by the aforementioned preparation method.
  • Metal complexes as well as pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable salt, solvate, non-covalent bond complex or prodrug of a main group metal complex containing a structure of the formula I or formula II can also be used as an active ingredient of a pharmaceutical composition.
  • the pharmaceutical composition may be prepared in various forms for predetermining the dosage of the active ingredient, for example, tablets, capsules, oral solutions, oral emulsions may be administered by gastrointestinal administration. Common dosage forms such as suppositories and granules.
  • the pharmaceutical composition provided by the present invention can also be administered by injection (including intravenous injection, intra-arterial injection, intramuscular injection, and intra-vertebral injection), by controlled release or by a delivery device, and the pharmaceutical composition can be, for example, an injection solution. Common dosage forms such as injection emulsion, injection slow release solution, and injection suspension.
  • the excipients in the composition should be inactive ingredients which are non-toxic to the human body in accordance with the route of administration or mode of administration.
  • the excipients can be in the form of a solid, liquid or gas.
  • Solid adjuvants include sodium chloride, dextrose, sodium lactate, poloxamer, sodium lauryl sulfate, sodium dodecylbenzenesulfonate sodium hydroxide, triethylamine, sodium carbonate, sodium hydrogencarbonate, sucrose , sodium carboxymethyl cellulose, gelatin, xanthan gum, povidone, starch, magnesium stearate, sodium carboxymethyl starch, talc and pectin; liquid adjuvants, for example, including ethylene glycol, hydrochloric acid, sulfuric acid , phosphoric acid, acetic acid, triethylamine, water, ethanol, isopropanol, peanut oil, soybean oil, syrup and glycerin; gaseous adjuvants, for example, including carbon dioxide and nitrogen.
  • the pharmaceutical composition provided by the present invention may be a sterile system in the form of an injection, the active ingredient and one or more excipients are prepared as a sterile solution or dispersion, or prepared as a sterile powder for preparing sterile water for injection before use. . It can be prepared by mixing with water, ethanol or a suitable excipient such as a blood isotonicity adjusting agent, a surfactant, an antioxidant, or the like.
  • the pharmaceutical composition should be stable in preparation and storage.
  • the active ingredient is used in a unit dosage form in an amount of from 0.01 mg to 10 g, and the amount of the active ingredient in the sterile system is from 0.01% to 10% by weight based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition provided by the present invention may be in an oral solid form, and the active ingredient is mixed with an auxiliary material such as a filler, a disintegrating agent, a binder and a lubricant, and then molded together by an appropriate apparatus.
  • an auxiliary material such as a filler, a disintegrating agent, a binder and a lubricant
  • the pharmaceutical composition may be an oral liquid prepared by dissolving or dispersing the active ingredient in a solvent, and mixing with an excipient such as a surfactant, a thickener, an emulsifier, a preservative, and the like.
  • an excipient such as a surfactant, a thickener, an emulsifier, a preservative, and the like.
  • the active ingredient and appropriate excipients may be prepared for topical administration, for example, rectal administration, transdermal administration, nasal administration, and the like.
  • the present invention also provides a main group metal complex, a pharmaceutically acceptable salt, a solvate, a non-covalent bond complex or a prodrug, or a pharmaceutical composition thereof, which comprises the structure of Formula I or Formula II, in the preparation of an anticancer Application in medicine.
  • the application is preparation for treatment including breast cancer, liver cancer, lung cancer, melanoma, prostate cancer, colon cancer, colon cancer, glioblastoma, renal cancer, pancreatic cancer, gastric cancer, lymphoma, cervical cancer, ovary Applications in cancer, esophageal cancer, nasal cancer, leukemia, ductal carcinoma of the breast, gallbladder cancer, testicular cancer, cardiac cancer, and thyroid cancer.
  • the specific dose may vary from patient to patient.
  • the dosage level of the drug is 0.01 to 200 mg/kg body weight per day, or 0.5 to 14 g per patient per day.
  • the invention also provides the use of a main group metal complex, salt, solvate, non-covalent bond complex or precursor material comprising a structure of formula I or formula II for optical labeling.
  • the main group metal complex of the structure represented by Formula I or Formula II has strong fluorescence emission, and can be used to prepare fluorescent labels by using its fluorescent property, thereby having the use in fluorescent labeling, especially in single-two-photon fluorescent labeling. use.
  • the complexes provided by the present invention have a fluorescent color that is significantly different from the autofluorescence of a biological system.
  • a complex containing the structure shown in Example 1 of the present invention has a red fluorescence emission and a fluorescence quantum yield of up to 50%, which is clearly distinguishable from autofluorescence in a biological system.
  • a main group metal complex containing a structure of the formula I or formula II can be used as an imaging probe.
  • cell activity can be studied using the fluorescent properties of the main group metal complex provided by the present invention, such as localization of host metal complexes or complexes thereof in cells, uptake of cells, and downstream of cell production. Physiological changes, etc.
  • the fluorescence imaging of the main group metal complex provided by the present invention can be utilized to study the distribution of the main metal complex in vivo to better achieve targeted administration so as to be set.
  • the active ingredient for example, a main group metal complex, a salt, a solvate, a prodrug, or a complex or chemical modification of a main group metal complex and other components provided by the present invention is positioned in the vicinity of the tumor tissue.
  • the main group metal complex containing the structure of Formula I or Formula II can be used to prepare a targeted formulation.
  • the main group metal complex containing the structure represented by Formula I or Formula II provided by the present invention has excellent luminescent properties, and can also be used as a small molecular material for luminescence in non-biological systems, in materials, OLEDs (organic light-emitting diodes), dyes.
  • OLEDs organic light-emitting diodes
  • the field of sensitized solar cells also has potential application value.
  • Complex 1 was characterized by nuclear magnetic resonance spectroscopy, carbon spectroscopy, high resolution mass spectrometry and infrared spectroscopy, and characterized by UV-visible absorption spectroscopy and fluorescence spectrometry.
  • M gallium
  • L acetonitrile
  • Y is hydrogen
  • two benzene rings are in the salicylaldehyde residue.
  • the modifications are N-propargyl-N-methylamino and diethylamino groups at the R3 position, respectively, and Z is a chloride ion.
  • the intermediate product a 4-N-propargyl-N-methylaminosalicylaldehyde and gallium trichloride were dissolved in acetonitrile in a ratio of 1:1:5, and refluxed at 90 ° C for 24 hours. After the refluxing was stopped, a large amount of diethyl ether was added to the system to precipitate a dark red solid, and the precipitated solid was collected by filtration and washed with diethyl ether to obtain a complex 2.
  • M gallium
  • L acetonitrile
  • Y is hydrogen
  • the modification on the benzene ring in the salicylaldehyde residue is the R3 position of the second Amino group
  • D is a chloride ion.
  • the complex 3 was characterized by nuclear magnetic resonance spectroscopy, carbon spectroscopy, high resolution mass spectrometry and infrared spectroscopy, and characterized by UV-visible absorption spectrometer and fluorescence spectrometer.
  • the substituted salicylaldehyde and diamine precursors corresponding to the complex 11 and gallium trichloride were placed in acetonitrile, and refluxed at 90 ° C for 24 hours. After the reflux was stopped, a large amount of diethyl ether was added to the system to precipitate a yellow solid, and the precipitated solid was collected by filtration and washed with diethyl ether to obtain a pure complex 11.
  • the complex 11 was characterized by nuclear magnetic resonance spectroscopy, carbon spectroscopy, high resolution mass spectroscopy and infrared spectroscopy, and characterized by UV-visible absorption spectroscopy and fluorescence spectrometry.
  • the complex 5 was characterized by nuclear magnetic resonance spectroscopy, carbon spectroscopy, high resolution mass spectrometry and infrared spectroscopy, and characterized by UV-visible absorption spectrometer and fluorescence spectrometer.
  • the cell line used in cell experiments was from Peking University. The cells were cultured in a cell culture incubator at a constant temperature of 37 ° C, containing 5% CO 2 and a saturated water vapor atmosphere.
  • the medium used was a high sugar Du's modified Eagle's medium containing 10% fetal calf serum, 100 ⁇ g/mL penicillin and 100 U/mL streptomycin. Cells were grown in six-well plates and passaged every other day. The cytotoxicity of the complex was assessed via the CCK-8 kit by passage of cells into 96-well plates containing approximately 25,000 cells per well and 200 [mu]L of medium.
  • A is the absorption value of light of 450 nm wavelength; the subscript s indicates the pore to be tested containing the sample, c indicates the living cell control well without the sample, and b indicates the blank control well containing no sample and cells. Cytotoxicity plotted curve obtained by cell viability at different concentrations of the complex, complex and accordingly reads out the median lethal concentration cell line IC 50.
  • the toxicity of the complex to the HeLa cell line was screened by the above method, and the cytotoxicity curve of the complex 1 against the human cervical cancer cell line HeLa is shown in FIG. 2 . Then, the complexes were subjected to multi-cell line toxicity selectivity experiments. The relevant results are shown in Figure 1.
  • A375 is a human malignant melanoma cell line
  • A549 is a human non-small cell lung cancer cell line
  • SW480 is a human colorectal cancer cell line, MCF7.
  • the 24-hour half-lethal concentration of the complexes 1, 11, and 5 for different cell lines is at a level of 0.1 nM to 2 ⁇ M, and has a significant killing effect on cancer cells.
  • the multi-cell line toxicity selective control experiment of the complex 3 (3#) and cisplatin prepared in Example 3 was carried out by the above method, and the cell lines used were Hela, HepG2 liver cancer cell line, A375, MCF7, MOLT-4 acute lymphoblastic leukemia cells, MDA-MB-231 highly metastatic malignant breast cancer cell line, A549, HEK293 human renal epithelial cell line, COS7 renal epithelial cells, DU145 prostate cancer cells, Raw264.7 mononuclear macrophages cell.
  • Table 1 The results are shown in Table 1 below.
  • the 24-hour half-lethal concentration of complex 3 for different cell lines is at a level of 0.1 M to 2 ⁇ M, which has a significant killing effect on cancer cells relative to cisplatin.
  • the cell line used in cell experiments was from Peking University. The cells were cultured in a cell culture incubator at a constant temperature of 37 ° C, containing 5% CO 2 and a saturated water vapor atmosphere.
  • the medium used was a high sugar Du's modified Eagle's medium containing 10% fetal calf serum, 100 ⁇ g/mL penicillin and 100 U/mL streptomycin. Cells were grown in six-well plates and passaged every other day. The cytotoxicity of the complex was assessed via the CCK-8 kit by passage of cells into 96-well plates containing approximately 25,000 cells per well and 200 [mu]L of medium.
  • A is the absorption value of light of 450 nm wavelength; the subscript s indicates the pore to be tested containing the sample, c indicates the living cell control well without the sample, and b indicates the blank control well containing no sample and cells. Examples of cell viability obtained at different concentrations of complex curves plotted cytotoxic 1-6, and accordingly reads out complex half lethal concentration IC 50 for the cell lines.
  • the safety index (SI) is calculated according to the following formula:
  • SI IC 50 (HUVEC) / IC 50 (Hela)
  • the cell lines used were: HeLa, HepG2, MCF7, SW480, A375, A549, normal colonic epithelial cells NCM460, human microglia CHEM5 and human umbilical vein endothelial cells HUVEC.
  • a IC 50 value is determined by the MTT method. .
  • the instrument used for live cell fluorescence imaging was a Nikon A1R-si laser scanning confocal fluorescence microscope (Japan).
  • the cells were transplanted on a 0.1 mM polylysine-treated round coverslip and attached, and placed in complete medium for 24 hours, after which they were treated with the sample to be tested.
  • the treated live cell sample was rinsed twice with a phosphate buffer solution and placed under a microscope for imaging.
  • Example 3 the complex prepared in Example 3 was excited by a 3,488 nm laser and detected by a 585/65 detector channel.
  • Fig. 3 (1) is a fluorescence diagram of the complex 3 in the cells, (2) is a commercially available mitochondrial marker fluorescence map, and (3) is (1) and (2) overlapped. Image, (4) is a cell-free fluorescent image. It can be seen that the complex 3 is mainly distributed in the mitochondria in the cells, and is also distributed in the mitochondria of the tumor cells when it is accumulated in the tumor site.
  • the instrument used was Xenogen's in vivo imaging system (Caliper Life Sciences, Hopkinton, MA, USA), using imaging parameters of 500 nm excitation, 560-620 detector channel detection. After 72 hours, the nude mice were dissected and the main organs were taken out, placed under an imager and imaged with the same parameters, and the distribution of the complexes in each organ was observed.
  • complex 3 and complex 11 accumulated a lot in tumor tissues after 72 hours of intravenous injection.
  • the accumulation of complexes in the main organs heart, liver, spleen, lung, and kidney is shown in Figure 4, B and C. 3# and 11# in the liver.
  • the accumulation of matter is much higher than other organs, and there is almost no accumulation in the heart and spleen.
  • the concentration of the 3# or 11# complex in the main organs was measured by ICP-MS (Inductively Coupled Plasma Mass Spectrometry).
  • concentrations of the 3# and 11# complexes in the tumor tissues were 8.84 and 9.55 ⁇ g/g, respectively, which were higher than those in the heart, spleen, lung and kidney, indicating that the complex could accumulate in the tumor tissue, which is consistent with the fluorescence image.
  • Nude mice bearing HeLa transplanted tumors were divided into 4 groups of 8 rats each. After the tumor volume was as long as substantially 200 mm 3 , treatment was performed with cisplatin, complex 3 prepared in Example 3, and complex 11 prepared in Example 4, respectively, and a tumor control group was set. The dosage of the drug was 4 ⁇ mol/kg, and the frequency was once every 2 days. The Tumor volume is calculated from the length and width of the tumor. The specific formula is as follows:
  • Wc and Wt were the tumor mass of the control group and the experimental group, respectively.
  • Fig. 5 After treatment, the tumor volume and mass change curves are shown in Fig. 5, A and B.
  • the therapeutic effect of complex 11# is better than that of complex 3#.
  • the volume and mass of the tumor after treatment in the complex group are always smaller than that of cisplatin group.
  • the groups were superior to the control group.
  • the free complexes 3# and 11# significantly inhibited the growth of the tumor, and after 21 days of treatment, the tumor inhibition rates of the complexes 3# and 11# were 56.8% and 84.6%, respectively.
  • the tumor inhibition rate of cisplatin was 29.9%. The results show that the free gallium complexes 3# and 11# have better antitumor effects than free cisplatin.
  • the body weight of the nude mice did not significantly fluctuate during the treatment of all the groups, indicating that these treatments were well tolerated and did not cause acute side effects during the treatment.
  • the histological changes of the tumor tissues were examined by H&E staining. As shown by D in Fig. 7, the tumor tissues showed different degrees of necrosis after treatment, and the complex treatment effect was superior to that of cisplatin.
  • ALT alanine aminotransferase
  • BUN urea nitrogen
  • TG triglyceride
  • CK creatine kinase
  • AST aspartate aminotransferase
  • CREA high Density lipoprotein
  • HDLC high Density lipoprotein
  • LDH lactate dehydrogenase
  • Renal function was associated with BUN and CREA blood parameters and liver function.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) showed results in the blood of nude mice, as shown in Figure 8, cisplatin It causes acute liver and kidney toxicity, while complexes 3# and 11# can significantly reduce the damage of kidney and liver function caused by cisplatin or tumor formation, and blood biochemical indicators return to the level of healthy groups.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了一种主族金属配合物，或其药学上可接受的盐、溶剂化物、非共价键复合物或前体药物，所述主族金属配合物由希夫碱类平面四齿配体和p区主族金属离子。该主族金属配合物的制备简单便利，得到的主族金属配合物对多种癌细胞系均表现出了高细胞毒性，并且对杀伤效果具有选择性。将本发明提供的主族金属配合物制备为药物组合物或药物制剂后可以用于肿瘤治疗。该主族金属配合物还具有荧光性能，可以用于荧光标记。

Description

主族金属配合物及其制备方法和应用 技术领域
本发明涉及一系列具有癌细胞杀伤效果的主族金属配合物及其制备方法和治疗癌症的用途。
背景技术
金属配合物类小分子抗癌药物是一类重要的癌症化疗药，在这一领域中现有研究多集中在以铂、钌、金等为主的过渡金属配合物上，对主族金属配合物的抗癌研究则相对较少。
不少研究表明，第13族、14族以及15族的主族金属配合物具有药用活性和抗癌活性(Seng,H-L.and E.R.T.Tiekink；Main-Group Medicinal Chemistry Including Li and Bi.Comprehensive Inorganic Chemistry II,Vol 3.Oxford:Elsevier；2013,951-974)。近年来被报道的具有细胞杀伤能力的主族金属配合物包括缩氨基硫脲的铟、锡的配合物(Galvan-Hidalgo,J.M.；et al.J.Organometal.Chem.2017,848,332-343)、镓的三麦芽酚和三-8-羟基喹啉配合物(Gogna,R.；Madan,E.；Keppler,B.；Pati,U.；Br.J.Pharmacol.,2012,166,617)、以及有机锗黄杨素配合物等(Yang F.,et al.；Bioorg.Med.Chem.Lett.,2013,23,5544)。除此之外，镓咔咯配合物也被报道有着明显高于配体的光动力治疗活性(M.Pribisko,J.Palmer,R.H.Grubbs,H.B.Gray,J.Termini,P.Lim；PNAS,2016,113(16),E2258)。
现有主族金属配合物的抗癌能力研究大多停留在体外实验阶段。与以顺铂为代表的过渡金属配合物相比，在作为抗癌药物的应用上有着治疗方式受限或是起效时间长、毒性低的缺点，但这些工作也展示了主族金属配合物作为抗癌药物应用的可能性。
越来越多的证据表明，第13族、14族以及15族的主族金属配合物中，主族金属元素、主族金属元素键合的配合物的种类和结构都会影响主族金属配合物的药用活性和抗癌活性。选择适当的主族金属元素和适当结构的配合物对于提高主族金属配合物的药用活性和抗癌活性则非常有意义。
发明内容
为了解决上述问题，本发明人进行了锐意研究，结果发现：水杨醛或取代水杨醛、二胺前体以及主族金属反应后可以得到具有抗肿瘤作用的主族金属配合物；该主族金属配合物还具有荧光性能，因而还可以作为光标记物使用，从而完成了本发明。
本发明的目的在于提供以下方面：
第一方面，本发明提供了一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物，或其药学上可接受的盐、溶剂化物、非共价键复合物或前体药物，
Figure PCTCN2019086272-appb-000001
所述主族金属配合物，包括其正离子，由希夫碱类平面四齿配体和p区主族金属离子组成，其中，
M表示p区主族金属；
X代表二胺残基，其两侧亚胺键的氮原子以取代或不取代的C 1-12烷基或C 2-12烯基互相连接，或是作为取代或不取代的芳基或杂环芳基中的临位取代基；
Y为氢、C 1-12烷基、卤素、卤素取代烷基、氰基、氨基、羰基、C 1-12烷氧基或取代氨基；
Z为氢、C 1-12烷基、卤素、硝基、羟基、巯基或羧基；
R 1、R 2、R 3和R 4为对配体骨架中苯环上的取代基，各自独立地选自氢、卤素、硝基、羟基、巯基、羧基、氨基、氰基、C 1-12烷基、C 2-12烯烷基、C 2-12炔烷基、C 1-8烷氧基、C 2-8烯氧基、C 2-8炔氧基、C 1-8烷硫基、C 3-8杂环基、芳基、C 1-8烷酰基、C 1-8烷酰胺基、C 1-8烷基磺酰基、芳基磺酰基、C 1-12烷基取代氨基或卤素取代C 1-12烷基；
或者，R 1、R 2、R 3和R 4中相邻的两个取代基(R 1与R 2、R 2与R 3和/或R 3与R 4)可以成环。
第二方面，本发明提供了一种上述主族金属配合物的制备方法，将式V所示水杨醛或取代水杨醛、式VI所示二胺前体以及主族金属盐MD置于有机溶剂L中，于50～150℃下进行反应12～24h，即得：
Figure PCTCN2019086272-appb-000002
其中，式Ⅳ可以按照以下反应方程式进行，将式Ⅶ所示配体以及主族金属盐MD置于有机溶剂L中，于50～150℃下进行反应12～24h，一步合成得到目标配合物分子：
Figure PCTCN2019086272-appb-000003
第三方面，本发明提供了一种使用上述主族金属配合物为活性成分的药物组合物，包括药学可接受的辅料。
第四方面，本发明提供了一种上述主族金属配合物的药物制剂，所述制剂包括经胃肠道给药制剂和注射给药制剂，
经胃肠道给药制剂包括片剂、胶囊剂、口服溶液剂、口服乳剂、栓剂和颗粒剂；
注射给药制剂包括注射溶液、注射乳剂、注射缓释溶液剂、注射混悬剂。
第五方面，本发明提供了一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物、药学可接受的盐、溶剂化物、非共价键复合物或前体药物，药物组合物或制剂在制备抗癌药物中的应用；
所述应用为制备治疗包括乳腺癌、肝癌、肺癌、黑色素瘤、前列腺癌、结肠癌、大肠癌、胶质母细胞瘤、肾癌、胰腺癌、胃癌、淋巴癌、宫颈癌、卵巢癌、食管癌、鼻癌、白血病、乳腺导管癌、胆囊癌、睾丸癌、贲门癌和甲状腺癌的药物中的应用；
药物的剂量水平为0.01～200mg/kg体重每天，或者每个病人每天0.5～14g。
第六方面，本发明提供了一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物、盐、溶剂化物、非共价键复合物或前体物质，在光标记中的用途；特别在荧光标记中的用途；
优选在荧光成像探针、靶向制剂、材料、有机发光二极管、染料敏化太阳能电池中的应用。
特别的，本发明提供了一种主族金属配合物，由希夫碱类平面四齿配体和p区主族金属离子以及轴向单齿配体组成，其结构如下式所示：
Figure PCTCN2019086272-appb-000004
(1)、其中，M代表p区主族金属；X代表二胺残基，其两侧亚胺键的氮原子以碳数1～5的脂肪链或取代脂肪链互相连接，或是作为芳香环的临位取代基；Y为氢或烷基；R 1、R 2、R 3和R 4各自独立选自氢、卤素、硝基、羟基、氨基、取代氨基、烷基、烷氧基、卤素取代烷基、巯基或烷硫基，其中相邻的两个取代基R 1与R 2、R 2与R 3和/或R 3与R 4可以成环；L代表一个或多个轴向单齿配体，为卤素、氧配位小分子或氮配位小分子；Z为氢或烷基。
M为铝、镓、铟、铊、锗、锡或铅。
所述X代表苯、取代苯或吡啶环，或者主链为C1-C3的脂肪链或是取代脂肪链。
所述卤素选自F、Cl、Br和I中的一种或多种；所述烷基为C1～C12烷基；所述取代氨基为C1～C12烷基取代氨基；所述烷氧基为C1～C8烷氧基；所述卤素取代烷基为一个或多个卤素取代的C1～C12烷基；所述烷硫基为C1～C8烷基取代巯基；所述氧配位小分子选自甲醇、乙醇、丙酮、二甲基亚砜、四氢呋喃和水中的一种或多种；所述氮配位小分子选自吡啶、哌啶、正丙胺、乙二胺和乙醇胺中的一种或多种。
R1与R2、R2与R3和/或R3与R4成环，联合代表1,3-丁二烯-1,4-二基或1,4-二丁基。
(2)、所述主族金属配合物是下列配合物之一：
Figure PCTCN2019086272-appb-000005
(3)、所述主族金属配合物的制备方法，其反应式如下：
Figure PCTCN2019086272-appb-000006
将式所示水杨醛或取代水杨醛和上式所示二胺前体以及主族金属盐ML置于有机溶剂中，于50～150℃下反应12～24h，一步合成式I所示配合物；其中X、Y、M、L、R1、R2、R3和R4如(1)中所述。
(4)、所述主族金属配合物的制备方法，其反应式如下：
Figure PCTCN2019086272-appb-000007
将上式所示配体以及主族金属盐ML置于有机溶剂中，于50～150℃下进行反应12～24h，一步合成式II所示配合物；其中X、Y、Z、M、L、R1、R2、R3和R4如(1)中所述。
在(3)和(4)中的有机溶剂为甲醇、乙醇或乙腈，反应后用乙腈/乙醚溶剂体系进行重结晶，使配合物固体从体系中析出。
(5)所述主族金属配合物在制备抗癌药物中的应用。
根据本发明提供的主族金属配合物、制备方法及其用途，具有以下有益效果：
(1)本发明提供的主族金属配合物对多种癌细胞系均表现出了高细胞毒性，并且对杀伤效果具有选择性，比现有金属抗癌药物效果更加显著；
(2)本发明提供的主族金属配合物具有优良的荧光性能，可以作为光标记物使用，用于荧光标记特别是单双光子荧光标记，例如活体成像追踪、靶向制剂、材料等领域；
(3)本发明提供的主族金属配合物制备方法简单，容易制得。
附图说明
图1示出实验例1中配合物对不同癌细胞系的半数致死浓度；图2示出实验例1中配合物对人子宫颈癌细胞系HeLa的细胞毒性曲线；图3示出实验例3中细胞成像图；图4示出实验例4中小鼠活体实验的荧光图像；图5中A和B分别示出实验例5中活体抑瘤实验中治疗后肿瘤体积和质量的变化图；图6示出实验例5中活体抑瘤实验中裸鼠治疗后体重变化曲线；图7中D示出实验例5中活体抑瘤实验中肿瘤组织H&E染色图；E示出各实验组肿瘤部位的核磁共振黑白图和彩图；F示出E中各组肿瘤组织变化的标准差；图8示出实验例5活体抑瘤实验中血液学分析结果图；图9示出实验例5活体抑瘤实验中主要器官的H&E染色图。
具体实施方式
下面通过对本发明进行详细说明，本发明的特点和优点将随着这些示例性说明而变得更为清楚、明确。
在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
以下详述本发明。
本发明提供了一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物，或其药学上可接受的盐、溶剂化物、非共价键复合物或前体药物，
Figure PCTCN2019086272-appb-000008
所述主族金属配合物，包括其正离子，由希夫碱类平面四齿配体和p区主族金属离子组成，其中，
M表示p区主族金属；
X代表二胺残基，其两侧亚胺键的氮原子以取代或不取代的C 1-12烷基或C 2-12烯基互相连接，或是作为取代或不取代的芳基或杂环芳基中的临位取代基；
Y为氢、C 1-12烷基、卤素、卤素取代烷基、氰基、氨基、羰基、C 1-12烷氧基或取代氨基；
Z为氢、C 1-12烷基、卤素、硝基、羟基、巯基或羧基；
R 1、R 2、R 3和R 4为对配体骨架中苯环上的取代基，各自独立地选自氢、卤素、硝基、羟基、巯基、羧基、氨基、氰基、C 1-12烷基、C 2-12烯烷基、C 2-12炔烷基、C 1-8烷氧基、C 2-8烯氧基、C 2-8炔氧基、C 1-8烷硫基、C 3-8杂环基、芳基、C 1-8烷酰基、C 1-8烷酰胺基、C 1-8烷基磺酰基、芳基磺酰基、C 1-12烷基取代氨基或卤素取代C 1-12烷基；
或者，R 1、R 2、R 3和R 4中相邻的两个取代基(R 1与R 2、R 2与R 3和/或R 3与R 4)可以成环。
在本发明中，所述p区主族金属是指根据现有的化学元素周期表划分为p区主族元素中的金属元素，一般是指化学元素周期表中13族金属铝、镓、铟、铊和14族金属锗、锡、铅。
所述式Ⅰ或式Ⅱ中的M为铝、镓、铟、铊、锗或锡中的一种；优选所述式Ⅰ或式Ⅱ中的M为铝、镓、铟、铊或锗中的一种，最好式Ⅰ或式Ⅱ中的M为铝、镓、铟或锗中的一种。
在本发明中，除非特别说明，所述烷基、烯烷基、炔烷基、烷氧基、烯氧基、炔氧基、烷硫基、烷硫基、杂环基、芳基、杂环芳基、烷酰基、烷酰胺基、烷基磺酰基、芳基磺酰基、烷氨基和烃基取代氨基中的碳原子可以被卤素、硝基、羟基、巯基、羧基、氨基、氰基或羰基取代或不取代。
所述烷基是指包括直链、支链或环状的饱和烃基，例如，甲基、乙基、丙基、异丙基、丁基、叔丁基、环己基和2-乙基-4丙基-环己基；C 1-12表示烃链中碳原子的长度为1-12。
所述烯烷基是指在直链、支链或环状的烃链中含有烯基的烃基，烯基碳原子与配体苯基团上的碳原子连接或不连接。例如，乙烯基、1-烯丙基、1-苯基-烯丙基和2-甲基丙烯基。类似地，C 2-12烯烷基表示烯烷基中碳原子的总数为2-12。
所述炔烷基是指包括炔基的直链、支链或环状的烃基，炔基碳原子与配体苯基团上的碳原子连接或不连接。例如，丙炔基、炔丙基、2-甲基丁炔基。类似地，C 2-12炔烷基表示炔烷基中碳原子的总数为2-12。
所述烷氧基是指包括前述烷基的氧醚基，例如甲氧基、乙氧基、丙氧基等；C 1-8烷氧基表示烷氧基中碳原子的总数为1-8。
所述烯氧基是指含有烯基的直链、支链或环状烃基的氧醚基；C 2-8烯氧基是指烯氧基中碳原子的总数为2-8。
所述炔氧基是指含有炔基的直链、支链或环状烃基的氧醚基；C 2-8炔氧基是指炔氧基中碳原子的总数为2-8。
所述烷硫基是指包括前述烷基的硫醚基，例如甲硫基、乙硫基、丙硫基等；C 1-8烷硫基表示烷硫基中碳原子的总数为1-8。
所述杂环基是指含有杂原子的稳定3-8元饱和环状基团，该杂原子与配体中苯连接或不连接，优选连接。典型的杂原子包括氧、硫和氮。例如，四氢吡咯基、喹啉、噻吩、呋喃等。C 3-8杂环基是指在杂环基中碳原子的总数为3-8。
所述芳基是指含有苯基团的芳香环，一般为苯、萘、蒽或菲，优选为苯、萘。
所述杂环芳基是指包括杂原子的单芳环或多芳环基团，优选为5-10元的环。所述多环芳香基团可以是双单芳环、苯并单芳环或者稠合芳香环基团。例如，芳基可以是呋喃、吡啶、噻吩、咪唑、吡咯、哒嗪、吡嗪、苯并吡咯、苯并呋喃、苯并异喹啉或吡嗪并哒嗪等。
烷酰基是指含有前述烷基的酰基，C 1-8烷酰基表示其中含有的碳原子总数为1-8。
烷酰胺基指含有前述烷基的烷酰胺基，C 1-8烷酰胺基表示其中含有碳原子的总数为1-8。
烷基磺酰基指含有前述烷基的烷基磺酰基，C 1-8烷基磺酰基表示其中含有碳原子的总数为1-8。
芳基磺酰基指含有前述芳基的磺酰基。
所述烷基取代氨基是指被前述烷基取代的氨基，例如甲胺基、乙胺基、二甲胺基、二乙胺基等；C 1-12烷氨基表示取代烷基中碳原子中总数为1-12。
进一步地，所述X两侧的氮原子以碳数1～5的脂肪链或取代脂肪链互相连接，或是作为芳香环的邻位取代基。
优选所述式Ⅰ或式Ⅱ中的X选自-CH 2-、-CH 2-CH 2-、-CH(CH 3)-CH 2-、-CH(CN)-CH(CN)-、-CH(CN)-CH 2-、-CH 2(Cl)-CH(CN)-、-CH 2(OH)-CH(CN)-、-CH 2(Cl)-CH 2-、-CH 2(OH)-CH 2-、-CH＝CH-、-CO-CH(CN)-、-C(CN)＝C(CN)-、-CH＝C(CN)-、-CH＝C(Cl)-、-CH＝CH-CH＝CH-、-CH＝C(CN)-CH＝CH-、-CH＝C(NH 3)-或-CO-CH 2-，或者作为取代或未取代的苯、萘、蒽、菲、吡啶、咪唑、吡咯、噻吩、呋喃、苯并吡咯或苯并呋喃的邻二取代基团。X为环状基团时通过相邻的两个环状骨架原子与对配体的亚氨基连接。
更优选X选自-CH 2-、-CH 2-CH 2-、-CH(CN)-CH(CN)-、-CH(CN)-CH 2-、-CH 2(Cl)-CH(CN)-、-CH 2(Cl)-CH 2-、-CH 2(OH)-CH 2-、-CH＝CH-、-C(CN)＝C(CN)-、-CH＝C(CN)-、-CH＝C(Cl)-或-CH＝C(NH 3)-，或者，作为苯、吡啶、苯并吡啶、咪唑、呋喃、氰基取代的苯、萘、氰基取代的萘的邻二取代基团。
在一些优选的实施方式中，所述式Ⅰ中的X与对配体中的两个亚氨基形成共轭结构。
在这些实施方式中，X可以选自乙烯、氰基取代的乙烯、1,3-丁二烯、氰基取代的1,3-丁二烯苯、苯、吡啶、苯并吡啶、萘、氰基取代的萘基团。
优选式Ⅰ或式Ⅱ中的X选自乙烯、氰基取代的乙烯、1,3-丁二烯、苯、苯、氰基取代的苯、吡啶或氰基取代的吡啶基团。
X最好选自-CH＝CH-、-C(CN)＝C(CN)-、-CH＝C(CN)-、-CH＝C(CN)-CH＝CH-、-CH＝C(NH 3)-或-CO-CH 2-；或者作为
Figure PCTCN2019086272-appb-000009
Figure PCTCN2019086272-appb-000010
的邻二取代基团。
在一些优选的实施方式中，X是-C(CN)＝C(CN)-。
在一些优选的实施方式中，X是苯基团。
在一些优选的实施方式中，X是4-氰基取代苯基团。
在一些优选的实施方式中，X是4,5-二氰基取代苯基团。
在一些优选的实施方式中，X是
Figure PCTCN2019086272-appb-000011
在一些实施方式中，所述式Ⅰ或式Ⅱ中的X为取代或不取代的饱和烷基，在这些实施方式中，所述X优选选自-CH 2-、-CH 2-CH 2-、-CH 2(Cl)-CH 2-、-CH(CN)-CH(CN)-、-CH 2(OH)-CH 2-或-CH 2(CH 3)-CH 2-；更优选X为-CH 2-、-CH 2-CH 2-、-CH 2(Cl)-CH 2-或-CH 2(CH 3)-CH 2-。
进一步地，所述式Ⅰ或式Ⅱ中的Y为氢、卤素、氰基、C 1-4烷基或C 1-4烷氧基。
其中，所述卤素包括F、Cl、Br和I。
所述式Ⅰ或式Ⅱ中的Y为烷基时进一步优选为C 1-3烷基。
优选所述Y为氢、卤素、氰基、甲基、乙基、异丙基、甲氧基、乙氧基、卤素取代C 1-3烷基或卤素取代C 1-3烷氧基。
更优选所述Y为氢、卤素、氰基、甲基或甲氧基。
所述Z为氢、C 1-10烷基、卤素、硝基、羟基、巯基或羧基；优选为Z为氢、C 1-6烷基、卤素、硝基、羟基、巯基或羧基。
在一些实施方式中，所述Z为氢。
本发明提供的主族金属配合物中，所述R 1、R 2、R 3和R 4各自独立地选自氢、卤素、硝基、羟基、巯基、羧基、氨基、氰基、C 1-12烷基、C 2-12烯烷基、C 2-12炔烷基、C 1-8烷氧基、C 2-8烯氧基、C 2-8炔氧基、C 1-8烷硫基、C 3-8杂环基、芳基、C 1-8烷酰基、C 1-8烷酰胺基、C 1-8烷基磺酰基、芳基磺酰基、N,N-二(C 1-6烷基)氨基、N-(C 1-6烷基)-N-(C 1-6烷基) 氨基、N-(C 1-6烷基)-N-C 1-6炔烷基)氨基、N,N-二芳基氨基、N-(C 1-6烷基)-N-芳基氨基、N-(C 1-6烷基)-N-杂环基氨基、-CF 3-、-ClCH 2-、-ClCH 2-CH 2-、(CH 3) 2C(CH 2Cl)-、CH2-CH 2Cl-CH(CH 3) 2-或卤素取代的C 3-6环状烷基，所述C 3-6环状烷基包括卤素取代环己基、卤素取代环戊基和卤素取代甲基环戊基。
优选地，所述式Ⅰ或式Ⅱ中的R 1、R 2、R 3和R 4各自独立地选自氢、氟、氯、溴、碘、硝基、羟基、巯基、氨基、氰基、C 1-5烷基、C 1-4烷硫基、C 1-4烷氧基、C 1-8烷氨基、N,N-二(C 1-6烷基)氨基、N-(C 1-6烷基)-N-(C 1-6烷基)氨基、N-(C 1-6烷基)-N-(C 3-6炔烷基)氨基、C 3-8不饱和杂环基、C 3-8饱和杂环基、卤素取代的C 5-6环状烷基或卤素取代的C 1-6烷基。
在一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 1、R 2和R 4各自独立地是氢、氰基、巯基、C 2-4烷硫基或C 1-5烷基；
在一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 1是氢，R 4是氢、氰基或C 1-5烷基，R 2是氢、巯基、C 2-4烷硫基或C 1-5烷基。
一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 1和R 2都是氢，R 4是巯基或C 2-4烷硫基；
一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 1和R 4都是氢，R 2是巯基或C 2-4烷硫基；
在一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 1、R 2和R 4都是氢。
所述式Ⅰ或式Ⅱ中的R 3选自氢、氟、氯、氨基、C 1-8烷氨基、C 1-4烷氧基、N,N-二(C 1-5烷基)氨基、N-(C 1-6烷基)-N-(C 1-4烷基)氨基、N-(C 1-4烷基)-N-(C 3-5炔烷基)氨基、C 3-8不饱和氮杂环基或C 3-8饱和氮杂环基。
优选所述式Ⅰ或式Ⅱ中的R 3选自氢、C 1-4烷氧基、N,N-二(C 1-5烷基)氨基、N-(C 1-4烷基)-N-(C 1-2烷基)氨基、N-(C 1-4烷基)-N-(C 3-5炔烷基)氨基或C 3-5饱和氮杂单环基。
更优选所述式Ⅰ或式Ⅱ中的R 3选自氢、甲氧基、乙氧基、异丙氧基、N,N-二甲基氨基、N,N-二乙基氨基、N,N-二丙基氨基、N-(2-甲基正丁基)氨基、N-正丁基-N-甲基氨基、N-乙基-N-甲基氨基、N-正丁基-N-乙基氨基、N-炔丙基-N-甲基氨基、N-炔丁基-N-乙基氨基、四氢吡咯、氢化吡啶或氢化咪唑。
一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 3是N,N-二甲基氨基，R 4是C 2-4烷硫基；
在一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 3是N,N-二乙基氨基，R 4是巯基或C 1-4烷基或C 1-4烷氧基；
在一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 3是氢、甲氧基、N,N-二乙基氨基、N,N-二甲基氨基、N-甲基-N-正丁基氨基、N-甲基-N-炔丙基氨基或四氢吡咯是，R 4是氢；
在一些优选的实施方式中，式Ⅰ或式Ⅱ中的R 1、R 2、R 3和R 4都是氢。
在本发明提供的主族金属配合物中，R 1、R 2、R 3和R 4中相邻的两个取代基(R 1与R 2、R 2与R 3和/或R 3与R 4)还可以成环。
R 1与R 2、R 2与R 3和/或R 3与R 4成环时，联合代表1,3-丁二烯-1,4-二基，1,4-二丁基等，与所在的苯环联合形成萘、四氢化萘等。
在一些实施方式中，式Ⅰ或式Ⅱ中R 2与R 3或R 3与R 4成环，优选形成，
Figure PCTCN2019086272-appb-000012
在一些实施方式中，式Ⅰ或式Ⅱ中R 2与R 3和R 3与R 4都成环，优选形成，
Figure PCTCN2019086272-appb-000013
优选地，本发明提供的含有式Ⅰ或Ⅱ所示结构的主族金属配合物还带有配体，如式Ⅲ和式Ⅳ所示：
Figure PCTCN2019086272-appb-000014
所述L表示一个或多个轴向单齿配体，包括阴离子配体、中性配体；所述L也可以是非配位阴离子；优选所述阴离子配体包括卤素(如氟、氯、溴、碘)离子、乙酸根离子；所述中性配体为氧配位或氮配位的配体，优选来自溶剂分子。
其中，氧配位的溶剂分子选自甲醇、乙醇、丙酮、二甲基亚砜、四氢呋喃、水、异丙醇、甘油、甲醛、乙酸、甲酸、乙醚和二甲基亚砜中的一种或多种；所述氮配位的溶剂分子选自吡啶、哌啶、正丙胺、乙二胺、乙醇胺、二甲基甲酰胺、乙腈、氨水和三乙胺中的一种或多种。
优选所述L选自氟离子、氯离子、溴离子、乙酸根离子、甲醇、乙醇、异丙醇、丙酮、二甲基亚砜、二甲基甲酰胺、吡啶或乙腈。
进一步地，本发明所提供的主族金属配合物，由希夫碱类平面四齿配体和p区主族金属离子以及轴向单齿配体组成，在式Ⅲ和式Ⅳ中，
M代表p区主族金属；X代表二胺残基，其两侧亚胺键的氮原子以碳数1～5的脂肪链或取代脂肪链互相连接，或是作为苯、取代苯、吡啶等芳香环的临位取代基；Y为氢或烷基；R 1、R 2、R 3和R 4为对配体骨架中苯环上的取代基，各自独立选自氢、卤素、硝基、羟基、氨基、取代氨基、烷基、烷氧基、卤素取代烷基、巯基或烷硫基，其中相邻的两个取代基(R 1与R 2、R 2与R 3和/或R 3与R 4)可以成环；L代表一个或多个轴向单齿配体，为卤素、氧配位小分子或氮配位小分子；式II中的Z为氢或烷基。
所述M优选为13族金属铝、镓、铟、铊或14族金属锗、锡、铅中的一种。
所述X例如苯、取代苯、吡啶等芳香环，以及主链为C1-C3的脂肪链或是取代脂肪链，其中所述取代脂肪链上取代基例如氰基。在本发明的一些实施例中，X为-CH 2-CH 2-、邻二取代苯或-C(CN)＝C(CN)-等。
所述卤素包括F、Cl、Br和I。
所述烷基优选为C1～C12烷基，更优选为C1～C6烷基，例如甲基、乙基、丙基、异丙基、丁基等。
所述取代氨基优选为C1～C12烷基取代氨基，更优选为C1～C6烷基取代氨基，例如甲胺基、乙胺基、二甲胺基、二乙胺基等。
所述烷氧基优选为C1～C8烷氧基，更优选为C1～C4烷氧基，例如甲氧基、乙氧基、丙氧基等。
所述卤素取代烷基优选一个或多个卤素取代的C1～C12烷基，更优选为一个或多个卤素取代的C1～C6烷基，例如三氟甲基等。
所述烷硫基优选C1～C8烷基取代巯基，更优选为C1～C4烷基取代巯基，例如甲硫基、乙硫基、丙硫基等。
R 1与R 2、R 2与R 3和/或R 3与R 4成环时，联合代表1,3-丁二烯-1,4-二基，1,4-二丁基等，与所在的苯环联合形成萘、四氢化萘等。
所述氧配位小分子例如甲醇、乙醇、丙酮、二甲基亚砜、四氢呋喃、水等；所述氮配位小分子例如吡啶、哌啶、正丙胺、乙二胺、乙醇胺等。
所包含主族金属配合物的代表性配合物，例如：
Figure PCTCN2019086272-appb-000015
配合物一：M为铟，L为氯，X为-CH 2-CH 2-，Y为氢，水杨醛残基中苯环上无修饰；
配合物二：M为镓，L为氯，X为邻二取代苯，Y为氢，水杨醛残基中苯环上的修饰为R 3位的二乙基氨基。
配合物三：M为锗，L为两个氯，X为-C(CN)＝C(CN)-，Y为氢，水杨醛残基中苯环上的修饰为R 3位的甲氧基。
进一步地，本发明提供了一些含有式Ⅰ或式Ⅱ所示结构的主族金属配合物的示例，包括：
Figure PCTCN2019086272-appb-000016
Figure PCTCN2019086272-appb-000017
本发明提供的含有式Ⅰ或式Ⅱ所示的主族金属配合物也可以以药学上可接受的盐的形式存在，如下式Ⅴ或式 Ⅵ所示：
Figure PCTCN2019086272-appb-000018
本发明提供的化合物的盐是指无毒的药学上可接受的盐，一般为无机酸盐或有机酸盐。在式Ⅴ或式Ⅵ中D-表示形成盐的无机酸或有机酸的酸根。
典型的有机或无机酸包括盐酸、氢溴酸、氢碘酸、高氯酸、硝酸、乙酸、硫酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、苦杏仁酸、甲磺酸、苯磺酸、草酸、对甲苯磺酸、三氟甲磺酸、环己胺磺酸、水杨酸或三氟乙酸。
优选所述主族金属配合物的无机酸盐或有机酸选自盐酸、氢溴酸、高氯酸、硝酸、乙酸、硫酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、甲磺酸、苯磺酸、草酸、对甲苯磺酸、三氟甲磺酸或水杨酸。
更优选所述主族金属配合物的无机酸盐或有机酸选自盐酸、硝酸、乙酸、硫酸、乳酸、琥珀酸、马来酸、酒石酸、甲磺酸、苯磺酸、对甲苯磺酸、三氟甲磺酸或水杨酸。
在一些优选的实施方式中，所述含有式Ⅰ或式Ⅱ所示的主族金属配合物的药学上可接受的盐为盐酸盐、硝酸盐或三氟甲磺酸。
本发明提供的含有式Ⅰ或式Ⅱ所示结构的主族金属配合物也可以以药学上可接受的溶剂化物、非共价键复合物或前体药物的形式存在。
本发明还提供了一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物，特别是式Ⅲ或式Ⅳ所示结构的主族金属配合物的制备方法：
将式V所示水杨醛或取代水杨醛、式VI所示二胺前体以及主族金属盐MD置于有机溶剂L中，于50～150℃下进行反应12～24h，即可一步合成得到目标配合物分子，如下：
Figure PCTCN2019086272-appb-000019
或者，将下式所示水杨醛或取代水杨醛和下式所示二胺前体以及主族金属盐ML置于有机溶剂中，于50～150℃下进行反应12～24h，即可一步合成得到目标配合物分子。最佳反应条件为90℃反应24h。所述有机溶剂为甲醇、乙醇或乙腈等。涉及到的反应方程式如下：
Figure PCTCN2019086272-appb-000020
式Ⅳ可以按照以下反应方程式进行，将式Ⅶ所示配体以及主族金属盐MD置于有机溶剂L中，于50～150℃下进行反应12～24h，一步合成得到目标配合物分子：
Figure PCTCN2019086272-appb-000021
Figure PCTCN2019086272-appb-000022
或者，将式Ⅶ所示配体以及主族金属盐ML置于有机溶剂中，于50～150℃下进行反应12～24h，一步合成得到目标配合物分子。所述有机溶剂为甲醇、乙醇或乙腈等。
Figure PCTCN2019086272-appb-000023
本发明中，MD表示金属盐。进一步地，当M为M 2+时，L为中性配体，如甲醇、乙腈等；当M为M 3+或M 4+时，L＝D，为阴离子配体，如氯离子、溴离子、乙酸根等。
反应时，所述有机溶剂选自包括丙酮、二甲基甲酰胺、二甲基亚砜、吡啶、甲醇、乙醇和乙腈中的任意；优选反应条件为90～150℃反应12～24h。
所述制备方法还包括后处理，典型的后处理是通过重结晶操作，将产物从反应体系中析出。
在一种优选的实施方式中，后处理用乙腈/乙醚溶剂体系进行重结晶，使配合物固体从体系中析出。
本发明提供的含有式Ⅰ或式Ⅱ所示结构的主族金属配合物对癌细胞系有明显的杀伤效果，对多种癌细胞系均具有显著的毒性，24小时半数致死浓度普遍在2μM以下。相比于对正常细胞系而言，此类化合物对癌细胞系的半数致死浓度差别最大可以达到10倍以上，因而对癌细胞系具有一定的杀伤选择性。
其中，本发明提供的主族金属配合物对癌细胞系有明显的杀伤效果，其中代表性配合物1对于多种癌细胞系均具有显著的毒性，24小时半数致死浓度普遍在2μM以下；配合物11对人恶性黑色素瘤细胞的半数致死浓度最低，可达到70nM。相比于对正常细胞系而言，此类化合物对癌细胞系有一定的杀伤选择性，半数致死浓度差别最大可以达到10倍以上。
本发明提供的主族金属配合物部分具有较强的荧光发射。通过共聚焦荧光成像辅以蛋白免疫印记、mRNA基因芯片以及蛋白质组学研究等实验手段可以对此类配合物的作用机制进行研究。我们发现这一类配合物通过被动扩散的方式进入细胞后，抑制内质网内蛋白质二硫键异构酶家族的酶活性，阻碍正常的蛋白质折叠过程，引起包括内质网应激在内的一系列未折叠蛋白反应，影响线粒体的状态和功能，使线粒体发生肿胀并消解线粒体内膜的膜电势，产生活性氧物种，最终破坏细胞内稳态造成的细胞死亡。这与以顺铂为代表的铂系抗癌药物靶向核DNA的癌细胞杀伤机理有着明显的区别。
本发明所提供的主族金属希夫碱类配合物对癌细胞有明显杀伤效果。实验测得该类化合物对癌细胞系24小时半数致死明显低于文献已有报道的主族金属配合物，甚至优于一部分包含顺铂在内的有抗癌活性的过渡金属配合物。这意味着该类化合物有望作为小分子抗癌药物在临床治疗中得到应用。
我们发现，含有式Ⅰ或式Ⅱ所示结构的主族金属配合物通过被动扩散的方式进入细胞后，抑制内质网内蛋白质二硫键异构酶家族的酶活性，阻碍正常的蛋白质折叠过程，引起包括内质网应激在内的一系列未折叠蛋白反应，影响线粒体的状态和功能，使线粒体发生肿胀并消解线粒体内膜的膜电势，产生活性氧物种，最终破坏细胞内稳态造成的细胞死亡。这与以顺铂为代表的铂系抗癌药物靶向核DNA的癌细胞杀伤机理有着明显的区别。
因此，本发明还提供了一种药物组合物，包括作为活性成分的式Ⅰ或式Ⅱ所示结构的主族金属配合物或前述制备方法获得的含有式Ⅰ或式Ⅱ所示结构的主族金属配合物，以及药学可接受的辅料。含有式Ⅰ或式Ⅱ所示结构的主族金属配合物的药学可接受的盐、溶剂化物、非共价键复合物或前体药物，也可以用作药物组合物的活性成分。
根据药物组合物的给药方式，所述药物组合物可以制备为预先确定活性成分剂量的各种形式，例如，经胃肠道给药时可以采用片剂、胶囊剂、口服溶液剂、口服乳剂、栓剂和颗粒剂等常见剂型。本发明提供的药物组合物还可以采用注射给药(包括静脉注射、动脉注射、肌肉注射和脊椎腔注射)，通过控释的方式或通过输送装置给药，药物组合物可以采用例如注射溶液、注射乳剂、注射缓释溶液剂、注射混悬剂等常见剂型。
根据药物组合物的应用形式，所述组合物中的辅料应是符合用药途径或给药方式的对人体无毒害作用的非活性成分。
所述辅料可以是固体、液体或气体形式。固体辅料，例如，包括氯化钠、葡萄糖、乳酸钠、泊洛沙姆、十二烷基硫酸钠、十二烷基苯磺酸钠氢氧化钠、三乙胺、碳酸钠、碳酸氢钠、蔗糖、羧甲基纤维素钠、明胶、黄原胶、聚维酮、淀粉、硬脂酸镁、羧甲基淀粉钠、滑石粉和果胶；液体辅料，例如，包括乙二醇、盐酸、硫酸、磷酸、乙酸、三乙胺、水、乙醇、异丙醇、花生油、豆油、糖浆和甘油；气体辅料，例如，包括二氧化碳和氮气。
本发明提供的药物组合物可以是注射形式的无菌体系，将活性成分与一种或多种辅料制备为无菌溶液或分散体系，或者，制备为使用前配制无菌注射用水的无菌粉末。可以使用水、乙醇或适当的辅料，例如血液等渗调节剂、表面活性剂、抗氧化剂等，混合后制得。所述药物组合物在制备和存储中应当稳定。优选地，在单位剂型中活性成分的用量为0.01mg-10g，在无菌体系中该活性成分的质量为药物组合物总重的0.01％-10％。
本发明提供的药物组合物可以是口服固体形式，将活性成分与辅料，例如填充剂、崩解剂、粘合剂和润滑剂，混合后一起通过适当的仪器制备成型。
所述药物组合物可以是口服液体，将活性成分溶解或分散于溶剂中，与辅料，例如表面活性剂、增稠剂、乳化剂、防腐剂等，混合后制得。
除上述提到的不同形式的药物组合物，还可以将活性成分和适当的辅料制备为局部给药，例如，直肠给药、经皮给药、鼻腔给药等。
本发明还提供了含有式Ⅰ或式Ⅱ所示结构的主族金属配合物、药学可接受的盐、溶剂化物、非共价键复合物或前体药物，或其药物组合物在制备抗癌药物中的应用。
优选地，所述应用为制备治疗包括乳腺癌、肝癌、肺癌、黑色素瘤、前列腺癌、结肠癌、大肠癌、胶质母细胞瘤、肾癌、胰腺癌、胃癌、淋巴癌、宫颈癌、卵巢癌、食管癌、鼻癌、白血病、乳腺导管癌、胆囊癌、睾丸癌、贲门癌和甲状腺癌的药物中的应用。
根据病人的年龄、体重、健康状况、饮食、给药途径、联合用药、治疗时间等，具体的用药剂量可能会在病人间不同。一般情况下，在治疗上述疾病时，药物的剂量水平为0.01～200mg/kg体重每天，或者每个病人每天0.5～14g。
本发明还提供了一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物、盐、溶剂化物、非共价键复合物或前体物质，在光标记中的用途。
式Ⅰ或式Ⅱ所示结构的主族金属配合物具有较强的荧光发射，可以利用其荧光性质制备荧光标记物，因而具有在荧光标记中的用途，特别是在单双光子荧光标记中的用途。
研究发现，本发明提供的配合物具有与生物体系自发荧光明显不同的荧光颜色。例如含有本发明示例1所示结构的配合物具有红色荧光发射且荧光量子产率高达50％，与生物体系内的自发荧光有明显区分。
因此含有式Ⅰ或式Ⅱ所示结构的主族金属配合物可以作为成像的探针。
进一步地，在细胞的层面，可以利用本发明提供的主族金属配合物的荧光性能研究细胞活动，例如主族金属配合物或其复合物在细胞中的定位、细胞的摄取以及细胞产生的下游的生理变化等。
在活体层面上，可以利用本发明提供的主族金属配合物的荧光性能活体成像研究，通过研究主族金属配合物在活体内的分布，更好地实现靶向给药，以便将设定的活性成分，例如本发明提供的主族金属配合物、盐、溶剂化物、前体药物，或主族金属配合物和其他成分的复配、化学修饰等，定位到肿瘤组织附近。
在一种优选的实施方式中，所述含有式Ⅰ或式Ⅱ所示结构的主族金属配合物可以用于制备靶向制剂。
在临床应用过程中，也有望利用主族金属配合物的荧光性能进行用药监测，根据药物体内分布情况以评估药物的有效性和个体差异。
本发明提供的含有式Ⅰ或式Ⅱ所示结构的主族金属配合物的发光性质十分优越，在非生物体系中也可以作为发光的小分子材料，在材料、OLED(有机发光二极管)、染料敏化太阳能电池等领域也有着潜在的应用价值。
实施例
实施例1
配合物1的合成过程如下：
Figure PCTCN2019086272-appb-000024
将配合物1对应的取代水杨醛和二胺前体以及三氯化铟置于乙腈中，于90℃下回流反应24h。停止回流后，向体系内加入大量乙醚使浅黄色固体析出，过滤收集析出的固体并用乙醚进行洗涤，即可得到纯净的配合物1。
性质鉴定：
配合物1经由核磁共振氢谱、碳谱、高分辨率质谱以及红外光谱进行结构表征，并由紫外可见吸收光谱仪和荧光光谱仪进行辅助的光物理性质表征。
1H NMR(400MHz,Methanol-d 4)δ8.12(s,2H),7.70(m,J＝4H),7.11(d,J＝8.65Hz,2H),6.98(t,J＝7.33Hz, 2H),3.91(s,2H)；
13C NMR(101MHz,Methanol-d 4)δ163.7,157.8,132.4,124.6,121.4,116.0,37.5；
HRMS(ESI+,DMSO,FT-ICR):m/z calcd.for C 16H 14InN 2O 2([M-Cl] +)381.00886,found 381.01022；calcd.for C 18H 20InN 2O 3S([M-Cl+DMSO] +)459.02279,found 459.02408.
FT-IR(KBr pellete,cm -1):1618(C＝N).
实施例2
配合物2(Gaa1(s1*s5))：M为镓，L为乙腈，X为-C(CN)＝C(CN)-，Y为氢，水杨醛残基中两个苯环上的修饰分别为R3位的N-炔丙基-N-甲基氨基和二乙基氨基，Z为氯离子。
配合物2的合成：
将4-二乙基氨基水杨醛和马来腈二胺前体按1:1当量溶于乙腈中，滴加入少量硫酸，于90℃下回流反应24h。停止回流后，向体系内加入大量乙醚使深紫色固体析出，过滤收集析出的固体并用乙醚进行洗涤，得到中间产物a。
将中间产物a、4-N-炔丙基-N-甲基氨基水杨醛以及三氯化镓按1:1:5当量溶于乙腈中，于90℃下回流反应24h。停止回流后，向体系内加入大量乙醚使深红色固体析出，过滤收集析出的固体并用乙醚进行洗涤，得到配合物2。
性质鉴定：
采用与实施例1相同的方法进行性质鉴定，如下：
1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝8.0Hz,1H),8.26(d,J＝7.3Hz,1H),7.58–7.47(m,1H),7.48–7.38(m,1H),6.55(t,J＝8.4Hz,1H),6.47(t,J＝8.9Hz,1H),6.17(d,J＝11.6Hz,1H),6.06(d,J＝12.0Hz,1H),4.34(s,2H),3.50(q,J＝5.4Hz,6H),3.12(d,J＝4.1Hz,3H),1.75(s,0H),1.17(t,J＝7.0Hz,7H).
实施例3
配合物3(Gaa1s1)：M为镓，L为乙腈，X为-C(CN)＝C(CN)-，Y为氢，水杨醛残基中苯环上的修饰为R3位的二乙基氨基，D为氯离子。
合成过程：
将配合物3对应的取代水杨醛和二胺前体以及三氯化镓置于乙腈中，于90℃下回流反应24h。停止回流后，向体系内加入乙醚使红色固体析出，过滤收集析出的固体并用乙醚洗涤，得到配合物3。
Figure PCTCN2019086272-appb-000025
性质鉴定：
配合物3经由核磁共振氢谱、碳谱、高分辨率质谱以及红外光谱进行结构表征，并由紫外可见吸收光谱仪和荧光光谱仪进行辅助的光物理性质表征。
1H NMR(400MHz,Methanol-d4)δ8.24(s,2H),7.30(d,J＝9.3Hz,2H),6.53(dd,J＝9.3,2.5Hz,2H),6.22(d,J＝2.4Hz,2H),3.56(q,J＝7.1Hz,8H),1.26(t,J＝7.1Hz,12H).
13C NMR(101MHz,Methanol-d4)δ172.1,158.3,157.9,139.5,118.0,112.1,111.8,108.9,101.6,46.3,13.1.
HRMS(ESI+,DMSO,FT-ICR):m/z calcd.for C 28H 32GaN 4O 2([M-Cl]+)525.17756,found 525.17923；calcd.for C30H38GaN2O3S([M-Cl+DMSO]+)603.19149,found 603.19322.
FT-IR(KBr pellete,cm -1):1616(C＝N).
实施例4
配合物11的合成过程如下：
Figure PCTCN2019086272-appb-000026
将配合物11对应的取代水杨醛和二胺前体以及三氯化镓置于乙腈中，于90℃下回流反应24h。停止回流后，向体系内加入大量乙醚使黄色固体析出，过滤收集析出的固体并用乙醚进行洗涤，即可得到纯净的配合物11。
性质鉴定：
配合物11经由核磁共振氢谱、碳谱、高分辨率质谱以及红外光谱进行结构表征，并由紫外可见吸收光谱仪和荧光光谱仪进行辅助的光物理性质表征。
1H NMR(400MHz,Methanol-d 4)δ8.82(s,2H),7.88–7.70(m,2H),7.42–7.14(m,4H),6.38(dd,J＝9.0,2.5Hz,2H),6.26(d,J＝2.5Hz,2H),3.50(q,J＝7.0Hz,8H),1.24(t,J＝7.0Hz,12H).
13C NMR(101MHz,Methanol-d 4)δ163.7,158.7,153.3,132.8,128.5,123.6,108.0,104.5,99.1,12.9.
HRMS(ESI+,DMSO,FT-ICR):m/z calcd.for C 28H 32GaN 4O 2([M-Cl] +)525.17756,found 525.17923；calcd.for C 30H 38GaN 2O 3S([M-Cl+DMSO] +)603.19149,found 603.19322.
FT-IR(KBr pellete,cm -1):1616(C＝N).
实施例5
配合物5的合成：
Figure PCTCN2019086272-appb-000027
将配合物5对应的取代水杨醛和二胺前体以及四氯化锗置于乙腈中，于90℃下回流反应24h。停止回流后，向体系内加入大量乙醚使红色固体析出，过滤收集析出的固体并用乙醚进行洗涤，即可得到纯净的配合物5。
性质鉴定：
配合物5经由核磁共振氢谱、碳谱、高分辨率质谱以及红外光谱进行结构表征，并由紫外可见吸收光谱仪和荧光光谱仪进行辅助的光物理性质表征。
1H NMR(400MHz,Methanol-d 4)δ8.24(s,1H),7.30(d,J＝9.4Hz,4H),6.53(dd,J＝9.3,2.4Hz,4H),6.22(d,J＝2.3Hz,4H),3.84(s,6H)；
13C NMR(101MHz,Methanol-d 4)δ164.3,163.7,158.8,133.4,125.8,110.8,107.0,102.1,55.8.
HRMS(ESI+,DMSO,FT-ICR):m/z calcd.for C 24H 26GeN 4O 6S 2([M-2Cl+2DMSO] +)604.05001,found 604.05185.FT-IR(KBr pellete,cm -1):1620(C＝N).
实施例6
采用与实施例1-5相同或基本类似的方法制备和鉴定配合物4、6-10、12-20，配合物结构及性质鉴定结果如下表所示：
Figure PCTCN2019086272-appb-000028
Figure PCTCN2019086272-appb-000029
Figure PCTCN2019086272-appb-000030
实验例
实验例1
配合物的活性检测实验和检测结果：
细胞实验所用细胞系来源为北京大学。细胞在37℃恒温、含有5％CO 2以及饱和水蒸气气氛的细胞培养箱内进行培养。所用培养基为含有10％胎牛血清，100μg/mL青霉素和100U/mL链霉素的高糖杜氏改良伊格尔培养基。细胞在六孔培养板中生长，隔天传代。配合物的细胞毒性经由CCK-8试剂盒进行评估，方法为将细胞传代至96孔板中，每孔约含有25000个细胞以及200μL培养基。待其稳定贴壁生长后，将培养基换成含有不同浓度待测配合物的完全培养基，每个浓度做3孔平行实验。在培养箱中培养24小时后，吸去培养基，用100μL pH＝7.4的PBS缓冲液洗涤3次后，在测试及对照孔中分别加入100μL含10％CCK-8溶液以及90％无血清培养基的混合液，置于培养箱中培养。约1小时后，用酶标仪测量试验及对照孔对450nm波长光的吸收值，并由下式计算各个配合物浓度下细胞存活率(CV,Cell Viability)：
Figure PCTCN2019086272-appb-000031
其中：A为450nm波长光的吸收值；下标s表示含样品的待测孔，c表示不含样品的活细胞对照孔，b表示不含样品及细胞的空白对照孔。通过得到的不同配合物浓度下的细胞存活率绘制细胞毒性曲线，并据此读出配合物对该细胞系的半数致死浓度IC 50。
利用上述方法对配合物对HeLa细胞系的毒性进行初筛，其中配合物1对人子宫颈癌细胞系HeLa的细胞毒性曲线如图2所示。然后对各配合物进行多细胞系的毒性选择性实验，相关结果如图1所示，其中A375为人恶性黑色素瘤细胞系，A549为人非小细胞肺癌细胞系，SW480为人结直肠癌细胞系，MCF7为原位ER阳性人乳腺癌细胞系。从图1可以看出，配合物1、11、5对于不同细胞系的24小时半数致死浓度处于0.1nM到2μM的水平，对癌细胞有明显杀伤效果。
同时，利用上述方法对实施例3制得的配合物3(3#)和顺铂进行多细胞系的毒性选择性对照实验，使用到的细胞系有Hela，HepG2肝癌细胞系，A375，MCF7，MOLT-4急性淋巴母细胞白血病细胞，MDA-MB-231高转移性恶性乳腺癌细胞系，A549，HEK293人肾上皮细胞系，COS7肾上皮细胞，DU145前列腺癌细胞，Raw264.7单核巨噬细胞。结果如下表1所示。
Table 1:in vitro Cytotoxicity of 3 and cisplatin against different cell lines(表1，配合物3与顺铂体外细胞毒性对照)
Figure PCTCN2019086272-appb-000032
从表1可以看出，配合物3对于不同细胞系的24小时半数致死浓度处于0.1M到2μM的水平，相对顺铂，对癌细胞有明显杀伤效果。
实验例2
细胞培养与细胞毒性的测量
细胞实验所用细胞系来源为北京大学。细胞在37℃恒温、含有5％CO 2以及饱和水蒸气气氛的细胞培养箱内进行培养。所用培养基为含有10％胎牛血清，100μg/mL青霉素和100U/mL链霉素的高糖杜氏改良伊格尔培养基。细胞在六孔培养板中生长，隔天传代。配合物的细胞毒性经由CCK-8试剂盒进行评估，方法为将细胞传代至96孔板中，每孔约含有25000个细胞以及200μL培养基。待其稳定贴壁生长后，将培养基换成含有不同浓度待测配合物的完全培养基，每个浓度做3孔平行实验。在培养箱中培养24小时后，吸去培养基，用100μL pH＝7.4的PBS缓冲液洗涤3次后，在测试及对照孔中分别加入100μL含10％CCK-8溶液以及90％无血清培养基的混合液，置于培养箱中培养。约1小时后，用酶标仪测量试验及对照孔对450nm波长光的吸收值，并由下式计算各个配合物浓度下细胞存活率(CV,Cell Viability)：
CV＝(A s-A b)/(A c-A b)×100％
其中：A为450nm波长光的吸收值；下标s表示含样品的待测孔，c表示不含样品的活细胞对照孔，b表示不含样品及细胞的空白对照孔。通过得到的实施例1-6中不同配合物浓度下的细胞存活率绘制细胞毒性曲线，并据此读出配合物对该细胞系的半数致死浓度IC 50。
安全指数(SI)根据下式计算：
bSafety Index(SI)＝IC 50(HUVEC)/IC 50(Hela)
所使用的细胞系为：HeLa，HepG2，MCF7，SW480，A375，A549，正常结肠上皮细胞NCM460，人小胶质细胞CHEM5和人脐静脉血管内皮细胞HUVEC。
结果如下表2(配合物体外抗癌活性)所示，
Table 1.In vitro anticancer activities of complexes. a
Figure PCTCN2019086272-appb-000033
aIC 50值由MTT法测定。.
可知，多个配合物对不同的癌细胞系显示出抗癌活性，而3#和11#配合物对许多癌细胞系显示出最大抗癌活性，IC50值远低于其他配合物。此外，3#和11#配合物对HUVEC细胞的安全性指数分别为1.89和1.42，显示出对正常细胞的较低细胞毒性。结果表明3#和11#配合物在癌症治疗中具有显著应用能力。
实验例3
细胞成像实验
活细胞荧光成像所用仪器为Nikon A1R-si激光扫描共聚焦荧光显微镜(日本)。将细胞移植在0.1mM多聚赖氨酸处理过的圆形盖玻片上使其贴附，并置于完全培养基中培养24h，之后用待测配合物样品进行处理。处理完毕的活细胞样品用磷酸盐缓冲溶液润洗两次后置于显微镜下进行成像。仪器参数：物镜为60倍油镜，成像分辨率1024×1024，扫速为每秒0.5帧。成像时使用不同波段的激发光和检测器进行检测。
其中，使用实施例3制得的配合物3，488nm激光激发，585/65检测器通道检测。
结果如图3所示，图3中(1)分别为配合物3在细胞中分布荧光图，(2)为市售线粒体标记荧光图、(3)为(1)和(2)重叠后的图像，(4)为细胞无荧光图像。可知，配合物3在细胞中主要分布于线粒体中，当其聚集在肿瘤部位时也分布于肿瘤细胞的线粒体中。
实验例4
小鼠活体实验
活体荧光实验：HeLa(1.5×10 6)分别被移植在6周大雄性裸鼠的髋关节附近形成移植瘤。待肿瘤体积长至基本为200mm 3之后，实施例3制得的配合物3(3#)和实施例4制得的配合物11(11#)，使用生理盐水配制不同浓度的给药溶液，通过尾静脉注射进入小鼠体内，用量为1.4～6.4mg/kg。在注射药物后5min～72h间取多个时间点进行活体成像观察配合物3在小鼠体内的分布情况以及肿瘤的定位。所用仪器为Xenogen的活体成像系统(Caliper Life Sciences,Hopkinton,MA,USA)，使用成像参数为500nm激发，560-620检测器通道检测。72h后将裸鼠解剖并取出其中的主要器官，置于成像仪下用相同参数进行成像，观察配合物在各个器官中的分布。
结果如图4中A所示，配合物3和配合物11在静脉注射72小时后在肿瘤组织中还积聚很多。图4中B和C中显示了配合物在主要器官心脏(heart)、肝脏(liver)、脾脏(spleen)、肺脏(lung)和肾脏(kidney)中的积聚，肝脏中3#和11#配合物的积累远远高于其他器官，而在心脏和脾脏中几乎没有累积。
此外，通过ICP-MS(电感耦合等离子体质谱仪)测定了主要器官中3#或11#配合物的浓度。肿瘤组织中3#和11#配合物的浓度分别为8.84和9.55μg/g，高于心脏、脾脏、肺脏和肾脏中的浓度，表明配合物可在肿瘤组织中积聚，这与荧光图像一致。
实验例5
活体抑瘤实验：
将携带HeLa移植瘤的裸鼠分为4组，每组8只。待肿瘤体积长至基本为200mm 3之后，分别用顺铂(cisplatin)、实施例3制得的配合物3、实施例4制备的配合物11处理，设置肿瘤对照组(tumor)。药物用量为4μmol/kg，频率为2天1次。肿瘤体积(Tumor volume)由肿瘤长度(length)和宽度(width)计算得到，具体公式如下：
Figure PCTCN2019086272-appb-000034
21天后将各组裸鼠处死并解剖。肿瘤抑制率(tumor inhibition)通过以下公式进行计算：
Figure PCTCN2019086272-appb-000035
其中Wc和Wt分别为对照组和实验组的肿瘤质量。
治疗后，肿瘤体积和质量变化曲线如图5中A和B所示，配合物11#治疗效果优于配合物3#，配合物组治疗后肿瘤的体积和质量始终都小于顺铂组，实验组都优于对照组。
由图7中D、E和F所示，游离配合物3#和11#显著抑制肿瘤的生长，处理21天后，配合物3#和11#的肿瘤抑制率分别为56.8％和84.6％，而顺铂的肿瘤抑制率为29.9％。结果表明，游离镓配合物3#和11#具有比游离顺铂更好的抗肿瘤效果。
同时，由图6可知，在所有组别的治疗期间裸鼠体重没有显着波动，表明这些治疗具有良好的耐受性，并且在治疗期间没有引起急性副作用。
此外，通过H&E染色检查了肿瘤组织的组织学变化，如图7中D所示，肿瘤组织在治疗后表现出不同程度的坏死，配合物治疗效果优于顺铂。
留取血液样本进行血液学分析，研究顺铂、配合物3#和11#对裸鼠肝肾功能的影响。研究指标包括丙氨酸氨基转移酶(ALT)、尿素氮(BUN)、甘油三酯(TG)、肌酸激酶(CK)、天冬氨酸氨基转移酶(AST)、肌酐(CREA)、高密度脂蛋白(HDLC)、乳酸脱氢酶(LDH)。
肾功能与BUN和CREA血液指标及肝功能有关，丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)在裸鼠血液中显示结果，如图8所示，顺铂可引起急性肝肾毒性，而配合物3#和11#可以显著减轻顺铂或肿瘤形成对肾脏和肝脏功能的损害，血液生化指标恢复至健康团体的水平。
另外，取心脏、脾脏、肺、肝、肾等部位进行H&E染色分析。
如图9所示，在实验条件下，在心脏、脾脏和肺中未发现显着的病理变化。但在顺铂治疗组观察到肝脏水肿变性和肾脏肿胀；而配合物3#和11#组肾脏没有受损，肝脏存在轻度受损。果表明配合物的潜在副毒性低于顺铂。
这些结果进一步证实了镓配合物3#和11#与顺铂相比具有更高的安全性和应用潜力。
以上结合具体实施方式和范例性实例对本发明进行了详细说明，不过这些说明并不能理解为对本发明的限制。本领域技术人员理解，在不偏离本发明精神和范围的情况下，可以对本发明技术方案及其实施方式进行多种等价替换、修饰或改进，这些均落入本发明的范围内。本发明的保护范围以所附权利要求为准。

Claims (10)

  1. 一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物，或其药学上可接受的盐、溶剂化物、非共价键复合物或前体药物，
    Figure PCTCN2019086272-appb-100001
    所述主族金属配合物，包括其正离子，由希夫碱类平面四齿配体和p区主族金属离子组成。
  2. 根据权利要求1所述的主族金属配合物，其特征在于，
    其中，M表示p区主族金属；
    X代表二胺残基，其两侧亚胺键的氮原子以取代或不取代的C 1-12烷基或C 2-12烯基互相连接，或是作为取代或不取代的芳基或杂环芳基中的临位取代基；
    Y为氢、C 1-12烷基、卤素、卤素取代烷基、氰基、氨基、羰基、C 1-12烷氧基或取代氨基；
    Z为氢、C 1-12烷基、卤素、硝基、羟基、巯基或羧基；
    R 1、R 2、R 3和R 4为对配体骨架中苯环上的取代基，各自独立地选自氢、卤素、硝基、羟基、巯基、羧基、氨基、氰基、C 1-12烷基、C 2-12烯烷基、C 2-12炔烷基、C 1-8烷氧基、C 2-8烯氧基、C 2-8炔氧基、C 1-8烷硫基、C 3-8杂环基、芳基、C 1-8烷酰基、C 1-8烷酰胺基、C 1-8烷基磺酰基、芳基磺酰基、C 1-12烷基取代氨基或卤素取代C 1-12烷基；
    或者，R 1、R 2、R 3和R 4中相邻的两个取代基(R 1与R 2、R 2与R 3和/或R 3与R 4)可以成环。
  3. 根据权利要求1或2所述的主族金属配合物，其特征在于，所述式Ⅰ或式Ⅱ中的M为铝、镓、铟、铊、锗或锡中的一种；优选所述式Ⅰ或式Ⅱ中的M为铝、镓、铟、铊或锗中的一种，最好式Ⅰ或式Ⅱ中的M为铝、镓、铟或锗中的一种；
    所述X两侧的氮原子以碳数1～5的脂肪链或取代脂肪链互相连接，或是作为芳香环的邻位取代基；优选所述式Ⅰ或式Ⅱ中的X选自-CH 2-、-CH 2-CH 2-、-CH(CH 3)-CH 2-、-CH(CN)-CH(CN)-、-CH(CN)-CH 2-、-CH 2(Cl)-CH(CN)-、-CH 2(OH)-CH(CN)-、-CH 2(Cl)-CH 2-、-CH 2(OH)-CH 2-、-CH＝CH-、-CO-CH(CN)-、-C(CN)＝C(CN)-、-CH＝C(CN)-、-CH＝C(Cl)-、-CH＝CH-CH＝CH-、-CH＝C(CN)-CH＝CH-、-CH＝C(NH 3)-或-CO-CH 2-，或者作为取代或未取代的苯、萘、蒽、菲、吡啶、咪唑、吡咯、噻吩、呋喃、苯并吡咯或苯并呋喃的邻二取代基团；X为环状基团时通过相邻的两个环状骨架原子与对配体的亚氨基连接；
    所述式Ⅰ或式Ⅱ中的Y为氢、卤素、氰基、C 1-4烷基或C 1-4烷氧基；
    优选所述Y为氢、卤素、氰基、甲基、乙基、异丙基、甲氧基、乙氧基、卤素取代C 1-3烷基或卤素取代C 1-3烷氧基；
    R 1、R 2、R 3和R 4各自独立地选自氢、卤素、硝基、羟基、巯基、羧基、氨基、氰基、C 1-12烷基、C 2-12烯烷基、C 2-12炔烷基、C 1-8烷 氧基、C 2-8烯氧基、C 2-8炔氧基、C 1-8烷硫基、C 3-8杂环基、芳基、C 1-8烷酰基、C 1-8烷酰胺基、C 1-8烷基磺酰基、芳基磺酰基、N,N-二(C 1-6烷基)氨基、N-(C 1-6烷基)-N-(C 1-6烷基)氨基、N-(C 1-6烷基)-N-C 1-6炔烷基)氨基、N,N-二芳基氨基、N-(C 1-6烷基)-N-芳基氨基、N-(C 1-6烷基)-N-杂环基氨基、-CF 3-、-ClCH 2-、-ClCH 2-CH 2-、(CH 3) 2C(CH 2Cl)-、CH 2-CH 2Cl-CH(CH 3) 2-或卤素取代的C 3-6环状烷基，所述C 3-6环状烷基包括卤素取代环己基、卤素取代环戊基和卤素取代甲基环戊基。
  4. 根据权利要求1～3之一所述的主族金属配合物，其特征在于，所述主族金属配合物还带有配体，如式Ⅲ和式Ⅳ所示：
    Figure PCTCN2019086272-appb-100002
    M代表p区主族金属；X代表二胺残基，其两侧亚胺键的氮原子以碳数1～5的脂肪链或取代脂肪链互相连接，或是作为芳香环的临位取代基；Y为氢或烷基；R 1、R 2、R 3和R 4各自独立选自氢、卤素、硝基、羟基、氨基、取代氨基、烷基、烷氧基、卤素取代烷基、巯基或烷硫基，其中相邻的两个取代基R 1与R 2、R 2与R 3和/或R 3与R 4可以成环；L代表一个或多个轴向单齿配体，为卤素、氧配位小分子或氮配位小分子；Z为氢或烷基；
    所述L表示一个或多个轴向单齿配体，包括阴离子配体、中性配体；所述L也可以是非配位阴离子；优选所述阴离子配体包括卤素(如氟、氯、溴、碘)离子、乙酸根离子；所述中性配体为氧配位或氮配位的配体，优选为溶剂分子，例如MeCN、MeOH、DMSO、DMF，
    优选地，所述主族金属配合物(包括阳离子型)包括：
    Figure PCTCN2019086272-appb-100003
    Figure PCTCN2019086272-appb-100004
    Figure PCTCN2019086272-appb-100005
  5. 一种权利要求1～4之一所述主族金属配合物的制备方法，其特征在于，将式V所示水杨醛或取代水杨醛、式VI所示二胺前体以及主族金属盐MD置于有机溶剂L中，于50～150℃下进行反应12～24h，即得：
    Figure PCTCN2019086272-appb-100006
  6. 一种权利要求1～4之一所述主族金属配合物的制备方法，其特征在于，式Ⅳ可以按照以下反应方程式进行，将式Ⅶ所示配体以及主族金属盐MD置于有机溶剂L中，于50～150℃下进行反应12～24h，一步合成得到目标配合物分子：
    Figure PCTCN2019086272-appb-100007
  7. 一种使用权利要求1～4之一所述主族金属配合物为活性成分的药物组合物，包括药学可接受的辅料。
  8. 一种含有权利要求1～4之一所述主族金属配合物的药物制剂，所述制剂包括经胃肠道给药制剂和注射给药制剂，
    经胃肠道给药制剂包括片剂、胶囊剂、口服溶液剂、口服乳剂、栓剂和颗粒剂；
    注射给药制剂包括注射溶液、注射乳剂、注射缓释溶液剂、注射混悬剂。
  9. 含有式Ⅰ或式Ⅱ所示结构的主族金属配合物、药学可接受的盐、溶剂化物、非共价键复合物或前体药物，药物组合物或制剂在制备抗癌药物中的应用；
    所述应用为制备治疗包括乳腺癌、肝癌、肺癌、黑色素瘤、前列腺癌、结肠癌、大肠癌、胶质母细胞瘤、肾癌、胰腺癌、胃癌、淋巴癌、宫颈癌、卵巢癌、食管癌、鼻癌、白血病、乳腺导管癌、胆囊癌、睾丸癌、贲门癌和甲状腺癌的药物中的应用；
    药物的剂量水平为0.01～200mg/kg体重每天，或者每个病人每天0.5～14g。
  10. 一种含有式Ⅰ或式Ⅱ所示结构的主族金属配合物、盐、溶剂化物、非共价键复合物或前体物质，在光标记特别是荧光标记中的用途；
    优选在荧光成像、靶向制剂、用药监测、发光材料、有机发光二极管、染料敏化太阳能电池中的应用。
PCT/CN2019/086272 2018-05-11 2019-05-09 主族金属配合物及其制备方法和应用 Ceased WO2019214691A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP19799825.5A EP3792268A4 (en) 2018-05-11 2019-05-09 MAIN GROUP METAL COMPLEX, ITS PREPARATION PROCESS AND ITS USES
AU2019265404A AU2019265404B2 (en) 2018-05-11 2019-05-09 Main-group metal complex, preparation method for same, and applications thereof
US16/973,474 US12018038B2 (en) 2018-05-11 2019-05-09 Main group metal complex and its preparation method and use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201810446199.9A CN108676026A (zh) 2018-05-11 2018-05-11 具有癌细胞杀伤能力的主族金属配合物及其制备和应用
CN201810446199.9 2018-05-11
CN201910251385.1 2019-03-29
CN201910251385.1A CN110467633B (zh) 2018-05-11 2019-03-29 主族金属配合物及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2019214691A1 true WO2019214691A1 (zh) 2019-11-14

Family

ID=63806157

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/086272 Ceased WO2019214691A1 (zh) 2018-05-11 2019-05-09 主族金属配合物及其制备方法和应用

Country Status (5)

Country Link
US (1) US12018038B2 (zh)
EP (1) EP3792268A4 (zh)
CN (2) CN108676026A (zh)
AU (1) AU2019265404B2 (zh)
WO (1) WO2019214691A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117089318A (zh) * 2023-07-25 2023-11-21 北京康美特科技股份有限公司 一种有机硅固晶胶及其制备方法和应用
EP4161379A4 (en) * 2020-06-05 2024-07-10 University of Maryland, Baltimore Gallium-salophen antimicrobial compounds and methods of use thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108676026A (zh) * 2018-05-11 2018-10-19 北京大学 具有癌细胞杀伤能力的主族金属配合物及其制备和应用
CN111359669B (zh) * 2020-04-29 2022-11-11 河北工程大学 一种非共价负载型GOx-Py-Co(Salen)催化剂及其合成方法
CN114957081B (zh) * 2022-05-27 2024-04-05 中国科学院上海有机化学研究所 薁类化合物、其中间体、其制备方法及其用途
CN115974933A (zh) * 2022-12-01 2023-04-18 桂林医学院 多吡啶环金属铱配合物及其制备方法和应用
CN119823189B (zh) * 2025-03-20 2025-06-03 汕头大学医学院 一种席夫碱三价锇配合物及其合成方法与应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108676026A (zh) * 2018-05-11 2018-10-19 北京大学 具有癌细胞杀伤能力的主族金属配合物及其制备和应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9111689D0 (en) * 1991-05-31 1991-07-24 Johnson Matthey Plc Gallium compounds
CN101130556A (zh) * 2007-08-31 2008-02-27 高健 抗癌环己二胺金属配合物
CN101830828B (zh) * 2010-03-23 2014-06-25 中山大学 一种Salen Zn(II)配合物及其制备方法和应用
CN106977709A (zh) * 2017-04-27 2017-07-25 华东理工大学 一种以CN为轴向配体的Salen催化剂及其制备方法和应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108676026A (zh) * 2018-05-11 2018-10-19 北京大学 具有癌细胞杀伤能力的主族金属配合物及其制备和应用

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CHENG, JINGHUI ET AL.: "A Class of Multiresponsive Colorimetric and Fluorescent pH Probes via Three Different Reaction Mechanisms of Salen Complexes: A Se- lective and Accurate pH Measurement", INORGANIC CHEMISTRY, vol. 55, no. 18, 26 August 2016 (2016-08-26), pages 9221 - 9229, XP055651160 *
GALVAN-HIDALGO, J.M. ET AL., J. ORGANOMETAL. CHEM., vol. 848, 2017, pages 332 - 343
GOGNA, R.MADAN, E.KEPPLER, B.PATI, U., BR. J. PHARMACOL., vol. 166, 2012, pages 617
HAI, YANG: "Luminescent zinc salen complexes as single and two-photon fluorescence subcellular imaging probes", CHEMICAL COMMUNICATIONS, vol. 47, no. 8, 31 December 2011 (2011-12-31), pages 2435 - 2437, XP055244616, DOI: 10.1039/c0cc04113k *
HUANG, SHUANG: "Computational Design of Two-Photon Fluorescent Probes for a Zinc Ion Based on a Salen Ligand", INORGANIC CHEMISTRY, vol. 52, no. 10, 8 May 2013 (2013-05-08), pages 5702 - 5713, XP055651171, DOI: 10.1021/ic3022062 *
M. PRIBISKOJ. PALMERR.H. GRUBBSH.B. GRAYJ. TERMINIP. LIM, PNAS, vol. 113, no. 16, 2016, pages E2258
See also references of EP3792268A4
SENG, H-L.E.R.T TIEKINK: "Comprehensive Inorganic Chemistry //", vol. 3, 2013, ELSEVIER, article "Main-Group Medicinal Chemistry Including Li and Bi", pages: 951 - 974
YANG F. ET AL., BIOORG. MED. CHEM. LETT., vol. 23, 2013, pages 5544

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4161379A4 (en) * 2020-06-05 2024-07-10 University of Maryland, Baltimore Gallium-salophen antimicrobial compounds and methods of use thereof
CN117089318A (zh) * 2023-07-25 2023-11-21 北京康美特科技股份有限公司 一种有机硅固晶胶及其制备方法和应用
CN117089318B (zh) * 2023-07-25 2024-05-10 北京康美特科技股份有限公司 一种有机硅固晶胶及其制备方法和应用

Also Published As

Publication number Publication date
EP3792268A4 (en) 2021-07-14
CN110467633A (zh) 2019-11-19
CN108676026A (zh) 2018-10-19
US12018038B2 (en) 2024-06-25
AU2019265404B2 (en) 2022-08-04
EP3792268A1 (en) 2021-03-17
CN110467633B (zh) 2021-03-30
AU2019265404A1 (en) 2021-01-07
US20210253603A1 (en) 2021-08-19

Similar Documents

Publication Publication Date Title
WO2019214691A1 (zh) 主族金属配合物及其制备方法和应用
Zhao et al. Designing luminescent ruthenium prodrug for precise cancer therapy and rapid clinical diagnosis
CN110981870B (zh) 基于pH和GSH双重响应的β-咔啉-环烯酮衍生物及其用途
JP6880023B2 (ja) 改善された特性を有するβ−グアニジノプロピオン酸の薬学的に許容される塩及びその使用
Bhuin et al. Solid-state emitting twisted π-conjugate as AIE-active DSE-gen: in vitro anticancer properties against FaDu and 4T1 with biocompatibility and bioimaging
JP2018531280A6 (ja) 改善された特性を有するβ−グアニジノプロピオン酸の薬学的に許容される塩及びその使用
CN115803330A (zh) 4-氨基-5-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮的盐和晶型
Vignesh et al. Pyrene aroylhydrazone-based Pd (II) complexes for DNA/protein binding, cellular imaging and in vitro anticancer activity via ROS production
Liu et al. Design and biological features of platinum (II) complexes with 3-hydroxy-3-(Trifluoromethyl) cyclobutane-1, 1-Dicarboxylate as a leaving ligand
CN116410233B (zh) 一种靶向TNBC的Pt（IV）-萘酰亚胺多胺配合物、其制备方法及应用
CN110526854B (zh) 一种ɑ,β-不饱和酮衍生物、制备方法及作为药物的用途
US20210317151A1 (en) Rhenium complexes and methods of use for treating cancer
CN112979718B (zh) 二茂铁甲酸衍生物、制备方法及其用途
JP2018524320A (ja) カルボプラチンベースの共結晶の医薬組成物及びその用途
US20170305946A1 (en) Compositions and methods comprising rhenium for the treatment of cancers
Harpstrite et al. Metalloprobes: synthesis, characterization, and potency of a novel gallium (III) complex in human epidermal carcinoma cells
KR102016699B1 (ko) 신규 루테늄 착화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물
KR20200134257A (ko) 엘라크리다의 중수소화 유사체
WO2023147196A2 (en) Ph-sensitive fluorophores
KR102025323B1 (ko) 신규 루테늄 착화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물
CN103351397B (zh) 一种藤黄酸类衍生物及其制备方法和用途
Delasoie et al. Highly Potent rhenium (I) Tricarbonyl Complexes with Dual Anticancer and Anti-Angiogenic Activity Against Colorectal Carcinoma
Yu et al. A viscosity-sensitive probe based on the structure of indole salt
CN119119131B (zh) 一种基于Lamp2介导的能够逆转胶质瘤进展的萘酰亚胺-铂（IV）配合物及其应用
CN114933599B (zh) 一种双β-咔啉类化合物及其药用盐、制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19799825

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019799825

Country of ref document: EP

Effective date: 20201211

ENP Entry into the national phase

Ref document number: 2019265404

Country of ref document: AU

Date of ref document: 20190509

Kind code of ref document: A

WWW Wipo information: withdrawn in national office

Ref document number: 2019799825

Country of ref document: EP