CN116870177B - Podophyllotoxin modified polyoxometallate hybrid compound and preparation method and application thereof - Google Patents
Podophyllotoxin modified polyoxometallate hybrid compound and preparation method and application thereof Download PDFInfo
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- 229960001237 podophyllotoxin Drugs 0.000 title claims abstract description 94
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 title claims abstract description 91
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 title claims abstract description 91
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 150000001875 compounds Chemical class 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000001384 succinic acid Substances 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000013460 polyoxometalate Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 8
- 238000000502 dialysis Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 229940014800 succinic anhydride Drugs 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000012986 modification Methods 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 238000007865 diluting Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 238000002386 leaching Methods 0.000 claims 1
- 230000001376 precipitating effect Effects 0.000 claims 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 15
- 238000004220 aggregation Methods 0.000 abstract description 3
- 230000001093 anti-cancer Effects 0.000 abstract description 3
- 230000002776 aggregation Effects 0.000 abstract description 2
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- 239000002994 raw material Substances 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 22
- 230000000694 effects Effects 0.000 description 12
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- 238000011068 loading method Methods 0.000 description 5
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- 231100000331 toxic Toxicity 0.000 description 5
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- 210000004881 tumor cell Anatomy 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
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- 201000011510 cancer Diseases 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
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- 238000002329 infrared spectrum Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 241000133570 Berberidaceae Species 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 230000010337 G2 phase Effects 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001495452 Podophyllum Species 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- WGYFACNYUJGZQO-UHFFFAOYSA-N aminomethanetriol Chemical compound NC(O)(O)O WGYFACNYUJGZQO-UHFFFAOYSA-N 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
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- 210000005260 human cell Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000007761 synergistic anti-cancer Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
- A61K47/6915—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes
-
- 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
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/62—Quaternary ammonium compounds
- C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
The application belongs to the technical field of medicines, and particularly relates to a preparation method and application of an podophyllotoxin modified Anderson polyoxometallate hybrid compound, and a preparation method and application of the hybrid compound in forming vesicles by self aggregation in a solution. The invention takes podophyllotoxin as an initial raw material, and synthesizes podophyllotoxin modified polyoxometallate hybrid compound molecules through three steps. The invention realizes the connection of the polyacid and the podophyllotoxin through a covalent bond for the first time, and simultaneously, compared with the single podophyllotoxin, the anticancer activity of the hybrid molecule combined with the polyacid is obviously enhanced. The preparation method is simple and easy to implement, the reaction process is easy to control, the purification is simple, and the method has good market development prospect.
Description
Technical Field
The application belongs to the technical field of medicines, and specifically relates to a medicine composition comprising: podophyllotoxin modified Anderson polyoxometallate hybrid compound and its synthesis method, and preparation method and application of hybrid compound in solution for self-aggregation to form vesicle.
Background
Podophyllotoxin (Podophyllotoxin) is a natural lignin active substance with remarkable antitumor effect, and is mainly derived from root or stem of Podophyllum plant of berberidaceae. It can block the cell cycle to split S phase and G2 phase by combining with topoisomerase II to prevent the formation of complete DNA chain, thereby exerting anti-tumor effect. However, the podophyllotoxin has the problems of poor water solubility, large toxic and side effects and the like in clinical use, and limits the clinical application of the podophyllotoxin.
Polyoxometalates (POM) are inorganic metal oxygen clusters of various structures formed by connecting transition metals (Mo, W, V, nb, ta, etc.) through oxygen atoms. Polyacids have been demonstrated to have broad-spectrum antitumor activity, which is one of the hot spots for the development of new antitumor drugs, and the mechanism of polyacid-induced apoptosis of tumor cells includes: can induce the increase of Reactive Oxygen Species (ROS) level in cells, reduce the expression of anti-apoptosis components NF- κB and bcl-2, interfere electron transfer to inhibit the synthesis of ATP, induce DNA damage to cause apoptosis, etc.
At present, covalent connection of hydrophilic polyacid and hydrophobic drug podophyllotoxin is not reported, and the covalent connection is used for solving the problems of poor water solubility of the podophyllotoxin and reducing toxicity of the podophyllotoxin.
Disclosure of Invention
The invention aims to solve the technical problem of providing a podophyllotoxin modified polyoxometallate hybrid compound, and a preparation method and application thereof.
A first object of the present invention is to provide podophyllotoxin modified Anderson polyoxometalate hybrid compounds characterized by the formula: { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNHCOC 25 H 25 O 9 ] 2 )}。
The second object of the present invention is to provide a process for preparing podophyllotoxin modified polyoxometalate hybrid compounds. The method comprises the following steps:
(1) Under the protection of nitrogen, dissolving podophyllotoxin, succinic anhydride, 4-Dimethylaminopyridine (DMAP) and Triethylamine (TEA) in turn into anhydrous dichloromethane, reacting for 4 hours at room temperature, diluting the reaction solution with dichloromethane after the reaction is finished, washing with 0.1mol/L HCl solution for three times, drying with anhydrous sodium sulfate, removing the dichloromethane through reduced pressure rotary evaporation, and drying the product in a vacuum drying oven overnight to obtain podophyllotoxin succinic acid monoester;
(2) Under the protection of nitrogen, the reaction mixture (TBA) 4 [α-Mo 8 O 26 ]、Mn(CH 3 COO) 3 ·2H 2 Adding O and tris (hydroxymethyl) aminomethane into a reaction vessel, adding acetonitrile to dissolve, and slowly heating to 85-90 ℃ under stirringRefluxing at maintained temperature for 16 hr, cooling the orange reaction liquid to room temperature after the reaction, filtering off precipitate, diffusing in diethyl ether vapor for 3-5 days to obtain a large amount of orange crystals, vacuum filtering, and vacuum drying to obtain orange { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 }；
(3) Under the protection of nitrogen, adding 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ) and podophyllotoxin succinic acid monoester into a reaction vessel in turn, adding acetonitrile to dissolve the materials, heating to a reflux state for reaction for 35 minutes, and then adding { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 Add to the reaction solution and reflux react for 20 hours. After the completion of the reaction, the obtained orange reaction solution was cooled to room temperature and concentrated under reduced pressure. And (3) dripping the concentrated reaction solution into ethyl acetate to precipitate, dissolving the precipitate obtained by suction filtration in a small amount of acetonitrile, and placing the acetonitrile in diethyl ether steam to precipitate. Finally obtaining the orange solid target product podophyllotoxin modified polyoxometallate hybrid compound.
Podophyllotoxin modified Anderson type polyoxometalate hybrid compounds { (TBA) described above 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNHCOC 25 H 25 O 9 ] 2 ) The synthetic route of } is as follows:
in the step (1), the mol ratio of the podophyllotoxin to the succinic anhydride to the 4-Dimethylaminopyridine (DMAP) to the Triethylamine (TEA) is 1:2-3:0.5-1.5:0.5-1.5, and the dosage ratio of the anhydrous dichloromethane solvent is 1g of the podophyllotoxin to 50-75 mL of the anhydrous dichloromethane solvent.
In step (2), the (TBA) 4 [α-Mo 8 O 26 ]、Mn(CH 3 COO) 3 ·2H 2 The mol ratio of O and the tris (hydroxymethyl) aminomethane is 1:1.5-2.5:3-3.5, and the dosage proportion of acetonitrile solvent is 1g (TBA) 4 [α-Mo 8 O 26 ]15-20 mL acetonitrile solvent.
In step (3), the { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 The molar ratio of the 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ) to the podophyllotoxin succinic acid monoester is 1:2.5-3.5:1-2.5, and the dosage ratio of the acetonitrile solvent is 1g of the podophyllotoxin succinic acid monoester to 50-100 mL of the acetonitrile solvent.
The third object of the present invention is to provide a method for preparing podophyllotoxin modified Anderson polyoxometallate hybrid vesicles, comprising the steps of:
dissolving podophyllotoxin modified Anderson polyoxometallate hybrid compound in an organic solvent, slowly dripping into a mixed solution of pure water and the organic solvent under uniform stirring, transferring the solution into a dialysis bag to remove the organic solvent to obtain a vesicle aqueous solution.
In the preparation method of the podophyllotoxin modified Anderson polyoxometallate hybrid compound vesicle, the organic solvent is one of acetonitrile and dimethyl sulfoxide (DMSO); in the mixed solution of pure water and organic solvent, the volume ratio of the organic solvent to the pure water is 1:1-1.5, and the dosage ratio is 1mg of podophyllotoxin modified Anderson polyoxometallate hybrid compound to 0.5-1 mL of organic solvent to 4-5 mL of mixed solution of pure water and the organic solvent.
The stirring speed of the uniform stirring is 800-1000 rpm, the stirring temperature is 25 ℃, the stirring is continued for 30 minutes after the dripping is finished, and then the dialysis is carried out after the standing at room temperature.
The prepared vesicle has the particle size of 80-120 nm, the tyndall effect, the hollow sphere shape, and compared with podophyllotoxin, the prepared vesicle can exist stably in water.
The term "vesicle": molecules with amphiphilicity disperse in water with hydrophobic forces, hydrophilic ends towards water, hydrophobic ends away from water and intermolecular ordered aggregation occurs, spontaneously forming a class of molecular ordered assemblies with a closed bilayer structure, known as vesicles (Chen, x.; dong, w.; zhang, x. Science child-chemistry.2010, 53,1853, neuhaus, f.; mueller, d.; tanasescu, r.; balg, s.; ishikawa, t.; brezesinski, g.; zumbuehl, a. Angwande Chemie International edition.2017,56,6515.;).
The fourth object of the invention is to provide the application of podophyllotoxin modified Anderson polyoxometallate hybrid compound vesicles in preparing antitumor drugs, wherein tumors are lung cancer and liver cancer.
The invention has the beneficial effects that:
(1) The invention provides an Anderson type polyoxometallate hybrid compound modified by podophyllotoxin and a preparation method thereof, wherein the podophyllotoxin is taken as an initial raw material, and hybridized molecules of the polyoxometallate and the podophyllotoxin are synthesized through three steps: 1) Firstly, obtaining podophyllotoxin succinic acid monoester by utilizing esterification reaction of podophyllotoxin and succinic anhydride; 2) Then carrying out alkoxylation modification on polyoxometallate by utilizing trihydroxy aminomethane to obtain an amino active reaction site; 3) The method is simple and easy to implement, the reaction process is easy to control, and the purification is simple.
(2) The invention provides a preparation method of podophyllotoxin modified Anderson polyoxometallate hybrid compound vesicles, which can obtain stable vesicle solution in water. The vesicle utilizes the drug itself as a part of the carrier material, which can reduce the use of additional carrier materials and improve the drug loading rate. The specific expression is as follows: the calculation formula of the drug loading rate is as follows: drug loading= [ m ] 1 /(m 1 +m 2 )]×100％，m 1 : drug content in drug-carrying carrier, m 2 : the total mass of the support material. Since the polyacid-podophyllotoxin compound of the present application is itself both a drug and a carrier, m is 1 ＝m 1 +m 2 The calculated drug loading of the polyacid-podophyllotoxin compound is 100%.
(3) Pharmacological test results show that the toxicity of the polyacid-podophyllotoxin compound vesicle to normal human cells is lower than that of the podophyllotoxin alone. The toxic and side effects of podophyllotoxin are improved after the podophyllotoxin is connected with polyacid.
(4) Compared with podophyllotoxin, the podophyllotoxin modified polyacid compound vesicle has stronger anticancer effect. Pharmacological experiment results show that under the same concentration, the compound vesicle prepared by the embodiment of the invention has proliferation inhibition effects on H1299 and A549 lung cancer cells and Hep-G2 liver cancer cells, the inhibition rate is obviously higher than that of podophyllotoxin, the synergistic inhibition effect on tumor cells is achieved, and higher anticancer activity is shown.
The covalent connection of polyacid and podophyllotoxin makes use of the vesicle constructed by the amphipathic drug molecule itself as a part of the carrier material to improve drug loading rate, and has incomparable advantages with the traditional carrier. Finally, the high-efficiency carrying and synergistic anticancer effects are achieved, and a foundation is laid for developing application of podophyllotoxin modified polyacid derivatives in tumor treatment.
Drawings
FIG. 1 is a schematic illustration of self-assembly of an organically modified polyacid compound to form vesicles;
FIG. 2 is an infrared spectrum of the podophyllotoxin modified polyoxometalate hybrid compound obtained by the invention;
FIG. 3 is a graph showing the results of the present invention for podophyllotoxin-modified polyoxometalate hybridization
FIG. 4 is a nuclear magnetic resonance spectrum of a polymetallic oxyacid salt hybridized compound modified by podophyllotoxin obtained by the invention
FIG. 5 is a graph of podophyllotoxin modified Mn-polyoxometalate vesicle particle size distribution;
FIG. 6 is a TEM image of podophyllotoxin modified Mn-polyoxometalate vesicles;
FIG. 7 is a graph showing the effect of POD, POM, mn-POM-POD vesicles on the activity of different tumor cells and normal cells;
table 1 shows comparison of the cell inhibition rates of Mn-POM-POD vesicles and podophyllotoxin alone on tumor cells and human normal cells at the same concentration;
TABLE 2POD, POM and Mn-IC of POM-POD vesicle to tumor cell and human normal cell 50 Values.
Detailed Description
The present application will be further described with reference to the drawings and detailed description so as to be more readily understood by those skilled in the art, but these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. Moreover, unless otherwise indicated, the numbering of the method steps is merely a convenient tool for identifying the method steps and is not intended to limit the order of arrangement of the method steps or to limit the scope of the invention in which the invention may be practiced, as such changes or modifications in their relative relationships may be regarded as within the scope of the invention without substantial modification to the technical matter.
In order to better understand the above technical solution, exemplary embodiments of the present invention are described in more detail below. While exemplary embodiments of the invention are shown, it should be understood that the invention may be embodied in various forms and should not be construed as being limited to the embodiments set forth herein
The embodiments are limited. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The test methods described in the following examples, unless otherwise specified, are all conventional; the reagents and biological materials, unless otherwise specified, are commercially available.
Example 1 preparation of podophyllotoxin modified Mn-Anderson type polyacid hybrid compound (Mn-POM-POD):
(1) Podophyllotoxin (1 g,2.42 mmol), succinic anhydride (0.72 g,7.2 mmol), triethylamine (0.27 g,2.65 mmol) and 4-dimethylaminopyridine (0.33 g,2.65 mmol) were dissolved in 50mL of anhydrous dichloromethane in this order under nitrogen protection, and reacted at room temperature for 4 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with 100mL of methylene chloride and washed three times with a 0.1mol/L hydrochloric acid solution (40 mL). Drying the organic phase by anhydrous sodium sulfate, removing dichloromethane by reduced pressure rotary evaporation, and drying the product in a vacuum drying oven overnight to obtain podophyllotoxin succinic acid monoester;
(2) Under the protection of nitrogen, the reaction mixture (TBA) 4 [α-Mo 8 O 26 ](1g，0.46mmol)、Mn(CH 3 COO) 3 ·2H 2 O (0.19 g,0.7 mmol) and tris (hydroxymethyl) aminomethane (0.2 g,1.6 mmol) were refluxed in 20mL acetonitrile for 16 hours. After the reaction, the orange reaction liquid is cooled to room temperature, precipitates are filtered, and a large amount of orange crystals are obtained by diffusing the orange reaction liquid in diethyl ether steam for 3 to 5 days, and the orange reaction liquid is washed by a small amount of cold acetonitrile and cold diethyl ether after the filtration, is filtered by suction, and is dried in vacuum to obtain orange { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 }；
(3) EEDQ (228 mg,0.92 mmol) and podophyllotoxin succinic monoester (315 mg,0.61 mmol) were added to the reaction vessel in this order under nitrogen protection, 25mL of acetonitrile was added to dissolve the sample, and the mixture was warmed to reflux and reacted for 35 minutes. POM (500 mg,0.265 mmol) was then added to the reaction mixture and reacted at reflux for 20 hours. After the completion of the reaction, the obtained orange reaction solution was cooled to room temperature and concentrated under reduced pressure. And (3) dripping the concentrated reaction solution into ethyl acetate to precipitate, dissolving the precipitate obtained by suction filtration into a small amount of acetonitrile, and placing the acetonitrile into diethyl ether steam to precipitate, thereby finally obtaining an orange solid target product.
FIG. 2 is an infrared spectrum of Mn-POM-POD hybrid wherein Anderson polyacids are found at 1041, 939, 918, 902, 797, 739, 664, 566, 521, 455, 413cm -1 The characteristic peaks at the positions are well reserved, so that the polyacid has been proved to have good integrity before and after the reaction. At 3291cm -1 The peak at the position is N-H stretching vibration peak of 1669cm -1 C=o stretching vibration peak, 1542cm -1 Peak of N-H bending vibration, 1253cm -1 Is C-N stretching vibration peak. These peaks demonstrate the presence of amide linkages in Mn-POM-POD, thereby demonstrating that the Anderson polyacid is covalently linked to the podophyllotoxin.
FIG. 3 is a mass spectrum of Mn-POM-POD hybrid compounds, labeled with three TBAs removed from the compound molecule + And two Na + The back zone has 5 negative ions and three TBAs are dropped + Front with three anionsPosition. The practical measured value and the theoretical value obtained in the graph completely coincide, and the Mn-POM-POD hybrid compound is proved to be successfully prepared.
FIG. 4 is a schematic diagram of Mn-POM-POD hybrid compounds 1 H NMR spectrum, the hydrogen spectrum showing: in Mn-POM-POD hybrid compounds, three counter ions TBA + The structural integrity of the Mn-POM-POD hybrid compound is further demonstrated by the complete existence of the amide bond peaks and the like in the figure.
Example 2 dialysis preparation of podophyllotoxin modified Mn-Anderson polyacid hybrid compound (Mn-POM-POD) vesicles.
Mn-POM-POD (1 mg) compound was precisely weighed and dissolved in 0.5mL of acetonitrile, followed by slowly dropping into a mixed solvent of 4.5mL of acetonitrile (2 mL) and water (2.5 mL). Then, the mixed solution was transferred to a dialysis bag, and dialyzed for 24 hours to obtain Mn-POM-POD vesicle solution. The dialysis medium is ultrapure water. The particle size was then determined by particle size analyzer to be 126nm (FIG. 5). A more regular hollow spherical nanovesicle structure was observed by TEM (fig. 6).
Experimental example 1 cytotoxicity experiment
The compound vesicle solution of the present invention (prepared in example 2) was tested for its inhibitory ability against lung cancer cells (H1299, a 549), human liver cancer cells (HepG-2) and cytotoxicity against human normal cells (HEK 293).
The method comprises the following steps: cell digestion, counting, dilution to a concentration of 5X 10 4 mu.L of each cell suspension was inoculated in a 96-well plate (3-5X 10 per well 3 Individual cells), 96-well plates were placed at 37℃with 5% CO 2 Incubate in incubator for 24 hours. Mn-POM-POD vesicles were diluted to different concentrations (20. Mu.g.mL) with DMEM complete medium -1 、40μg·mL -1 、60μg·mL -1 、100μg·mL -1 、200μg·mL -1 ) 100 mu L of culture medium containing vesicle is added into each well, 3 compound wells are arranged at each concentration, a blank group and a control group are arranged, the blank group is not inoculated with cells, the control group is added with DMEM complete culture medium without vesicle, and then a 96-well plate is placed at 37 ℃ and 5% CO 2 After incubation in an incubator for 24 hours, 10. Mu.L MTT was added to each well, and then protected from lightIncubation was performed for 4 hours, medium was removed, 100 μl of dimethyl sulfoxide (DMSO) was added to each well, and mixed well on a shaker for 10 minutes. Then, the OD value is measured at 490nm of the enzyme labeling instrument to calculate the cell viability, and the cell viability calculation formula is as follows:
cell inhibition (%) =1-cell survival rate
The results are shown in FIG. 7 and Table 1.
TABLE 1
Table 1 shows that the concentration of the surfactant is 200. Mu.g.mL -1 The comparison of the inhibition rate of Mn-POM-POD and POD shows that under the same concentration, the compound vesicle prepared by the embodiment of the invention has proliferation inhibition effect on three cancer cells of H1299, A549 and Hep-G2, and the inhibition rate is obviously higher than that of podophyllotoxin.
The results of FIG. 7 and Table 1 show that for human normal cells HEK293, the cell activity in the Mn-POM-POD vesicle environment is higher than that in the Podophyllotoxin (POD) environment alone, indicating that Mn-POM-POD vesicles have much lower toxicity to human normal cells than Podophyllotoxin alone, thus demonstrating improved toxic side effects of Podophyllotoxin after attachment with polyacids. Normal cell IC incubated for 24 hours at different concentrations in combination with three drugs 50 (Table 2), the result shows that Mn-POM-POD has good safety and can effectively reduce the toxic and side effects on normal cells. Therefore, the Mn-POM-POD not only can effectively kill cancer cells, but also can reduce toxic and side effects on normal cells compared with a parent drug, and shows that the Mn-POM-POD drug vesicle can have potential for clinical application.
TABLE 2
Experimental example 2: determination of Mn-POM-POD solubility
(1) The experimental basis is as follows: chinese pharmacopoeia 2020 edition valve
(2) The operation method comprises the following steps: weighing 1g of podophyllotoxin, polyacid and Mn-POM-POD compound which are ground into fine powder respectively, placing into a volumetric flask, adding 10mL of water (25 ℃ +/-2 ℃) each time, and shaking forcefully for 30 seconds every 5 minutes; dissolution within 30 minutes, such as when no visually observable solute particles or droplets are observed, is considered complete dissolution. If not, continuing to add, and operating once according to the method until the solution is completely dissolved.
(3) Experimental results
| Compounds of formula (I) | Solubility of |
| Podophyllotoxin | 0.09g/L |
| Polyacids | 10.42g/L |
| Mn-POM-POD | 3.57g/L |
The results show a significant increase in the solubility of Mn-POM-POD in water compared to podophyllotoxin alone. This means that the water solubility of the podophyllotoxin is enhanced by the linkage with the polyacid.
Claims (8)
1. An podophyllotoxin modified Anderson polyoxometallate hybrid compound vesicle, which is characterized in that,
the podophyllotoxin modified Anderson polyoxometallate hybrid compound has a chemical formula of { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNHCOC 25 H 25 O 9 ] 2 ) Abbreviation Mn-POM-POD; TBA in the chemical formula is tetrabutylammonium ion, and the molecular formula is as follows: [ (C) 4 H 9 ) 4 N] + ；
The preparation method of the vesicle comprises the following steps:
(1) Under the protection of nitrogen, dissolving podophyllotoxin, succinic anhydride, 4-dimethylaminopyridine and triethylamine in anhydrous dichloromethane in sequence, reacting for 4 hours at room temperature, diluting a reaction solution with dichloromethane after the reaction is finished, washing with 0.1mol/L HCl solution for three times, drying with anhydrous sodium sulfate, removing the dichloromethane through reduced pressure rotary evaporation, and drying the product in a vacuum drying oven overnight to obtain podophyllotoxin succinic acid monoester;
(2) Under the protection of nitrogen, the reaction mixture (TBA) 4 [α-Mo 8 O 26 ]、Mn(CH 3 COO) 3 ·2H 2 Adding O and tris (hydroxymethyl) aminomethane into a reaction vessel, adding acetonitrile to dissolve, slowly heating to 85-90 ℃ under stirring, refluxing for 16 hours, cooling the orange reaction liquid to room temperature after the reaction is finished, filtering off precipitate, diffusing in diethyl ether steam for 3-5 days to obtain a large amount of orange crystals, filtering, and vacuum drying to obtain orange { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 }；
(3) Under the protection of nitrogen, 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline and podophyllotoxin succinic acid monoester are sequentially dissolved in acetonitrile, heated to a reflux state for reaction for 35 minutes, and then { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 Adding into reaction liquid, reflux reacting for 20 hr, cooling the orange reaction liquid to room temperature, vacuum concentrating, dropping the concentrated reaction liquid into ethyl acetate to separate out precipitate, leaching to obtain precipitate, dissolving in small amount of acetonitrile, and setting in diethyl ether steamSeparating out to obtain podophyllotoxin modified Anderson polyoxometallate hybrid compound;
(4) Dissolving podophyllotoxin modified Anderson polyoxometallate hybrid compound in organic solvent, slowly dripping into mixed solution of pure water and organic solvent under stirring at uniform speed, changing the solution into pale yellow clear solution, transferring into dialysis bag, and removing organic solvent.
2. A process for preparing podophyllotoxin modified Anderson polyoxometalate hybrid compound vesicles as claimed in claim 1 comprising the steps of:
(1) Under the protection of nitrogen, dissolving podophyllotoxin, succinic anhydride, 4-dimethylaminopyridine and triethylamine in anhydrous dichloromethane in sequence, reacting for 4 hours at room temperature, diluting a reaction solution with dichloromethane after the reaction is finished, washing with 0.1mol/L HCl solution for three times, drying with anhydrous sodium sulfate, removing the dichloromethane through reduced pressure rotary evaporation, and drying the product in a vacuum drying oven overnight to obtain podophyllotoxin succinic acid monoester;
(2) Under the protection of nitrogen, the reaction mixture (TBA) 4 [α-Mo 8 O 26 ]、Mn(CH 3 COO) 3 ·2H 2 Adding O and tris (hydroxymethyl) aminomethane into a reaction vessel, adding acetonitrile to dissolve, slowly heating to 85-90 ℃ under stirring, refluxing for 16 hours, cooling the orange reaction liquid to room temperature after the reaction is finished, filtering off precipitate, diffusing in diethyl ether steam for 3-5 days to obtain a large amount of orange crystals, filtering, and vacuum drying to obtain orange { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 }；
(3) Under the protection of nitrogen, 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline and podophyllotoxin succinic acid monoester are sequentially dissolved in acetonitrile, heated to a reflux state for reaction for 35 minutes, and then { (TBA) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 Adding the mixture into the reaction solution, refluxing for 20 hours, and cooling the obtained orange reaction solution to room temperature after the reactionConcentrating under reduced pressure, dripping the concentrated reaction solution into ethyl acetate to precipitate, dissolving the precipitate obtained by suction filtration into a small amount of acetonitrile, and precipitating in diethyl ether steam to obtain the podophyllotoxin modified Anderson polyoxometallate hybrid compound;
(4) Dissolving podophyllotoxin modified Anderson polyoxometallate hybrid compound in organic solvent, slowly dripping into mixed solution of pure water and organic solvent under stirring at uniform speed, changing the solution into pale yellow clear solution, transferring into dialysis bag, and removing organic solvent.
3. The method for preparing podophyllotoxin-modified Anderson-type polyoxometallate hybrid vesicles according to claim 2 wherein the organic solvent in step (4) is one of acetonitrile or dimethyl sulfoxide; in the mixed solution of pure water and the organic solvent, the volume ratio of the organic solvent to the pure water is 1:1-1.5, and the dosage ratio is 1mg of podophyllotoxin modified Anderson polyoxometallate hybrid compound to 0.5-1 mL of the organic solvent to 4-5 mL of the mixed solution of the pure water and the organic solvent.
4. The method for preparing podophyllotoxin-modified Anderson polyoxometallate hybrid compound vesicles according to claim 2, wherein the stirring speed of the uniform stirring in the step (4) is 800-1000 rpm, the stirring temperature is 25 ℃, stirring is continued for 30 minutes after the dripping is completed, and then dialysis is performed after standing at room temperature.
5. A process for the preparation of podophyllotoxin modified Anderson polyoxometalate hybrid vesicles according to claim 2, wherein: in the step (1), the mol ratio of the podophyllotoxin to the succinic anhydride to the 4-dimethylaminopyridine to the triethylamine is 1:2-3:0.5-1.5:0.5-1.5, and the dosage ratio of the anhydrous dichloromethane solvent is 1g podophyllotoxin to 50-75 mL of the anhydrous dichloromethane solvent.
6. Podophyllotoxin modification according to claim 2The preparation method of Anderson polyoxometallate hybrid compound vesicles is characterized by comprising the following steps of: the step (2) is described (TBA) 4 [α-Mo 8 O 26 ]、Mn(CH 3 COO) 3 ·2H 2 The mol ratio of O to the tris (hydroxymethyl) aminomethane is 1:1.5-2.5:3-3.5, and the dosage ratio of acetonitrile solvent is 1g (TBA) 4 [α-Mo 8 O 26 ]15-20 mL of acetonitrile solvent.
7. A process for the preparation of podophyllotoxin modified Anderson polyoxometalate hybrid vesicles according to claim 2, wherein: { (TBA) as described in step (3) 3 (MnMo 6 O 18 [(OCH 2 ) 3 CNH 2 ] 2 The molar ratio of the 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline to the podophyllotoxin succinic acid monoester is 1:2.5-3.5:1-2.5, and the dosage ratio of the acetonitrile solvent is 1g podophyllotoxin succinic acid monoester to 50-100 mL acetonitrile solvent.
8. The use of podophyllotoxin modified Anderson type polyoxometallate hybrid compound vesicles as claimed in claim 1 in the preparation of anti-tumor drugs, wherein the tumors are lung cancer and liver cancer.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225207A (en) * | 2011-04-20 | 2011-10-26 | 南开大学 | Dehydrocholic acid-molybdenum heteropoly salt-dehydrocholic acid compound and synthesis method thereof |
| CN102304152A (en) * | 2011-04-20 | 2012-01-04 | 南开大学 | Molybdenum-containing polyoxometalate and adamantane hybrid compound and preparation method thereof |
| CN102432641A (en) * | 2011-09-23 | 2012-05-02 | 南开大学 | Diacetone-D-galactose modified heteropoly acid hybrid and preparation method thereof |
| CN102443034A (en) * | 2011-09-23 | 2012-05-09 | 南开大学 | Cholesterol hybrid compound of molybdenum-containing polyoxometallate and preparation method of cholesterol hybrid compound |
| CN102491997A (en) * | 2011-11-25 | 2012-06-13 | 南开大学 | Cholic acid-molybdenum polyoxometallate-cholic acid compound and synthetic method |
| CN108586753A (en) * | 2018-05-15 | 2018-09-28 | 南开大学 | The preparation method for the cubic phase vesica nano material that multi-metal oxygen cluster-cage-type silsesquioxane hybrid molecule is constructed |
| CN109394782A (en) * | 2018-12-03 | 2019-03-01 | 中北大学 | The modified polyoxomolybdate hybrid of cholesterol derivative and its preparation and application |
| CN110049866A (en) * | 2016-10-26 | 2019-07-23 | 爱默蕾大学 | Polyoxometallic acid salt complex and its application in cancer treatment |
| CN114539292A (en) * | 2022-01-28 | 2022-05-27 | 遵义医药高等专科学校 | Novel podophyllotoxin spliced anti-tumor active molecular compound and preparation method and application thereof |
-
2022
- 2022-09-29 CN CN202211194863.8A patent/CN115572302A/en not_active Withdrawn
-
2023
- 2023-07-07 CN CN202310829315.6A patent/CN116870177B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225207A (en) * | 2011-04-20 | 2011-10-26 | 南开大学 | Dehydrocholic acid-molybdenum heteropoly salt-dehydrocholic acid compound and synthesis method thereof |
| CN102304152A (en) * | 2011-04-20 | 2012-01-04 | 南开大学 | Molybdenum-containing polyoxometalate and adamantane hybrid compound and preparation method thereof |
| CN102432641A (en) * | 2011-09-23 | 2012-05-02 | 南开大学 | Diacetone-D-galactose modified heteropoly acid hybrid and preparation method thereof |
| CN102443034A (en) * | 2011-09-23 | 2012-05-09 | 南开大学 | Cholesterol hybrid compound of molybdenum-containing polyoxometallate and preparation method of cholesterol hybrid compound |
| CN102491997A (en) * | 2011-11-25 | 2012-06-13 | 南开大学 | Cholic acid-molybdenum polyoxometallate-cholic acid compound and synthetic method |
| CN110049866A (en) * | 2016-10-26 | 2019-07-23 | 爱默蕾大学 | Polyoxometallic acid salt complex and its application in cancer treatment |
| CN108586753A (en) * | 2018-05-15 | 2018-09-28 | 南开大学 | The preparation method for the cubic phase vesica nano material that multi-metal oxygen cluster-cage-type silsesquioxane hybrid molecule is constructed |
| CN109394782A (en) * | 2018-12-03 | 2019-03-01 | 中北大学 | The modified polyoxomolybdate hybrid of cholesterol derivative and its preparation and application |
| CN114539292A (en) * | 2022-01-28 | 2022-05-27 | 遵义医药高等专科学校 | Novel podophyllotoxin spliced anti-tumor active molecular compound and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 多金属氧酸盐及其溶液自聚集行为研究进展;党利芳等;《应用化学》;第35卷(第6期);第625-644页，尤其是第628页倒数第1段、第633页第2-3段 * |
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