CN102516341B - 黄芩苷金属配合物及其制备方法和应用 - Google Patents
黄芩苷金属配合物及其制备方法和应用 Download PDFInfo
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- CN102516341B CN102516341B CN201110363357.2A CN201110363357A CN102516341B CN 102516341 B CN102516341 B CN 102516341B CN 201110363357 A CN201110363357 A CN 201110363357A CN 102516341 B CN102516341 B CN 102516341B
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- baicalin
- metal complexes
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- IPQKDIRUZHOIOM-UHFFFAOYSA-N Oroxin A Natural products OC1C(O)C(O)C(CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IPQKDIRUZHOIOM-UHFFFAOYSA-N 0.000 title claims abstract description 229
- 229960003321 baicalin Drugs 0.000 title claims abstract description 229
- AQHDANHUMGXSJZ-UHFFFAOYSA-N baicalin Natural products OC1C(O)C(C(O)CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 AQHDANHUMGXSJZ-UHFFFAOYSA-N 0.000 title claims abstract description 229
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- -1 Baicalin metal complex Chemical class 0.000 title abstract description 27
- IKIIZLYTISPENI-ZFORQUDYSA-N baicalin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IKIIZLYTISPENI-ZFORQUDYSA-N 0.000 claims abstract description 205
- 229910052751 metal Inorganic materials 0.000 claims abstract description 54
- 239000002184 metal Substances 0.000 claims abstract description 54
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000003513 alkali Substances 0.000 claims abstract description 22
- 229910052727 yttrium Inorganic materials 0.000 claims abstract description 18
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 11
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims abstract description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims abstract description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims abstract description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 6
- 239000001632 sodium acetate Substances 0.000 claims abstract description 6
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 6
- 239000001488 sodium phosphate Substances 0.000 claims abstract description 6
- 229910000162 sodium phosphate Inorganic materials 0.000 claims abstract description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims abstract description 6
- 235000011056 potassium acetate Nutrition 0.000 claims abstract description 4
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims abstract description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims abstract description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims abstract description 4
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 4
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 17
- 229910052746 lanthanum Inorganic materials 0.000 claims description 16
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 241000894006 Bacteria Species 0.000 claims description 6
- 229940088710 antibiotic agent Drugs 0.000 claims description 5
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 5
- 235000019800 disodium phosphate Nutrition 0.000 claims description 5
- 235000011008 sodium phosphates Nutrition 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 244000063299 Bacillus subtilis Species 0.000 claims description 3
- 241000222122 Candida albicans Species 0.000 claims description 3
- 241000607142 Salmonella Species 0.000 claims description 3
- 229940095731 candida albicans Drugs 0.000 claims description 3
- 230000000968 intestinal effect Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229940093916 potassium phosphate Drugs 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 230000000941 anti-staphylcoccal effect Effects 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000010949 copper Substances 0.000 abstract description 17
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical group [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 150000002603 lanthanum Chemical class 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 238000011161 development Methods 0.000 abstract description 2
- 239000004280 Sodium formate Substances 0.000 abstract 1
- 229940124350 antibacterial drug Drugs 0.000 abstract 1
- 150000001879 copper Chemical class 0.000 abstract 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 abstract 1
- 235000015497 potassium bicarbonate Nutrition 0.000 abstract 1
- 239000011736 potassium bicarbonate Substances 0.000 abstract 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 abstract 1
- 235000019254 sodium formate Nutrition 0.000 abstract 1
- 230000000536 complexating effect Effects 0.000 description 26
- 238000010521 absorption reaction Methods 0.000 description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 229910052782 aluminium Inorganic materials 0.000 description 14
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 239000012634 fragment Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 10
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 10
- 229910052802 copper Inorganic materials 0.000 description 10
- 229910021645 metal ion Inorganic materials 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000004411 aluminium Substances 0.000 description 7
- 229910052742 iron Inorganic materials 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 150000001793 charged compounds Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 5
- 229940097043 glucuronic acid Drugs 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000003385 bacteriostatic effect Effects 0.000 description 3
- FXNFHKRTJBSTCS-UHFFFAOYSA-N baicalein Chemical compound C=1C(=O)C=2C(O)=C(O)C(O)=CC=2OC=1C1=CC=CC=C1 FXNFHKRTJBSTCS-UHFFFAOYSA-N 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 150000003746 yttrium Chemical class 0.000 description 3
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 240000004534 Scutellaria baicalensis Species 0.000 description 1
- 235000017089 Scutellaria baicalensis Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940111685 dibasic potassium phosphate Drugs 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229910001447 ferric ion Inorganic materials 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- CZMAIROVPAYCMU-UHFFFAOYSA-N lanthanum(3+) Chemical compound [La+3] CZMAIROVPAYCMU-UHFFFAOYSA-N 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910021654 trace metal Inorganic materials 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000000207 volumetry Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/02—Iron compounds
- C07F15/025—Iron compounds without a metal-carbon linkage
-
- 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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 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
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种黄芩苷金属配合物,分子通式为(C21H17O11)xM(H2O)y,式中M为Cu(II),x为1,y为2;或M为Fe(III),x为2,y为0;或M为La(III)或Y(III),x为3,y为0;其制备方法是向黄芩苷中加入碱水溶液至黄芩苷和碱(碳酸氢钠、碳酸氢钾、甲酸钠、甲酸钾、乙酸钠、乙酸钾、磷酸氢二钠、磷酸氢二钾、磷酸钠或磷酸钾)恰好完全反应,再加入金属盐(铜盐、铁盐、镧盐或钇盐)反应制得;本发明的黄芩苷金属配合物的抗菌、抗肿瘤活性均明显强于黄芩苷,可用于制备抗菌药物和抗肿瘤药物,具有良好的开发应用前景;其制备方法不使用有机溶剂,不采用强碱性条件,简便易行,绿色环保,成本低,产物纯度高,产率高。
Description
技术领域
本发明属于化学制药领域,涉及一种金属配合物,还涉及该金属配合物的制备方法及其医药用途。
背景技术
黄芩苷是中药黄芩的主要有效成分,有抑菌抗炎、降压利尿、清除自由基、抑制脂肪酶等药理作用。近年来研究表明,某些微量金属本身有一定的生理活性,而黄芩苷分子中的氧原子具有强配位能力,其空间结构也有利于金属配合物的形成,因此,将黄芩苷转化为金属配合物有可能增强其疗效,甚至产生新的药理作用。目前,已有文献报道某些黄芩苷金属配合物具有清除自由基、增强免疫功能、抗菌、抗病毒、抑制脂加氧酶、抗炎抗变态反应等作用,且作用强于黄芩苷。因此,加强对黄芩苷金属配合物的研究,将有助于黄芩苷的开发利用及寻找新药,也为传统中药的应用寻找新的方向。
贾朝霞等将黄芩苷溶于50%甲醇溶液中,在pH=7.4条件下与CuCl2反应,制得了络合比为2:1的黄芩苷铜配合物。张素俊等将黄芩苷溶于无水乙醇溶液中,在碳酸钠碱性条件下分别与Cu(Ac)2、Ni(Ac)2、Co(Ac)2反应,制得了络合比为1:2的黄芩苷铜、黄芩苷镍、黄芩苷钴配合物。吴巍等将黄芩苷与Al(NO3)3分别用甲醇溶解后,反应制得了络合比分别为2:1、1:1的黄芩苷铝配合物。李思睿等将黄芩苷溶于60%乙醇溶液中,再加入抗坏血酸在pH=9条件下与FeSO4反应,制得了络合比为2:1的黄芩苷亚铁配合物。邓毅等将黄芩苷溶于60%乙醇溶液中,在pH=9条件下与CrCl3反应,制得了络合比为2:1的黄芩苷铬配合物。王学军等将黄芩苷、Y(NO3)3或Ce(NO3)3分别用吡啶溶解后,反应制得了络合比为1:1的黄芩苷钇、黄芩苷铈配合物。冯今明等在黄芩苷中加入Zn(Ac)2的甲醇溶液反应,制得了黄芩苷锌。中国专利申请200410079576.8采用乙醇溶解黄芩苷,加入Zn(Ac)2水溶液,在pH=7~8条件下反应,制得了络合比为2:3的黄芩苷锌配合物。但上述黄芩苷金属配合物的制备方法均存在一定的缺陷,例如,反应溶剂均采用甲醇、乙醇、吡啶等有机溶剂,存在毒性较大,安全性较差、环境污染较大等问题;而且,由于黄芩苷不溶于水,微溶于甲醇和乙醇,故上述反应均为小量反应,大规模生产成本高。此外,部分方法还将黄芩苷与金属盐在强碱性条件如pH=9条件下反应,一方面,黄芩苷在强碱性条件下结构易被破坏;另一方面,金属盐在强碱性条件下易生成氢氧化物沉淀,而难以与生成的黄芩苷金属配合物沉淀分离。
发明内容
有鉴于此,本发明的目的之一在于合成新的黄芩苷金属配合物,以期筛选出活性较黄芩苷明显增强的化合物进行新药开发。
为达到上述目的,本发明提供如下黄芩苷金属配合物,分子通式为(C21H17O11)xM (H2O)y,当M为Cu(II)、x为1、y为2时,其代表络合比为1:1的黄芩苷铜配合物,分子式为C21H17O11Cu(H2O)2,结构式如I所示;当M为Fe(III)、x为2、y为0时,其代表络合比为2:1的黄芩苷铁配合物,分子式为(C21H17O11)2Fe,结构式如II所示;当M为La(III)、x为3、y为0时,其代表络合比为3:1的黄芩苷镧配合物,分子式为(C21H17O11)3La,结构式如III所示;当M为Y(III)、x为3、y为0时,其代表络合比为3:1的黄芩苷钇配合物,分子式为(C21H17O11)3Y,结构式如IV所示。所述Cu(II)、Fe(III)、La(III)、Y(III)分别表示二价铜离子、三价铁离子、三价镧离子、三价钇离子。
本发明的目的之二在于提供上述黄芩苷金属配合物的制备方法,不使用有机溶剂,不采用强碱性条件,简便易行,绿色环保,低成本,高产率。
为达到此目的,本发明的黄芩苷金属配合物的制备方法,是向黄芩苷中加入碱水溶液至黄芩苷和碱恰好完全反应,再加入金属盐进行反应,固液分离,所得固体即为黄芩苷金属配合物;所述碱为碳酸氢钠、碳酸氢钾、甲酸钠、甲酸钾、乙酸钠、乙酸钾、磷酸氢二钠、磷酸氢二钾、磷酸钠或磷酸钾;所述金属盐为铜盐、铁盐、镧盐或钇盐。当所述碱为碳酸氢钠、碳酸氢钾、甲酸钠、甲酸钾、乙酸钠或乙酸钾时,黄芩苷与碱恰好完全反应的摩尔比为1:1;当所述碱为磷酸氢二钠或磷酸氢二钾时,黄芩苷与碱恰好完全反应的摩尔比为2:1;当所述碱为磷酸钠或磷酸钾时,黄芩苷与碱恰好完全反应的摩尔比为3:1。
优选的,所述碱为碳酸氢钠,所述黄芩苷与金属盐的摩尔比为3:1~6即1:1/3~2。
优选的,所述金属盐为铜、铁、镧或钇的硫酸盐、硝酸盐或氯化物。
优选的,所述黄芩苷与铜盐或铁盐的反应温度为20~70℃,黄芩苷与镧盐或钇盐的反应温度为20~35℃。
本发明的目的之三在于提供上述黄芩苷金属配合物的医药用途,以期为临床疾病的治疗提供更多、更好的药物。
为达到上述目的,本发明提供上述黄芩苷金属配合物的两个医药用途:一是在制备抗菌药物中的应用,例如,抗金黄色葡萄球菌、枯草杆菌、大肠杆菌、沙门氏菌和白色念珠菌中任一种或多种的药物;二是在制备抗肿瘤药物中的应用,例如,抗肺癌或肝癌的药物。
本发明的有益效果在于:本发明利用黄芩苷可溶于碱水溶液的特性,将其用碱水溶液溶解并通过控制黄芩苷与碱的比例使最终溶液呈中性,再在该中性条件下加入金属盐与黄芩苷反应制备黄芩苷金属配合物,①不使用价格较昂贵、易燃易爆的有机溶剂,无毒性,操作人员和环境安全性好,环境污染小,生产成本低;②不使用强碱性条件,避免了黄芩苷遭强碱破坏的可能性,也避免了产生金属氢氧化物的可能性,产品纯度高,产率(>70%,最高达到97.75%)远高于目前文献报道的黄芩苷金属配合物的产率(20~60%)。本发明制得的络合比为1:1的黄芩苷铜、络合比为2:1的黄芩苷铁、络合比为3:1的黄芩苷镧和黄芩苷钇配合物目前尚未见文献报道,经小鼠急性毒性实验证明经口给药属实际无毒范围,且抗菌、抗肿瘤活性均明显强于黄芩苷,尤其是络合比为1:1的黄芩苷铜配合物,其抗菌、抗肿瘤活性较黄芩苷有大幅度提高,在抗菌、抗肿瘤药物领域具有良好的开发应用前景。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚,下面将对本发明的优选实施例进行详细的描述。
实施例1、黄芩苷金属配合物的制备
(1)黄芩苷铜配合物的制备
向黄芩苷中加入质量百分浓度为1%的碳酸氢钠水溶液,黄芩苷与碳酸氢钠的摩尔比为1:1,搅拌使黄芩苷完全溶解,再按照黄芩苷与Cu(NO3)2的摩尔比为1:2加入Cu(NO3)2,温度20℃搅拌反应4小时,过滤,所得棕黄色沉淀用水洗涤,烘干,即得黄芩苷铜配合物,产率73.93%。
(2)黄芩苷铝配合物的制备
向黄芩苷中加入质量百分浓度为1%的乙酸钠水溶液,黄芩苷与乙酸钠的摩尔比为1:1,搅拌使黄芩苷完全溶解,再按照黄芩苷与Al2(SO4)3的摩尔比为2:1加入Al2(SO4)3,温度40℃搅拌反应6小时,过滤,所得橙红色沉淀用水洗涤,烘干,即得黄芩苷铝配合物,产率91.08%。
(3)黄芩苷铁配合物的制备
向黄芩苷中加入质量百分浓度为1%的磷酸氢二钠水溶液,黄芩苷与磷酸氢二钠的摩尔比为2:1,搅拌使黄芩苷完全溶解,再按照黄芩苷与FeCl3的摩尔比为2:1加入FeCl3,温度70℃搅拌反应2小时,过滤,所得黑色沉淀用水洗涤,烘干,即得黄芩苷铁配合物,产率97.75%。
(4)黄芩苷镧配合物的制备
向黄芩苷中加入质量百分浓度为1%的磷酸氢二钾水溶液,黄芩苷与磷酸氢二钾的摩尔比为2:1,搅拌使黄芩苷完全溶解,再按照黄芩苷与La(NO3)3的摩尔比为2:1加入La(NO3)3,温度20℃搅拌反应3小时,过滤,所得棕黑色沉淀用水洗涤,烘干,即得黄芩苷镧配合物,产率91.42%。
(5)黄芩苷钇配合物的制备
向黄芩苷中加入质量百分浓度为1%的磷酸钠水溶液,黄芩苷与磷酸钠的摩尔比为3:1,搅拌使黄芩苷完全溶解,再按照黄芩苷与Y2(SO4)3的摩尔比为2:1加入Y2(SO4)3,温度35℃搅拌反应2小时,过滤,所得棕红色沉淀用水洗涤,烘干,即得黄芩苷钇配合物,产率94.27%。
发明人通过大量研究发现:①关于黄芩苷与碱的投料比,因黄芩苷分子中含有一个羧基,当其与碱恰好完全反应时,则黄芩苷恰好完全溶解于碱水溶液中且溶液pH约为7,呈中性,不需再用pH调节剂调节溶液pH至中性,因此,黄芩苷与碱的投料比以二者恰好完全反应为最佳比例。②关于黄芩苷与金属盐的投料比,采用本发明所述方法,当金属种类固定时,不同比例的黄芩苷与金属盐反应生成的配合物结构是相同的,因此,黄芩苷与金属盐的投料比并不局限于上述实施例中给出的比例,只是综合考虑产率和成本,本发明优选黄芩苷与金属盐的摩尔比为1:1/3~2。③关于黄芩苷与金属盐的反应温度,黄芩苷与铜盐、铝盐或铁盐在20~70℃反应均可以生成本发明所述的黄芩苷铜、黄芩苷铝或黄芩苷铁配合物,而黄芩苷与镧盐或钇盐的反应则以20~35℃为宜,超过35℃可能无法得到目标产物。④参照上述实施例,采用铜、铝、铁、镧和钇以外的其它金属的盐与黄芩苷反应,也可以制备出其它黄芩苷金属配合物。因此,本发明的制备方法实际具有普遍适用性。
实施例2、黄芩苷金属配合物的结构表征
(1)紫外表征结果
将实施例1制得的五种黄芩苷金属配合物分别溶于质量百分浓度为1%的NaOH水溶液中,用紫外分光光度计测定最大吸收波长,结果见表1。
表1 黄芩苷及其金属配合物的紫外吸收波长
由表1可知,黄芩苷分别在275nm、317nm处有两个吸收峰,而黄芩苷铜、黄芩苷铝、黄芩苷铁、黄芩苷镧和黄芩苷钇配合物仅在289nm或277nm有一个吸收峰,即黄芩苷原317nm处的吸收峰消失,原275nm处的吸收峰发生了红移。由于黄芩苷形成配合物后,分子中电子的离域程度增大且金属离子有一定的吸电子能力,使电子跃迁所需的激发能减小,可导致吸收峰红移。因此,上述结果说明黄芩苷和金属离子之间发生了反应。
(2)红外表征结果
实施例1制得的五种黄芩苷金属配合物的红外表征结果见表2。
表2 黄芩苷及其金属配合物主要基团的红外光谱数据
由表2可知,黄芩苷4位C=O的伸缩振动吸收峰为1661.05cm-1,与其相比,黄芩苷铜、黄芩苷铝、黄芩苷铁、黄芩苷镧和黄芩苷钇配合物的C=O吸收峰分别红移了约37cm-1、36 cm-1、36cm-1、53cm-1和53cm-1。由于氧的孤对电子与金属离子的空轨道形成配位键后会导致C=O的电子云密度降低,进而使吸收峰发生红移。因此,上述结果说明黄芩苷与金属离子的结合部位之一为4位C=O。
黄芩苷5位O-H的伸缩振动吸收峰为3398.45cm-1,与其相比,黄芩苷铜、黄芩苷铝和黄芩苷铁配合物的5位O-H吸收峰分别蓝移了约30cm-1、14cm-1和13cm-1,黄芩苷镧和黄芩苷钇配合物的5位O-H吸收峰分别红移了约42cm-1和36cm-1,说明黄芩苷的5位O-H也与金属离子发生了作用。
黄芩苷5位C-O伸缩振动吸收峰为1201.25cm-1,与其相比,黄芩苷铜、黄芩苷铝、黄芩苷铁、黄芩苷镧和黄芩苷钇配合物的C-O吸收峰分别红移了约10 cm-1、12 cm-1、12 cm-1、9cm-1和13cm-1。由于金属离子对C-O中氧的电子离域作用可导致该吸收峰红移,因此,上述结果说明5位C-O中的氧与金属离子之间发生了作用。
综上,黄芩苷的4位C=O和5位O-H与金属离子发生了配位。
(3)金属含量测定结果
采用EDTA滴定法分别测定实施例1制得的五种黄芩苷金属配合物的金属离子含量,结果见表3。
表3 黄芩苷金属配合物中金属离子的含量
(4)质谱表征结果
实施例1制得的黄芩苷金属配合物的质谱表征结果见表4。
表4 黄芩苷及其金属配合物的分子离子峰及碎片峰
由表4可知,黄芩苷铜配合物的分子离子峰为543.6,碎片峰506.5为分子离子断裂失去两分子水(18Da×2)所得,碎片峰366.5为分子离子断裂失去一分子葡萄糖醛酸(176Da)所得,因此,推定黄芩苷铜配合物由黄芩苷+Cu+2H2O组成。另根据红外结果知其在4位C=O和5位O-H配位,因此,推定黄芩苷铜配合物的结构如I所示,黄芩苷与Cu的络合比为1:1,与文献报道的络合比为2:1或1:2的黄芩苷铜配合物结构不同,为新化合物。
黄芩苷铝配合物的分子离子峰为918.3,碎片峰740.5为分子离子断裂失去一分子葡萄糖醛酸(176Da)所得,碎片峰366.5为分子离子断裂失去两分子葡萄糖醛酸(176Da×2)所得,因此,推定黄芩苷铝配合物由黄芩苷×2+Al组成。另根据红外结果知其在4位C=O和5位O-H配位,因此,推定黄芩苷铝配合物的结构如V所示,黄芩苷与Al的络合比为2:1,与文献报道的络合比为2:1的黄芩苷铝配合物结构相同。
黄芩苷铁配合物的分子离子峰为944.8,碎片峰769.2为分子离子断裂失去一分子葡萄糖醛酸(176Da)所得,碎片峰675.4为分子离子断裂失去一分子黄芩苷元(270Da)所得,碎片峰498.6为分子离子断裂失去一分子黄芩苷(446Da)所得,因此,推定黄芩苷铁配合物由黄芩苷×2+Fe(III)组成。另根据红外结果知其在4位C=O和5位O-H配位,因此,推定黄芩苷铁配合物的结构如II所示,黄芩苷与Fe(III)的络合比为2:1。目前仅见文献报道了一种络合比为2:1的黄芩苷亚铁配合物,还未见文献报道黄芩苷铁配合物,因此,该化合物为新化合物。
黄芩苷镧配合物的分子离子峰为1473.8,碎片峰1297.2为分子离子断裂失去一分子葡萄糖醛酸(176Da)所得,碎片峰445.7为分子离子断裂后所得黄芩苷的峰,因此,推定黄芩苷镧配合物由黄芩苷×3+La组成。另根据红外结果知其在4位C=O和5位O-H配位,因此,推定黄芩苷镧配合物的结构如III所示,黄芩苷与La的络合比为3:1。目前尚未见文献报道黄芩苷镧配合物,因此,该化合物为新化合物。
黄芩苷钇配合物的分子离子峰为1422.9,碎片峰1247.9为分子离子断裂失去一分子葡萄糖醛酸(176Da)所得,碎片峰893.6为分子离子断裂失去三分子葡萄糖醛酸(176Da×3)所得,因此,推定黄芩苷钇配合物由黄芩苷×3+Y组成。另根据红外结果知其在4位C=O和5位O-H配位,因此,推定黄芩苷钇配合物的结构如IV所示,黄芩苷与Y的络合比为3:1,与文献报道的络合比为1:1的黄芩苷钇配合物结构不同,为新化合物。
实施例3、黄芩苷金属配合物的急性毒性
将实施例1制得的五种黄芩苷金属配合物用质量百分浓度为1%的NaOH水溶液溶解制成质量百分浓度为10%的溶液,按最大耐受剂量法每只小鼠灌胃给予5g/kg,连续观察两周,记录小鼠活动及死亡情况。
结果显示,灌胃给药后,所有小鼠活动稍有减弱,但短时间内得到恢复;两周内所有小鼠均生长良好,未观察到有中毒反应,无小鼠死亡;说明实施例1制得的五种黄芩苷金属配合物对小鼠灌胃的LD50均大于5g/kg。根据急性毒性(LD50)剂量分级,上述五种配合物经口给药属实际无毒范围。
实施例4、黄芩苷金属配合物的药理活性
(1)抑菌活性
将黄芩苷和实施例1制得的五种黄芩苷金属配合物分别用质量百分浓度为1%的NaOH水溶液溶解,采用96孔板法倍比稀释成5个浓度:0.125、0.25、0.5、1、2 mg/mL,每个浓度设5个复孔,每孔中加入等量菌液(菌液浓度为2×105/mL),置培养箱中37℃培养24小时(真菌于30℃培养48小时),测得每种化合物对不同细菌的最小抑菌浓度(MIC)。结果见表5。
表5 黄芩苷及其金属配合物的抑菌活性
由表5可知,实施例1制得的五种黄芩苷金属配合物对革兰氏阳性菌(金黄色葡萄球菌、枯草杆菌)、革兰氏阴性菌(大肠杆菌、沙门氏菌)和真菌(白色念珠菌)的抑菌活性较黄芩苷均显著增强,其中,以黄芩苷铜配合物的抗菌活性最好。中国专利申请CN1462619A公开了络合比为1:1的黄芩苷锌配合物对金黄色葡萄球菌和大肠杆菌的MIC分别为0.63 mg/mL、5.0 mg/mL;CN1634952A公开了络合比为2:3的黄芩苷锌配合物对金黄色葡萄球菌和大肠杆菌的MIC分别为1 mg/mL、>1 mg/mL。本发明的黄芩苷铜配合物对金黄色葡萄球菌的抑制活性明显强于上述文献报道的黄芩苷锌化合物,而本发明的黄芩苷铜、黄芩苷铝、黄芩苷铁、黄芩苷镧和黄芩苷钇配合物对大肠杆菌的抑制效果均明显强于上述文献报道的黄芩苷锌化合物。
(2)抗肿瘤活性
分别取对数生长期的肺癌A549细胞和肝癌HepG2细胞,用含体积百分浓度为10%的胎牛血清的RPMI-1640培养基稀释至菌液浓度为1×104/mL,接种于96孔板,每孔100μL,置培养箱中于温度为37℃、CO2体积分数为5%的条件下培养24小时,弃去培养基,加入新鲜培养基100μL,再加入不同浓度(20、40、80、160、320μM)的黄芩苷或其金属配合物溶液,每孔100μL,每个浓度设5个复孔,并设溶剂对照组,继续于相同条件下培养48小时,再每孔加入MTT培养4小时,弃去上清液,加入DMSO振荡,用酶标仪于490nm处测定吸光度,取5个复孔的平均值,计算每种化合物对不同肿瘤细胞的半数有效抑制浓度(IC50)。结果见表6。
表6 黄芩苷及其金属配合物的抗肿瘤活性
由表6可知,实施例1制得的五种黄芩苷金属配合物对肺癌A549细胞和肝癌HepG2细胞的抑制活性较黄芩苷均显著增强,其中黄芩苷铜配合物的抑制活性最好。目前尚无文献报道黄芩苷金属配合物的抗肿瘤作用。
基于以上实验结果,实施例1制得的五种黄芩苷金属配合物可用于制备抗菌药物和抗肿瘤药物。
最后说明的是,以上实施例仅用于说明本发明的技术方案,并不构成对本发明内容的限制。尽管通过上述实施例已经对本发明做了较为详细的例举,但本领域技术人员仍然可以根据发明内容部分和实施例部分所描述的技术内容,在形式上和细节上对其作出各种各样的改变,而不偏离所附权利要求书所限定的本发明的精神和范围。
Claims (8)
2.权利要求1所述黄芩苷金属配合物的制备方法,其特征在于,向黄芩苷中加入碱水溶液至黄芩苷和碱恰好完全反应,再加入金属盐进行反应,固液分离,所得固体即为黄芩苷金属配合物;所述碱为碳酸氢钠、碳酸氢钾、甲酸钠、甲酸钾、乙酸钠、乙酸钾、磷酸氢二钠、磷酸氢二钾、磷酸钠或磷酸钾;所述金属盐为镧或钇的硫酸盐、硝酸盐或氯化物。
3.根据权利要求2所述黄芩苷金属配合物的制备方法,其特征在于,所述碱为碳酸氢钠,所述黄芩苷与金属盐的摩尔比为3:1~6。
4.根据权利要求2或3所述黄芩苷金属配合物的制备方法,其特征在于,所述黄芩苷与金属盐的反应温度为20~35℃。
5.权利要求1所述黄芩苷金属配合物在制备抗菌药物中的应用。
6.根据权利要求5所述黄芩苷金属配合物在制备抗菌药物中的应用,其特征在于,所述抗菌药物为抗金黄色葡萄球菌、枯草杆菌、大肠杆菌、沙门氏菌和白色念珠菌中任一种或多种的药物。
7.权利要求1所述黄芩苷金属配合物在制备抗肿瘤药物中的应用。
8.根据权利要求7所述黄芩苷金属配合物在制备抗肿瘤药物中的应用,其特征在于,所述抗肿瘤药物为抗肺癌或肝癌的药物。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1244533A (zh) * | 1998-04-28 | 2000-02-16 | 蔡传英 | 一种新药黄芩甙锌 |
CN1462754A (zh) * | 2003-06-24 | 2003-12-24 | 清华大学 | 一种药用络合物二黄芩苷锌及其制备方法 |
CN1634952A (zh) * | 2004-11-24 | 2005-07-06 | 昆明贵金属研究所 | 药用含锌配合物及其制备方法 |
CN1695631A (zh) * | 2005-05-20 | 2005-11-16 | 昆明医学院 | 一种黄芩甙锌络合物水溶液的制备方法 |
DE102009045981A1 (de) * | 2009-10-26 | 2010-08-05 | Henkel Ag & Co. Kgaa | Antifalten-Kosmetikum mit Strandkamillenextrakt |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102336773B (zh) * | 2011-03-21 | 2014-04-02 | 北京华牧伟业科技有限公司 | 黄芩甙铜配合物及其制备方法 |
-
2011
- 2011-11-16 CN CN201110363357.2A patent/CN102516341B/zh not_active Expired - Fee Related
-
2012
- 2012-03-20 WO PCT/CN2012/072601 patent/WO2013071724A1/zh active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1244533A (zh) * | 1998-04-28 | 2000-02-16 | 蔡传英 | 一种新药黄芩甙锌 |
CN1462754A (zh) * | 2003-06-24 | 2003-12-24 | 清华大学 | 一种药用络合物二黄芩苷锌及其制备方法 |
CN1634952A (zh) * | 2004-11-24 | 2005-07-06 | 昆明贵金属研究所 | 药用含锌配合物及其制备方法 |
CN1695631A (zh) * | 2005-05-20 | 2005-11-16 | 昆明医学院 | 一种黄芩甙锌络合物水溶液的制备方法 |
DE102009045981A1 (de) * | 2009-10-26 | 2010-08-05 | Henkel Ag & Co. Kgaa | Antifalten-Kosmetikum mit Strandkamillenextrakt |
Non-Patent Citations (8)
Title |
---|
Barry D. Davis,等.Determination of the Glycosylation Site of Flavonoid Monoglucosides by Metal Complexation and Tandem Mass Spectrometry.《J. AM.SOC.Specttom》.2004,第15卷第1287-1299页,特别是第1291、1292页. * |
Junmei Zhang,等.Threshold Dissociation and Molecular Modeling of Transition Metal Complexes of Flavonoids.《J Am Soc Mass Spectrom》.2004,第16卷第139-151页. * |
Luisa Helena Cazarolli,等.Follow-up studies on glycosylated flavonoids and their complexes with vanadium: Their anti-hyperglycemic potential role in diabetes.《Chemico-Biological Interactions》.2006,第163卷第177-191页. * |
Regina M. S. Pereira,等.Synthesis and Characterization of a Metal Complex Containing Naringin and Cu, and its Antioxidant, Antimicrobial,Antiinflammatory and Tumor Cell Cytotoxicity.《Molecules》.2007,第12卷第1352-1366页,特别是第1355页figure2. * |
刘春明,等.淫羊藿甙及其与金属离子配合物的电喷雾多级串联质谱研究.《质谱学报》.2003,第24卷(第4期),第482-485页. * |
李延峰,等.黄芩甙金属配合物研究进展.《时珍国医国药》.1999,第10卷(第2期),第152-153页. * |
李思睿,等.黄芩苷- Fe(Ⅱ) 配合物的合成与表征.《北京化工大学学报》.2006,第33卷(第2期),第97-101. * |
王学军,等.黄芩苷稀土配合物的合成与表征.《中医药学报》.2009,第37卷(第5期),第66-67页. * |
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