CN107951880A - A kind of benzopyrone is used for the purposes that for aristolochic acid and the Chinese medicine containing aristolochic acid is attenuated - Google Patents
A kind of benzopyrone is used for the purposes that for aristolochic acid and the Chinese medicine containing aristolochic acid is attenuated Download PDFInfo
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- CN107951880A CN107951880A CN201711263842.6A CN201711263842A CN107951880A CN 107951880 A CN107951880 A CN 107951880A CN 201711263842 A CN201711263842 A CN 201711263842A CN 107951880 A CN107951880 A CN 107951880A
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- aristolochic acid
- benzopyrone
- chinese
- chinese medicine
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- BBFQZRXNYIEMAW-UHFFFAOYSA-N aristolochic acid I Chemical compound C1=C([N+]([O-])=O)C2=C(C(O)=O)C=C3OCOC3=C2C2=C1C(OC)=CC=C2 BBFQZRXNYIEMAW-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 239000003814 drug Substances 0.000 title claims abstract description 53
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 230000002238 attenuated effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 20
- 239000000284 extract Substances 0.000 claims abstract description 17
- 231100000417 nephrotoxicity Toxicity 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 239000006187 pill Substances 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 241000046585 Aristolochia clematitis Species 0.000 claims abstract description 7
- 241001369615 Aristolochia fangchi Species 0.000 claims abstract description 6
- 241000758794 Asarum Species 0.000 claims abstract description 6
- 244000292697 Polygonum aviculare Species 0.000 claims abstract description 6
- 235000006386 Polygonum aviculare Nutrition 0.000 claims abstract description 6
- 239000008629 longdanxiegan Substances 0.000 claims abstract description 5
- 240000004980 Rheum officinale Species 0.000 claims abstract description 4
- 235000008081 Rheum officinale Nutrition 0.000 claims abstract description 4
- 235000001361 Styrax officinalis Nutrition 0.000 claims abstract description 4
- 208000029078 coronary artery disease Diseases 0.000 claims abstract description 4
- 235000019382 gum benzoic Nutrition 0.000 claims abstract description 4
- 210000002784 stomach Anatomy 0.000 claims abstract description 4
- BBFQZRXNYIEMAW-UHFFFAOYSA-M Aristolochate I Natural products C1=C([N+]([O-])=O)C2=C(C([O-])=O)C=C3OCOC3=C2C2=C1C(OC)=CC=C2 BBFQZRXNYIEMAW-UHFFFAOYSA-M 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 244000303379 Styrax officinalis Species 0.000 claims description 3
- 241001647745 Banksia Species 0.000 claims 1
- 244000025254 Cannabis sativa Species 0.000 claims 1
- 241000220317 Rosa Species 0.000 claims 1
- 241001060310 Styracaceae Species 0.000 abstract 1
- VOTLUFSYIRHICX-LBPRGKRZSA-N Hamaudol Chemical compound C1[C@H](O)C(C)(C)OC2=C1C(O)=C1C(=O)C=C(C)OC1=C2 VOTLUFSYIRHICX-LBPRGKRZSA-N 0.000 description 26
- 241000700159 Rattus Species 0.000 description 26
- VOTLUFSYIRHICX-UHFFFAOYSA-N hamaudol Natural products C1C(O)C(C)(C)OC2=C1C(O)=C1C(=O)C=C(C)OC1=C2 VOTLUFSYIRHICX-UHFFFAOYSA-N 0.000 description 15
- 206010023421 Kidney fibrosis Diseases 0.000 description 11
- 230000006907 apoptotic process Effects 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 238000003304 gavage Methods 0.000 description 9
- 235000015097 nutrients Nutrition 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 8
- 210000005084 renal tissue Anatomy 0.000 description 8
- 241000382455 Angelica sinensis Species 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 206010016654 Fibrosis Diseases 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 241000411851 herbal medicine Species 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- -1 Aristolochic Acid compound Chemical class 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000004577 thatch Substances 0.000 description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 description 2
- 241000758795 Aristolochiaceae Species 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 208000033626 Renal failure acute Diseases 0.000 description 2
- 201000011040 acute kidney failure Diseases 0.000 description 2
- 208000012998 acute renal failure Diseases 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 239000008157 edible vegetable oil Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 201000002793 renal fibrosis Diseases 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 240000008027 Akebia quinata Species 0.000 description 1
- 235000007756 Akebia quinata Nutrition 0.000 description 1
- 102000004121 Annexin A5 Human genes 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 208000004884 Balkan Nephropathy Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 150000004777 chromones Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000011617 nephropathy animal model Methods 0.000 description 1
- 230000004987 nonapoptotic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical group OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- 210000004926 tubular epithelial cell Anatomy 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000012224 working solution Substances 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
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/26—Aristolochiaceae (Birthwort family), e.g. heartleaf
- A61K36/264—Aristolochia (Dutchman's pipe)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/26—Aristolochiaceae (Birthwort family), e.g. heartleaf
- A61K36/268—Asarum (wild ginger)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/57—Magnoliaceae (Magnolia family)
- A61K36/575—Magnolia
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- Natural Medicines & Medicinal Plants (AREA)
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- General Health & Medical Sciences (AREA)
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- Medical Informatics (AREA)
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- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of benzopyrone to be used for the purposes that for aristolochic acid and the Chinese medicine containing aristolochic acid is attenuated.It is a discovery of the invention that benzopyrone provided by the invention can reduce the renal toxicity of aristolochic acid, can be used for preparing the single medicinal material containing aristolochic acid or Chinese medical extract or the toxicity-reducing medicament of compound Chinese medicinal preparation.Above-mentioned benzopyrone can both develop into single medicine, take, the single medicinal material containing aristolochic acid or Chinese medical extract or Chinese medicine compound prescription can also be developed into pharmaceutical composition with above-mentioned benzopyrone at the same time with the single medicinal material containing aristolochic acid or Chinese medical extract or compound Chinese medicinal preparation.Chinese medicine can be the Chinese medicine containing aristolochic acid such as caulis aristologhiae manshuriensis, birthwort, aristolochia fangchi, dutchmanspipe root, Ciliatenerve Knotweed Root, berba aristolochiae mollissimae, herba aristolochiae, Cortex Magnoliae Officinalis, asarum.Chinese medicine compound prescription can be the Chinese medicine compound prescriptions containing aristolochic acid such as rheum officinale clearing stomach ball, children-welfare tablet, Fenqing Wulin pill, Longdan Xiegan wan, shixiang fansheng pill, storax pill for treating coronary heart disease.
Description
Technical field
The invention belongs to field of medicaments, is related to benzopyrone and is used to be aristolochic acid and the Chinese medicine attenuation containing aristolochic acid
Purposes.
Background technology
On October 18th, 2017, the researcher from Singapore and TaiWan, China is in Science periodicals Science
Translational Medicine issue entitled " Aristolochic acids and their derivatives are
The research paper of widely implicated in liver cancers in Taiwan and throughout Asia ".
This article points out dark aspect (toxic side effect) of Chinese herbal medicine, its leading role-aristolochic acid in the form of cover story
(aristolochic acids, AA) is a kind of chemistry being widely present in aristolochiaceae plant and a variety of natural herbals into
Point.The chemical constitution of four kinds of main aristolochic acids is as follows：
The toxicity that state food pharmaceuticals administration general bureau of China (CFDA) and the world of medicine also pay special attention to aristolochic acid is made
With.The China that is operated in that standardized administration contains Aristolochic Acid compound Chinese herbal medicine is unfolded already, and is continued for carrying out.
The case of acute renal failure has been caused to be reported excessive use Aristolochiaceae caulis aristologhiae manshuriensis early in Wu Han pines in 1964
(bibliography：Wu Songhan, two reports of akebi induced Acute renal failure, Jiangsu traditional Chinese medicine, 1964).90 years 20th century
Generation, the generation of the event such as " Belgian slimming drugs (aristolochia fangchi) ", " Longdan Xiegan wan ", and Chinese patent drug containing aristolochic acid trigger
The case quantity of kidney function damage is also on the increase, and promotes the toxicity research of the Chinese herbal medicine containing aristolochic acid further to go deep into, manage
It is stringenter.Version in 2000《Chinese Pharmacopoeia》Carried out under caulis aristologhiae manshuriensis kind using limiting, being indicated in the case where paying attention to item " can not be more
With, long term usage；Renal insufficiency and be not taken by pregnant women "；CFDA took again in the medicinal standard for eliminating caulis aristologhiae manshuriensis in 2003,2004
The medicinal standard of the aristolochia fangchi that disappeared and dutchmanspipe root, and propose to strengthen the Chinese medicine containing birthwort, berba aristolochiae mollissimae, herba aristolochiae and Ciliatenerve Knotweed Root
The supervision and management of preparation；Version in 2005《Chinese Pharmacopoeia》Also start to phase out the Chinese herbal medicine containing aristolochic acid in record, extremely
Version in 2015《Chinese Pharmacopoeia》Only 3 kinds of herba aristolochiae, birthwort and asarum medicines containing aristolochic acid still record wherein.
But have much that the Chinese medicine containing aristolochic acid has its special purposes in tcm field, and do not have also at present
There is the side's of the entering substitute for searching out these Chinese medicines containing aristolochic acid.This results in some Gus for passing through succession in hundreds and thousands of years
Allusion quotation recipe cannot be further continued for using because of the renal toxicity of aristolochic acid, tangible sorry.
The content of the invention
Be used for it is an object of the invention to overcome the deficiencies of the prior art and provide a kind of benzopyrone for aristolochic acid and
The purposes of Chinese medicine attenuation containing aristolochic acid, for reducing the renal toxicity of the Chinese medicine containing aristolochic acid.
The above-mentioned purpose of the present invention is achieved by following technical solution：
The benzopyrone of following chemical constitution is used to prepare the purposes of aristolochic acid toxicity-reducing medicament：
Wherein, R3、R4For alkyl or contain heteroatomic alkyl.
Preferably, benzopyrone is preferably as follows the compound of chemical constitution：
Preferably, the attenuation refers to the renal toxicity for reducing aristolochic acid.
Preferably, the aristolochic acid is Aristolochic acid-I, Aristolochic acid-I I, Aristolochic acid-I II and Aristolochic acid-I V
In one or more.
Above-mentioned benzopyrone is used to prepare the purposes of the toxicity-reducing medicament of the single medicinal material containing aristolochic acid；The attenuation
Referring to reduces the renal toxicity of the single medicinal material containing aristolochic acid.
Above-mentioned benzopyrone is used to prepare the purposes of the toxicity-reducing medicament of the Chinese medical extract containing aristolochic acid；It is described to subtract
Poison refers to the renal toxicity for reducing the Chinese medical extract containing aristolochic acid.
Preferably, the Chinese medicine is caulis aristologhiae manshuriensis, birthwort, aristolochia fangchi, dutchmanspipe root, Ciliatenerve Knotweed Root, berba aristolochiae mollissimae, herba aristolochiae, thickness
Piao, asarum etc..
Above-mentioned benzopyrone is used to prepare the purposes of the toxicity-reducing medicament of the compound Chinese medicinal preparation containing aristolochic acid；It is described
Attenuation refers to the renal toxicity for reducing the compound Chinese medicinal preparation containing aristolochic acid.
Preferably, the compound Chinese medicinal preparation for rheum officinale clearing stomach ball, children-welfare tablet, Fenqing Wulin pill, Longdan Xiegan wan,
Shixiang fansheng pill, storax pill for treating coronary heart disease etc..
A kind of pharmaceutical composition, including the single medicinal material containing aristolochic acid, Chinese medical extract or Chinese medicine compound prescription, further include
Above-mentioned benzopyrone.
Advantages of the present invention：
It is a discovery of the invention that benzopyrone provided by the invention can reduce the renal toxicity of aristolochic acid, can be used for making
The standby single medicinal material containing aristolochic acid or Chinese medical extract or the toxicity-reducing medicament of compound Chinese medicinal preparation.Above-mentioned benzopyrone
Both single medicine can have been developed into, it is same with the single medicinal material containing aristolochic acid or Chinese medical extract or compound Chinese medicinal preparation
When take, can also be by the single medicinal material containing aristolochic acid or Chinese medical extract or Chinese medicine compound prescription and above-mentioned benzopyrone
Develop into pharmaceutical composition.
Brief description of the drawings
Fig. 1 is each group HK-2 Apoptosis ratio (%)；
Fig. 2 compares for each group renal interstitial fibrosis rat relative area；
Fig. 3 is the relative expression levels of each group renal tissues of rats markers of fibrosis PROTEIN C OL- I.
Embodiment
The specific guarantor for introducing essentiality content of the present invention, but the present invention not being limited with this with reference to the accompanying drawings and examples
Protect scope.
The benzopyrone that following embodiments use is the compound of following chemical constitution, and purchase or self-control, purity is not low
In 95%.
It is also tested for the optical isomer R- hamaudols (CAS 204779-06-6) of hamaudol, its difference with hamaudol
It is：Carbon atom where hamaudol hydroxyl is S configurations, and R- hamaudols are R configurations.
Embodiment 1：The protective effect for causing people's renal cells to damage to aristolochic acid
First, experiment material
People's kidney proximal tubular cell line (HK-2) is purchased from China typical culture collection center；
Aristolochic acid-I (AA- I) is purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute；
Hyclone (FCS), Gibico companies；DMEM：HamsF-12 culture mediums (Hyclone)；Annexin-V reagents
Box, Invitrogen companies；
Enzyme-linked immunosorbent assay instrument, Thermo fisher companies of the U.S.；Flow cytometer, U.S. company BD.
2nd, experimental method
1st, cell culture and packet
Well-grown HK-2 cells are taken, are suspended in the DMEM containing 10%FCS and 1% penicillin+streptomysin：HamsF-12
In culture medium, with 6 × 107/ L cell suspension inoculations are inoculated with 100 μ L per hole, in 37 DEG C, 5%CO in 96 orifice plates2, humidity
After cultivating 24h cell attachments under 100% environment, nutrient solution is abandoned in suction, continues to be incubated training by the following relative medicine that is separately added into
Support 48h.8 groups are set up in experiment altogether, and each group sets 8 multiple holes：
(1) control group：Nutrient solution is not added with AA- I；
(2) aristolochic acid group：AA- I is added in nutrient solution (25mg/L, each pharmaceutical intervention group are same)；
(3) hamaudol group：Hamaudol (5mg/L, is final concentration, similarly hereinafter) and AA- I are added in nutrient solution at the same time；
(4) acetic acid esters hamaudol group：Hamaudol -3 '-acetic acid esters (5mg/L) and AA- I are added in nutrient solution at the same time；
(5) Angelica sinensis acyl hamaudol group：Add 3 '-O- angeloyl groups hamaudols (5mg/L) and AA- I at the same time in nutrient solution；
(6) windproof chromone group：Windproof chromone (5mg/L) and AA- I are added in nutrient solution at the same time；
(7) windproof chromone alcohol group：Windproof chromone alcohol (5mg/L) and AA- I are added in nutrient solution at the same time；
(8) R- hamaudols group：R- hamaudols (5mg/L) and AA- I are added in nutrient solution at the same time；
2nd, mtt assay measure cell survival rate
Each group 4h before culture terminates, the 20 μ L of MTT solution of 5mg/L are added per hole, after culture, 100 μ are added per hole
L DMSO, using the OD values that each hole is measured at enzyme-linked immunosorbent assay instrument 480nm.
3rd, flow cytometry detection apoptosis rate
After culture, cell 1 × 10 is collected6A/mL, 1000rpm centrifuge 5min, abandon supernatant, and cell is resuspended with PBS,
Operated according to Annexin-VFITC cell apoptosis detection kits specification, detect the percentage of apoptotic cell and non-viable non-apoptotic cell.
4th, statistical method
Analyzed using 19.0 software statistics of SPSS, data represent that comparison among groups uses single factor test variance with mean value ± deviation
Analysis.
3rd, experimental result
1st, mtt assay measure cell survival rate
Compared with control group, after AA- I acts on 48h, aristolochic acid group HK-2 cytoactives are obvious suppressed (P ＜ 0.05)；
Compared with aristolochic acid group, hamaudol group, acetic acid esters hamaudol group, Angelica sinensis acyl hamaudol group, windproof chromone group, anti-how the wind blows
Keto-alcohol group HK-2 cytoactives significantly improve (P ＜ 0.05)；R- hamaudols group HK-2 cytoactives and aristolochic acid group HK-2
Cytoactive difference unobvious.OD values under the conditions of each group 480nm wavelength detectings are shown in Table 1.
OD values under the conditions of 1 each group 480nm wavelength detectings of table
2nd, flow cytometry detection apoptosis rate
Compared with control group, after AA- I acts on 48h, aristolochic acid group HK-2 Apoptosis ratios substantially increase (P ＜
0.05)；Compared with aristolochic acid group, hamaudol group, acetic acid esters hamaudol group, Angelica sinensis acyl hamaudol group, windproof chromone group,
Windproof chromone alcohol group HK-2 Apoptosis ratio substantially reduces (P ＜ 0.05)；R- hamaudol group HK-2 Apoptosis ratios with
Aristolochic acid group HK-2 Apoptosis proportional difference unobvious.Each group apoptosis value is shown in Table 2 and Fig. 1.
2 each group HK-2 Apoptosis ratios of table
The embodiment illustrates that Aristolochic Acid in Antagonizing Human Renal Tubular epithelial cell HK-2 has obvious cytotoxicity, can cause
HK-2 survival rates reduce, apoptosis rate rise；Chromone compound hamaudol provided by the invention, hamaudol -3 '-acetic acid
Ester, 3 '-O- angeloyl groups hamaudols, windproof chromone, windproof chromone alcohol can be thin with antagonism Aristolochic Acid in Antagonizing Human Renal tubular epithelial
The cytotoxicity of born of the same parents HK-2, has prospect of the exploitation into aristolochic acid toxicity-reducing medicament.
Embodiment 2：Cause the protective effect of renal interstitial fibrosis rat to aristolochic acid
First, experiment material
SPF grades of male SD rats, weight 280-300g, is purchased from Jiangning county Qinglongshan animal reproduction field；
3,4-methylenedioxy-8-methoxy-10-nitro-1-phenanthrenecarboxylic acid is dissolved with edible oil, as gavage working solution.
2nd, experimental method
1st, aristolochic acid kidney fibrosis rat model and experiment packet are established
Aristolochic acid kidney fibrosis modeling method (bibliography：The foundation of Chronic Aristolochic Acid Nephropathy animal model and ox
Sulfonic acid acts on its early protection, the special collection of Chinese combination of Chinese tradiational and Western medicine magazine in June, 2003 fundamental research of volume 23, Beijing
Department of pathology of University Hospital portion)：Rat is first pressed to dosage the continuous gavage 5d, drug withdrawal 9d of 20mg/kg/d 3,4-methylenedioxy-8-methoxy-10-nitro-1-phenanthrenecarboxylic acids；Hereafter
Dosage reduces to 15mg/kg/d, every other week gastric infusion, until the 11st week.
SPF grades of male SD rat adaptability are fed after a week, 8 groups, every group 10 are randomly divided into according to weight：
(1) control group：Gavage gives isometric solvent (edible oil)；
(2) aristolochic acid group：Modeling according to the method described above；
(3) hamaudol group：Modeling as stated above, and from first week the next day gavage 15mg/kg/d hamaudols；
(4) acetic acid esters hamaudol group：Modeling as stated above, and from first week the next day gavage 15mg/kg/d acetic acid esters last of the twelve Earthly Branches
Thatch phenol；
(5) Angelica sinensis acyl hamaudol group：Modeling as stated above, and from first week the next day gavage 15mg/kg/d Angelica sinensis acyl last of the twelve Earthly Branches
Thatch phenol；
(6) windproof chromone group：Modeling as stated above, and from first week the next day the windproof chromones of gavage 15mg/kg/d；
(7) windproof chromone alcohol group：Modeling as stated above, and from first week the next day the windproof chromone alcohol of gavage 15mg/kg/d；
(8) R- hamaudols group：Modeling as stated above, and from first week the next day gavage 15mg/kg/dR- hamaudols；
2nd, renal fibrosis pathologic finding
After culture, put to death rat, take out rat kidney, PBS buffer elutes totally on ice, conventional dehydration, embed,
After section and Masson dyeing, the renal interstitial image of light microscope (× 100) collection cortical section (adopt at random by every rat
Collect 15 visuals field), carry out automatic measurement with multi-functional true color pathological image analysis system (BJ University of Aeronautics ＆ Astronautics manufactures)
Analysis, the kidney region fibrosis relative area=renal interstitial Lv Ran areas area/visual field gross area × 100%.
3rd, the detection that renal fibrosis marker protein COL- I is expressed
After culture, rat is put to death, rat kidney is taken out, is positioned on ice, prevents protein degradation.Clip about 35mg
Tissue, adds the lysate that 350 μ L concentration are 100mg/mL, is fully ground with grinding rod, stands 20min on ice, phase at 4 DEG C
To centrifugal force 5.67 × 104× g centrifuges 15min.Protein supernatant is drawn, discards precipitation.Relative centrifugal force 5.67 at 4 DEG C
×104× g centrifuges 15min, draws protein supernatant again, discards precipitation.Using GAPDH albumen as internal reference, using protein
The relative expression levels of blotting (western blot) measure each group renal tissues of rats COL- I.
4th, statistical method
Analyzed using 19.0 software statistics of SPSS, data represent that comparison among groups uses single factor test variance with mean value ± deviation
Analysis.
3rd, experimental result
1st, each group renal interstitial fibrosis rat relative area
Compared with control group, aristolochic acid group renal interstitial fibrosis rat relative area significantly raises (P ＜ 0.05)；With horse
Pocket bell acid group compares, hamaudol group, acetic acid esters hamaudol group, Angelica sinensis acyl hamaudol group, windproof chromone group, windproof chromone alcohol
Group renal interstitial fibrosis rat relative area substantially reduces (P ＜ 0.05)；R- hamaudol group renal interstitial fibrosis rats are opposite
Area and aristolochic acid group renal interstitial fibrosis rat relative area difference unobvious.
Each group renal interstitial fibrosis rat relative area is shown in Table 3 and Fig. 2.
3 renal interstitial fibrosis rat relative area (%) of table
2nd, I expressions of each group renal tissues of rats markers of fibrosis PROTEIN C OL-
Compared with control group, I protein expression levels of COL- significantly raise (P ＜ in aristolochic acid group renal tissues of rats
0.05)；Compared with aristolochic acid group, hamaudol group, acetic acid esters hamaudol group, Angelica sinensis acyl hamaudol group, windproof chromone group,
I protein expression levels of COL- substantially reduce (P ＜ 0.05) in windproof chromone alcohol group renal tissues of rats；R- hamaudol group rats
I protein expression levels of COL- and I protein expression level differences of COL- in aristolochic acid group renal tissues of rats are unknown in nephridial tissue
It is aobvious.
The relative expression levels of each group renal tissues of rats markers of fibrosis PROTEIN C OL- I are as shown in Figure 3.
The embodiment illustrates that aristolochic acid can cause renal tissues of rats fibrosis；Chromone provided by the invention
Compound hamaudol, hamaudol -3 '-acetic acid esters, 3 '-O- angeloyl groups hamaudols, windproof chromone, windproof chromone alcohol can be short of money
The internal renal toxicity of anti-aristolochic acid, has prospect of the exploitation into aristolochic acid toxicity-reducing medicament.
Embodiment 3：Pharmaceutical composition is made with single medicinal material
A kind of pharmaceutical composition, is single medicinal material and hamaudol, hamaudol -3 '-acetic acid esters, 3 '-O- angeloyl groups last of the twelve Earthly Branches thatches
One or more combinations in phenol, windproof chromone, windproof chromone alcohol；The single medicinal material can be caulis aristologhiae manshuriensis, birthwort,
The Chinese medicine containing aristolochic acid such as aristolochia fangchi, dutchmanspipe root, Ciliatenerve Knotweed Root, berba aristolochiae mollissimae, herba aristolochiae, Cortex Magnoliae Officinalis, asarum.
Embodiment 4：Pharmaceutical composition is made with Chinese medical extract
A kind of pharmaceutical composition, is Chinese medical extract and hamaudol, hamaudol -3 '-acetic acid esters, the 3 '-O- angeloyl groups last of the twelve Earthly Branches
One or more combinations in thatch phenol, windproof chromone, windproof chromone alcohol；The Chinese medicine can be caulis aristologhiae manshuriensis, birthwort, wide
The Chinese medicine containing aristolochic acid such as the root of fangji, dutchmanspipe root, Ciliatenerve Knotweed Root, berba aristolochiae mollissimae, herba aristolochiae, Cortex Magnoliae Officinalis, asarum.
The pharmaceutical composition can be used for pharmacy or the products such as slim tea be made into.
Embodiment 5：Pharmaceutical composition is made with Chinese medicine compound prescription
A kind of pharmaceutical composition, is Chinese medicine compound prescription and hamaudol, hamaudol -3 '-acetic acid esters, 3 '-O- angeloyl groups last of the twelve Earthly Branches thatches
One or more combinations in phenol, windproof chromone, windproof chromone alcohol；The Chinese medicine compound prescription can be rheum officinale clearing stomach ball, children
The Chinese medicine compound prescription containing aristolochic acid such as Jindan piece, Fenqing Wulin pill, Longdan Xiegan wan, shixiang fansheng pill, storax pill for treating coronary heart disease.
To sum up, benzopyrone provided by the invention can reduce the renal toxicity of aristolochic acid, can be used for preparation and contain
The single medicinal material or Chinese medical extract of aristolochic acid or the toxicity-reducing medicament of compound Chinese medicinal preparation.Above-mentioned benzopyrone both can be with
Single medicine is developed into, is taken at the same time with the single medicinal material containing aristolochic acid or Chinese medical extract or compound Chinese medicinal preparation,
Single medicinal material containing aristolochic acid or Chinese medical extract or Chinese medicine compound prescription can also be developed patent medicine with above-mentioned benzopyrone
Compositions.
The effect of above-described embodiment is the essentiality content for specifically introducing the present invention, but those skilled in the art should know
Protection scope of the present invention, should not be confined to the specific embodiment by road.
Claims (10)
1. the benzopyrone of following chemical constitution is used to prepare the purposes of aristolochic acid toxicity-reducing medicament：
Wherein, R3、R4For alkyl or contain heteroatomic alkyl.
2. purposes according to claim 1, it is characterised in that benzopyrone is preferably as follows the compound of chemical constitution：
3. purposes according to claim 1 or 2, it is characterised in that：The attenuation refers to the renal toxicity for reducing aristolochic acid.
4. purposes according to claim 3, it is characterised in that：The aristolochic acid for Aristolochic acid-I, aristolochic acid-
One or more in II, Aristolochic acid-I II and Aristolochic acid-I V.
5. the benzopyrone described in claim 1 or 2 is used to prepare the toxicity-reducing medicament of the single medicinal material containing aristolochic acid
Purposes；The attenuation refers to the renal toxicity for reducing the single medicinal material containing aristolochic acid.
6. the benzopyrone described in claim 1 or 2 is used to prepare the toxicity-reducing medicament of the Chinese medical extract containing aristolochic acid
Purposes；The attenuation refers to the renal toxicity for reducing the Chinese medical extract containing aristolochic acid.
7. the purposes according to claim 5 or 6, it is characterised in that：The Chinese medicine is caulis aristologhiae manshuriensis, birthwort, aristolochia fangchi, green grass or young crops
The banksia rose, Ciliatenerve Knotweed Root, berba aristolochiae mollissimae, herba aristolochiae, Cortex Magnoliae Officinalis, asarum etc..
8. the benzopyrone described in claim 1 or 2 is used to prepare the attenuation medicine of the compound Chinese medicinal preparation containing aristolochic acid
The purposes of thing；The attenuation refers to the renal toxicity for reducing the compound Chinese medicinal preparation containing aristolochic acid.
9. purposes according to claim 8, it is characterised in that：The compound Chinese medicinal preparation is rheum officinale clearing stomach ball, little Er Jin
Red piece, Fenqing Wulin pill, Longdan Xiegan wan, shixiang fansheng pill, storax pill for treating coronary heart disease etc..
10. a kind of pharmaceutical composition, including the single medicinal material containing aristolochic acid, Chinese medical extract or Chinese medicine compound prescription, its feature
It is：Further include the benzopyrone described in claim 1 or 2.
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| PCT/CN2018/084057 WO2019109576A1 (en) | 2017-12-05 | 2018-04-23 | Use of benzopyran compound |
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