CN110372731A - Quinoline-yaruru alkaline bisindole alkaloid compound and its application - Google Patents
Quinoline-yaruru alkaline bisindole alkaloid compound and its application Download PDFInfo
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- CN110372731A CN110372731A CN201910748648.XA CN201910748648A CN110372731A CN 110372731 A CN110372731 A CN 110372731A CN 201910748648 A CN201910748648 A CN 201910748648A CN 110372731 A CN110372731 A CN 110372731A
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- alkaline
- yaruru
- quinoline
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- -1 bisindole alkaloid compound Chemical class 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 20
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 9
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 3
- 229940079593 drug Drugs 0.000 claims description 5
- TYGUTURXHKSOBP-UHFFFAOYSA-N 10-bromo-5,12-dihydroindolo[2,3-g]carbazole-2,3-diol Chemical class C1=C(Br)C=C2NC3=C(C4=C(C=C(C(=C4)O)O)N4)C4=CC=C3C2=C1 TYGUTURXHKSOBP-UHFFFAOYSA-N 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 8
- 229960003957 dexamethasone Drugs 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 239000002260 anti-inflammatory agent Substances 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 3
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- WNGSUWLDMZFYNZ-UHFFFAOYSA-N Leonurine Chemical compound COC1=CC(C(=O)OCCCCN=C(N)N)=CC(OC)=C1O WNGSUWLDMZFYNZ-UHFFFAOYSA-N 0.000 description 2
- 108090000913 Nitrate Reductases Proteins 0.000 description 2
- 241001529246 Platymiscium Species 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 1
- XQINTCORIZHGFD-UHFFFAOYSA-O 1,2,10-trimethoxy-6,6-dimethyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-6-ium-11-ol Chemical compound C1=C(OC)C(OC)=C2C3=C(O)C(OC)=CC=C3CC3[N+](C)(C)CCC1=C23 XQINTCORIZHGFD-UHFFFAOYSA-O 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- ZSBXGIUJOOQZMP-UHFFFAOYSA-N Isomatrine Natural products C1CCC2CN3C(=O)CCCC3C3C2N1CCC3 ZSBXGIUJOOQZMP-UHFFFAOYSA-N 0.000 description 1
- ZSBXGIUJOOQZMP-JLNYLFASSA-N Matrine Chemical compound C1CC[C@H]2CN3C(=O)CCC[C@@H]3[C@@H]3[C@H]2N1CCC3 ZSBXGIUJOOQZMP-JLNYLFASSA-N 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000005550 inflammation mediator Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229930014456 matrine Natural products 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses structural formula quinoline as shown in formula I, formula II-yaruru alkaline bisindole alkaloid compounds:Wherein R1~R4It is respectively selected from hydrogen, hydroxyl, methoxyl group, ethyoxyl, acetyl group, alkyl hydrocarbon, halogen；Experiments have shown that the compounds of this invention has anti-inflammatory activity；The compounds of this invention provides lead compound to develop anti-inflammatory preparation, is conducive to develop and use plant medicine resource.
Description
Technical field
The present invention relates to a kind of quinoline-yaruru alkaline bisindole alkaloid compound and its prepare in anti-inflammatory drug
Using.
Background technique
Inflammatory reaction is a clinical common pathologic process, can be born in the tissue and each organ at each position of body, main
Swelling, red, hot, pain and dysfunction are shown as, after pro-inflammatory cytokine acts on body, on the one hand causes histiocytic damage
It is bad, so that local organization cell is shown denaturation, necrosis；On the other hand, induction body disease-resistant function increases, with beneficial to remove cause it is scorching because
Son repairs damaged tissues, thus make to reach new equilibrium between the interior environment and interior environment and external environment of body, it is scorching
The regulation and treatment of disease reaction are of great significance to human health.Internal inflammatory reaction is related to the participation of various kinds of cell,
Middle macrophage is that regulation body inflammatory reacts one of most important cell.(mouse is huge by the RAW264.7 induced using LPS stimulation
Phagocyte) cell as inflammatory model, passes through enzyme-linked immunosorbent assay (Enzyme linked immunosorbent
Assay, ELISA) NO in inflammation RAW264.7 cell culture medium supernatant under each monomeric compound various concentration intervention of detection
Content, evaluate the influence of compound on inflammation mediator expression levels with this, and then the extracorporeal anti-inflammatory of comprehensive analysis compound is living
Property.
The a variety of natural products extracted in plant all have anti-inflammatory activity, at present widely applied anti-inflammatory agent on the market
Object is mainly non-steroidal anti-inflammatory drugs (non-steroidal anti-inflammatory drugs, NSAIDs), is that one kind is free of
There is the anti-inflammatory agent of steroidal structure.NSAIDs from aspirin in 1898 for the first time synthesize after, have over more than 100 years over one hundred kind it is thousands of
The listing of a brand, this kind of drug include aspirin, paracetamol, Indomethacin, naproxen, Nabumetone, Diclofenac,
Brufen, aulin, rofecoxib, celecoxib etc., such drug have anti-inflammatory, antirheumatic, relieve pain, bring down a fever and anticoagulation
The effects of, be clinically widely used in osteoarthritis, rheumatoid arthritis, it is a variety of fever and various pain symptoms alleviation.
Alkaloid is the important natural products monoid of one kind during natural drug discovery, while being also patent medicine coefficient highest
Natural products；Wherein colchicin, leonurine, matrine and menispermine have significant anti-inflammatory activity.The present invention mentions
The quinoline of confession-yaruru alkaline bisindole alkaloid compound and its there is not been reported as anti-inflammatory drug.
Summary of the invention
It is an object of the present invention to provide a kind of noval chemical compound, i.e. quinoline-yaruru alkaline bisindole alkaloid compound,
Be isolated from mountain orange platymiscium scape Dongshan orange (MelodinuskhasianusHook. f.), chemical structural formula such as formula I, formula II
It is shown:
Wherein R1~R4It is respectively selected from hydrogen, hydroxyl, methoxyl group, ethyoxyl, acetyl group, alkyl hydrocarbon, halogen etc..
As R in structural formula I1、R2For hydroxyl, R3、R4When for hydrogen, the structural formula of compound is as shown in formula III:
Formula III:。
As R in structural formula I1For hydroxyl, R2、R3、R4When for hydrogen, the structural formula of compound is as shown in formula IV:
Formula IV:。
As R in structural formula II1For methoxyl group, R2、R3When for hydrogen, the structural formula of compound is as shown in formula V:
Formula V:。
The present invention is another object is that above-mentioned quinoline-yaruru alkaline bisindole alkaloid compound is applied anti-in preparation
In scorching drug.
One or more pharmaceutically acceptable auxiliary materials can also be added in present anti-inflammatory drug, the auxiliary material includes medicine
Filler, diluent, adhesive, excipient, sorbefacient, filler, surfactant and the stabilizer of field routine
Deng can also be added if necessary flavouring agent, pigment and sweetener etc..
Pill, pulvis, tablet, granula, oral solution and injection can also be made in addition to capsule is made in application of the present invention
The diversified forms such as liquid.
With 264.7 inflammatory cell of RAW for testing in the present invention；264.7 cell of RAW of logarithmic growth phase is through digesting
After counting, with 1 × 104A/hole is inoculated in 96 orifice plates, in 5% CO2, cultivate under the conditions of 37 DEG C be added afterwards for 24 hours various concentration by
Test agent continues after cultivating 2h, the LPS of 1.0 μ g/mL is added, continue culture for 24 hours, it is to be measured to collect medium supernatant；Pass through
Mtt assay measures the light absorption value of different grouping respectively, so that it is big to the toxicity of 264.7 cell of RAW to evaluate different test-compounds
It is small；The experimental results showed that the RAW that quinoline of the invention-yaruru alkaline bisindole alkaloid compound stimulates LPS
264.7 cells have the toxic effect of very little；It is aobvious that the result that LPS induces 264.7 cell of RAW to generate NO is measured by supernatant
Show, the content that compound generates NO to LPS induction 264.7 cell of RAW has more significant inhibitory activity.
Advantage and technical effect of the present invention: the present invention obtains three quinoline-yaruru alkaline from the orange platymiscium of mountain for the first time
Bisindole alkaloid compound, anti-inflammatory activity is the experimental results showed that such compound resists when concentration is 30 μM with certain
Scorching active, three compounds in the present invention provide lead compound to develop anti-inflammatory preparation, are conducive to develop and use plant
Medicine resource.
Specific embodiment
Below by embodiment, invention is further described in detail, but the contents of the present invention are not limited thereto, this
Method operating according to a conventional method unless otherwise specified in embodiment, agents useful for same unless otherwise specified use conventional commercial
Reagent or the reagent configured according to a conventional method.
Embodiment 1: quinoline-yaruru alkaline bisindole alkaloid compound extraction separation
Find a view Dongshan total 10kg of orange sample, methanol solution refluxing extraction 3 times that volumetric concentration 80% is used after drying, crushing, every time
3 h, combined extract obtains medicinal extract 900g after being filtered to remove filter residue, and the diluted hydrochloric acid dissolution of medicinal extract volumetric concentration 0.2% simultaneously adjusts pH value
To 2 ~ 3, it is extracted with ethyl acetate 3 times, by the ammonium hydroxide tune pH value of acid solution extracted volumetric concentration 5% to 9 ~ 10, uses acetic acid
Ethyl ester extracts 3 times, collects ethyl acetate layer, and being concentrated to get total alkali part is 95g；Normal phase silicagel column is crossed in total alkali part, using stone
Oily ether-acetone (volume ratio 100:1,10:1,1:1) elution, 3 parts of collection eluent concentration acquisition (Fr.A, Fr.B,
Fr.C)；
Fr.A(14.4g purification on normal-phase silica gel (300-400 mesh) column) is crossed, is eluted through petroleum ether-acetone (20:1,15:1,10:1), is collected
Eluent is concentrated to give three part Fr.A- I (210mg), Fr.A- II (580mg) and Fr.A- III (560mg), wherein Fr.A- III
(560mg) crosses silicagel column, is eluted with petroleum ether-acetone (volume ratio 10:1), collects eluent and is concentrated to get IV compound of formula
(3.2mg)；
Fr.C(6.3g medium pressure liquid chromatography column) is crossed, obtains four portions with methanol/water (10%, 20%, 40%, 60%) gradient elution
Point；Wherein Fr.C- I (10%, 500mg) is partially through purification on normal-phase silica gel post separation, and with chloroform: acetone (volume ratio 10:1) elutes, and collects
Eluent is concentrated to get III compound 21mg of formula；Fr.C- II (20%, 650mg) is partially through preparative high performance liquid chromatography
(CH3CN-H2O, volume ratio 40:60, TR=12.2 min) purifies and separates, it is concentrated to get V compound 21mg of formula；
Qualification result is as follows:
Quinoline-yaruru alkaline bisindole alkaloid compound (formula III): yellow oily； [α]20 D =-20 (c 0.1,
MeOH); UV (MeOH) λmax (log ε): 203 (5.3), 254 (4.8), 324 (4.5) nm; IR (KBr)
νmax 3443, 2962, 2925, 2853, 1747, 1673, 1619, 1506, 1339, 1210, 1031, 992,
712, 652 cm–1; HRESIMS m/z 678.3104 [M+H]+ (calcd. for C41H42N4O6, 687.3169). 1H
(600 MHz) and13C NMR (150 MHz) (CDCl3) NMR data are shown in Table 1；Above data combination 2D NMR analysis confirms
The quinoline of formula III-yaruru alkaline bisindole alkaloid compound is river mountain orange base first；
Quinoline-yaruru alkaline bisindole alkaloid compound 2(formula IV): yellow oily； [α]20 D =-10 (c
0.8, MeOH); UV (MeOH) λmax (log ε): 202 (4.50), 247 (4.02), 332 (3.87) nm; IR
(KBr) νmax 3443, 1747, 1670, 1623, 1338, 1046 cm–1; HRESIMS m/z 671.3226 [M+H]+
(calcd. for C41H42N4O5, 671.3228). 1H (600 MHz) and13C NMR (150 MHz) (CDCl3) NMR number
According to being shown in Table 2.Above data combination 2D NMR analysis confirmation formula IV quinoline-yaruru alkaline bisindole alkaloid compound be
River mountain orange base second；
Quinoline-yaruru alkaline bisindole alkaloid compound (formula V): yellow oily； [α]20 D =-40 (c 0.1,
MeOH); UV (MeOH) λmax (log ε): 203 (5.34), 254 (4.8), 327 (4.7) nm; IR (KBr)
νmax 3442, 2964, 2852, 1739, 1488, 1455, 1338, 1317, 1261, 1046, 495 cm–1;
HRESIMS m/z 699.3468 [M+H]+ (calcd. for C43H46N4O5, 699.3533). 1H (600 MHz) and13C
NMR (150 MHz) (CDCl3) NMR data are shown in Table 3.Quinoline-the Bai Jian of above data combination 2D NMR analysis confirmation formula V
The wooden alkaline bisindole alkaloid compound is river mountain orange base third；
These three quinoline of compound 1,2,3-yaruru alkaline bisindole alkaloid compound described above is new natural
Organic compound.
Table 1: quinoline-yaruru alkaline bisindole alkaloid compound 11H NMR and13C NMR data
；
Table 2: quinoline-yaruru alkaline bisindole alkaloid compound 21H NMR and13C NMR data
Table 3: quinoline-yaruru alkaline bisindole alkaloid compound 31H NMR and13C NMR data
。
Embodiment 2: the inhibiting effect of 1,2,3 couple of LPS induction 264.7 cell of RAW release NO of compound
(1) material
DMEM culture solution (Gibco company, the U.S.), fetal calf serum (Gibco company, the U.S.), the RPMI-1640 culture solution (U.S.
Gibco company), phosphate buffer (Shanghai beyotime company), dual anti-(HyClone company, the U.S.), the U.S. DMSO(
Sigma company), MTT(Sigma Co., USA), the compounds of this invention and dexamethasone are prepared with DMSO；
(2) toxic effect of mtt assay measurement 1,2,3 pair of RAW264.7 cell of compound
It is made into cell suspending liquid with the culture solution (DMEM or RMPI1640) containing 10% fetal calf serum, takes every 200 μ L's of hole
RAW264.7 cell suspension (5 × 104A/mL) 96 well culture plates are inoculated in, in 5%CO2, 24 are cultivated in 37 DEG C of constant incubators
Hour；The testing compound solution that 200 μ L concentration are 30 μM is added after the culture medium of the inside is sucked out, 200 μ are added in blank control group
L DMEM complete culture solution, every 200 μ L of hole final volume；After 37 DEG C of cultures for 24 hours, inhales and abandon culture supernatant in hole, every hole adds MTT molten
200 μ L of liquid；It is placed in 37 DEG C, 5% CO2Continue after cultivating 4h in incubator, remove supernatant, isometric DMSO dissolution first is added
Za measures the light absorption value in every hole at 570nm after concussion uniformly；The number of living cells is deduced according to optical density OD value, is recorded
As a result, and calculate the survival rate of 264.7 cell of RAW, the results are shown in Table 4.
(3) compound 1-3 generates the measurement of NO to the RAW264.7 cell that LPS is induced
The release of NO in 264.7 cell of RAW is assessed by the amount of sodium nitrite in Nitrate reductase method detection culture medium,
Allow 264.7 cell of RAW in 96 porocyte culture plates (every hole 2 × 10 4A cell) on grow, and in 5%CO2Environment in 37
For 24 hours, experimental group is separately added into the compound 1,2,3 that 200 μ L concentration are 30 μ L, and blank control group is then added 200 μ L's for DEG C culture
DMEM complete culture solution, positive controls add the dexamethasone solution that 200 μ L concentration are 30 μM, and negative control group is then added
200 μ L concentration are the LPS of 5 μ g/mL, continue to cultivate 2h, LPS(5 μ g/mL is added), continue to cultivate 24 h under the same conditions, receive
Collection culture supernatant is detected；Illustrate to measure in cell according to nitric oxide (NO) assay kit (nitrate reductase method)
The content of NO.
(4) data processing
Experimental data OD value indicates that mathematical statistics and variance analysis work are complete using SPSS using " average ± standard deviation "
At.
(5) results and discussion
Table 4: compound 1-3 is under 30 μM to the survival rate of 264.7 cell of RAW
| Compound | Survival rate (%) |
| Dexamethasone | 89.93 ± 0.79 |
| Compound 1 | 88.65 ± 6.64 |
| Compound 2 | 88.11 ± 4.68 |
| Compound 3 | 89.84 ± 4.67 |
The result proves compound 1,2,3 when concentration is 30 μM to the survival rate and dexamethasone of 264.7 cell of RAW
Substantially quite；
Table 5: compound 1-3 generates the influence of NO under 30 μM to LPS induction 264.7 cell of RAW
| Group | The content (pg/mL) of NO |
| Blank control group | 2.03 ± 0.08 |
| Negative control group | 15.76 ± 0.17 |
| Dexamethasone | 9.78 ± 0.16 |
| Compound 1 | 9.85 ± 0.17 |
| Compound 2 | 10.34 ± 0.03 |
| Compound 3 | 9.64 ± 0.29 |
Compound 1,3, which generates NO to LPS induction 264.7 cell of RAW under 30 μM of concentration, has significant inhibitory activity, wherein
The activity of compound 3 is significantly better than dexamethasone；Compound 1,3 can be substantially reduced LPS induction 264.7 cell supernatant of RAW
In nitrite anions concentration.As shown in table 5, compared to the blank group, a large amount of nitrous are contained in the cell supernatant of negative control group
Acid group shows that LPS can obviously cause inflammatory reaction.Compared with LPS group, show the nitrite anions of administration group and positive controls
Concentration is substantially reduced, and the release of NO is inhibited.Compound 1,3 can almost completely inhibit the release of NO, with effects of dexamethasone
Quite；Compound 2 significantly inhibits effect to the release of NO compared with LPS group, but its activity is lower than dexamethasone.
Claims (5)
1. structural formula quinoline as shown in formula I, formula II-yaruru alkaline bisindole alkaloid compound:
Wherein R1~R4It is respectively selected from hydrogen, hydroxyl, methoxyl group, ethyoxyl, acetyl group, alkyl hydrocarbon, halogen.
2. quinoline according to claim 1-yaruru alkaline bisindole alkaloid compound, it is characterised in that: work as knot
R in structure formula I1、R2For hydroxyl, R3、R4When for hydrogen, the structural formula of compound is as shown in formula III:
Formula III:。
3. quinoline according to claim 1-yaruru alkaline bisindole alkaloid compound, it is characterised in that: work as knot
R in structure formula I1For hydroxyl, R2、R3、R4When for hydrogen, the structural formula of compound is as shown in formula IV:
Formula IV:。
4. quinoline according to claim 1-yaruru alkaline bisindole alkaloid compound, it is characterised in that: work as knot
R in structure formula II1For methoxyl group, R2、R3When for hydrogen, the structural formula of compound is as shown in formula V:
Formula V:。
5. quinoline of any of claims 1-4-yaruru alkaline bisindole alkaloid compound prepare it is anti-inflammatory
Application in drug.
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| CN113603711A (en) * | 2021-08-25 | 2021-11-05 | 山东省分析测试中心 | Bisindole alkaloid compound and preparation method and application thereof |
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| CN115073481A (en) * | 2021-03-13 | 2022-09-20 | 中国科学院昆明植物研究所 | Furan quebrachitol dimer or pharmaceutically acceptable salt thereof, preparation method and application thereof, and pharmaceutical composition |
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| CN113603711A (en) * | 2021-08-25 | 2021-11-05 | 山东省分析测试中心 | Bisindole alkaloid compound and preparation method and application thereof |
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