CN109776477A - Iso-Penicillixanthone A and anti-vincristine drug resistance application derived from penicillium oxalicum - Google Patents
Iso-Penicillixanthone A and anti-vincristine drug resistance application derived from penicillium oxalicum Download PDFInfo
- Publication number
- CN109776477A CN109776477A CN201811473641.3A CN201811473641A CN109776477A CN 109776477 A CN109776477 A CN 109776477A CN 201811473641 A CN201811473641 A CN 201811473641A CN 109776477 A CN109776477 A CN 109776477A
- Authority
- CN
- China
- Prior art keywords
- vincristine
- penicillium oxalicum
- compound
- penicillixanthone
- iso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 241000985513 Penicillium oxalicum Species 0.000 title claims abstract description 22
- 229960004528 vincristine Drugs 0.000 title claims abstract description 21
- 206010059866 Drug resistance Diseases 0.000 title abstract description 7
- 150000001875 compounds Chemical group 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 17
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims abstract description 17
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 230000004663 cell proliferation Effects 0.000 claims abstract description 6
- 238000000855 fermentation Methods 0.000 claims description 6
- 230000004151 fermentation Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- RJGDLRCDCYRQOQ-UHFFFAOYSA-N anthrone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 RJGDLRCDCYRQOQ-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 abstract 1
- 150000004056 anthraquinones Chemical class 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 238000000926 separation method Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 239000000287 crude extract Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- -1 Anthraquinones organic compound Chemical class 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 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
- 239000007836 KH2PO4 Substances 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000005100 correlation spectroscopy Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229910052564 epsomite Inorganic materials 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000001641 gel filtration chromatography Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 2
- 235000013923 monosodium glutamate Nutrition 0.000 description 2
- 239000004223 monosodium glutamate Substances 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 238000004262 preparative liquid chromatography Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 240000001829 Catharanthus roseus Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000004362 fungal culture Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000006101 laboratory sample Substances 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000024053 secondary metabolic process Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to the iso-Penicillixanthone A for being derived from penicillium oxalicum and anti-vincristine drug resistance applications.The compound structure is characterized in:
Description
Technical field
The present invention relates to a kind of iso-Penicillixanthone A derived from penicillium oxalicum and its anti-vincristine drug resistances
The application of aspect, belongs to biomedicine field.
Background technique
At present in clinical treatment, many tumours obtain preferable effect by first drug therapy, but finally often swell
Tumor recurrence, is substantially reduced the sensibility of anti-tumor drug after recurrence, seriously affects life quality and the time of patient.Changchun is new
Alkali (Vinristine, vcr) is two Benzazole compounds by proposing in catharanthus roseus in 1962.VCR is thin by acting on tumour
Born of the same parents' tubulin and interfere tumour cell to be metabolized, clinical application is relatively broad (such as: acute lymphoblastic leukemia, lymthoma, palace
Neck cancer, breast cancer etc.).But clinically kinds of tumor cells generates after contacting VCR to its drug resistance, eventually leading at present
Treat failure.
Mould anthrone was a kind of Anthraquinones organic compound generated by fungal secondary metabolism, from mould anthrone A in 2002
For the first time fromPenicillium thomiiMiddle discovery so far, has pass by more than ten years.Such compound has been reported 2 so far
It is a, it is mould anthrone A, B respectively and is all 2-4 ' connection.Such compound on tumor cell inhibits obvious, is that exploitation is antitumor
The desirable feedstock of drug or tumor cell proliferation inhibitor.But for the antitumor activity of their enantiomers or sky
It is white.
The present inventor studies and learns, penicillium oxalicum (Penicillium oxalicum) IBPT-6, (in 2013
December 25 was deposited in China typical culture collection center, address: Wuhan, Wuhan University, deposit number are: CCTCC NO:M
2013714) crude extract of tunning has good cell inhibitory effect activity, studies then its active constituent.
Research finds that shown mould anthracene ketone compounds have anti-human vincristine drug-resistant cell strain activity, has not yet to see the compound
To the report of the proliferation inhibition activity of people's vincristine mdr cell, therefore in the market also there is not yet drug related to this.
Summary of the invention
The purpose of the present invention is to provide a kind of iso-Penicillixanthone A derived from penicillium oxalicum and anti-Changchun
New alkali drug resistance application.
To achieve the above object, using following technical scheme:
Derived from the iso-Penicillixanthone A of penicillium oxalicum, which, which has, inhibits vincristine mdr cell to increase
The effect of growing has anti-human vincristine drug resistance activity.Its structural formula are as follows:
。
The preparation method of the compound, be by fermented and cultured penicillium oxalicum (Penicillium oxalicum)
IBPT-6 obtains fermentation mycelium, the compound is then isolated and purified out from mycelium.Specific step is as follows:
1 fermenting and producing
Cultivate microorganism conventional method, take penicillium oxalicum (Penicillium oxalicum) to be inoculated into plate solid by IBPT-6
2-3 d is cultivated on body culture medium in 28 DEG C of incubators, is then seeded into fungi culture medium, after 28 DEG C of 30 d of static gas wave refrigerator,
Mycelium and fermentation liquid are obtained through multilayer filtered through gauze；The fungal culture based component: 10.0 g of glucose, maltose 20.0
G, 20.0 g of mannitol, 10.0 g of monosodium glutamate, yeast extract 3.0 g, NaCl 15.0 g, KH2PO4 0.5 g、MgSO4·7H2O 0.3
G, ultrapure water is settled to 1 L.
The acquisition of 2 medicinal extract
With gauze by mycelium and separation of fermentative broth.Mycelium with acetone soln (contain 20% ~ 30% water) continuous ultrasound broken wall 3 times,
Filtering removal residue, obtains the mycelial crude extract containing acetone and water.Removal acetone is concentrated under reduced pressure, obtains the water-soluble of runic object
Liquid, then ethyl acetate is added with aqueous solution and ethyl acetate volume ratio 1:2 and is extracted 3 times, ethyl acetate crude extract is obtained, concentration is evaporated
Obtain 36.5 g of mycelium medicinal extract.
The separation and purification of 3 compounds
Mycelium medicinal extract is by 100-200 mesh silica gel mixed sample, and using petroleum ether: methylene chloride: methanol is subtracted as gradient eluent
Press silica gel chromatographic column chromatography.By simple thin-layer chromatographic analysis, merges, is separated into component A-E.Component C (12.7 g) with
Methylene chloride: methanol=1:2 is gradient elution agent, is carried out gel filtration chromatography (Sephadex LH-20), by thin-layer chromatographic analysis
Merge afterwards and obtains four subfraction C1-C4.Subfraction C3(4.9 g) by semi-preparative liquid chromatography (1010 type ODS-A, 10 ×
250 mm, 5 μm): separation flow velocity is 5 mL/min, and mobile phase is that 55% acetonitrile contains 0.1% TFA, obtains shown compound (510
Mg, tR 22.8 min)。
The penicillium oxalicum (Penicillium oxalicum) IBPT-6, it has been deposited on December 25th, 2013
State's Type Tissue Collection, address: Wuhan, Wuhan University, deposit number are: CCTCC NO:M 2013714.
The invention also includes the compounds to inhibit answering in people's vincristine mdr cell hyperproliferation agent in preparation
With and the compound preparing the application in anti-human vincristine medicine-resistant medicine.
Remarkable advantage of the invention is:
The mould anthrone compound shown in studying has significant inhibition people's vincristine mdr cell proliferation activity, at present not yet
The compound is seen to the report of people's vincristine mdr cell proliferation inhibition activity, therefore in the market also there is not yet related to this
Drug.
Detailed description of the invention
The main COSY of Fig. 1 Iso-Penicillixanthone A, HMBC and NOE signal.
Specific embodiment
The chemical structure of signified compound in the following example:
The fermenting and producing and separation and purification of 1 compound of embodiment
1 fermenting and producing
Produce bacterium fermented and cultured: by culture microorganism conventional method, take penicillium oxalicum (Penicillium oxalicum)
IBPT-6 (be deposited in China typical culture collection center on December 25th, 2013, address: protect by Wuhan, Wuhan University
Hiding number is: CCTCC NO:M 2013714) in right amount, being inoculated on Solid media for plates and cultivates 2- in 28 DEG C of incubators
3 d。
Make even plate culture 2-3 d penicillium oxalicum (Penicillium oxalicum) appropriate IBPT-6, it is inoculated into dress
By 400 mL culture solutions [culture solution forms (grams per liter): glucose 10.0, maltose 20.0, mannitol 20.0, monosodium glutamate 10.0,
Yeast extract 3.0, NaCl 15.0, KH2PO4 0.5、MgSO4·7H2O 0.3, ultrapure water are settled to 1 L, 28 DEG C of static gas wave refrigerators 30
After d, mycelium and fermentation liquid are obtained.
The acquisition of 2 medicinal extract
With gauze by mycelium and separation of fermentative broth.Mycelium with acetone soln (contain 20% ~ 30% water) continuous ultrasound broken wall 3 times,
Filtering removal residue, obtains acetone and the mycelial of water contains crude extract.Removal acetone is concentrated under reduced pressure, obtains the water-soluble of runic object
Liquid, then ethyl acetate is added with aqueous solution and ethyl acetate volume ratio 1:2 and is extracted 3 times, ethyl acetate crude extract is obtained, is concentrated under reduced pressure
36.5 g of mycelium medicinal extract is done to obtain to close.
The separation and purification of 3 compounds
Mycelium medicinal extract is by 100-200 mesh silica gel mixed sample, and using petroleum ether: methylene chloride: methanol is subtracted as gradient eluent
Press silica gel chromatographic column chromatography.By simple thin-layer chromatographic analysis, merges, be separated into component A-E.Component C (12.7 g) with
Methylene chloride: methanol=1:2 is gradient elution agent, is carried out gel filtration chromatography (Sephadex LH-20), by thin-layer chromatographic analysis
Merge afterwards and obtains four subfraction C1-C4.Subfraction C3(4.9 g) by semi-preparative liquid chromatography (1010 type ODS-A, 10 ×
250 mm, 5 μm): separation flow velocity is 5 mL/min, and mobile phase is that 55% acetonitrile contains 0.1% TFA, obtains shown compound (510
Mg, tR 22.8 min)。
Compound: being yellow powder, [α] under room temperature20 D + 105.6° (c 1, pyridine); [α]20 D + 3.1°
(c 1, Me2CO);High-resolution electrospray ionization mass spectrum HRESI-MS provides molecular ion peak [M+Na] at m/z:661.1550+
(calcd for C32H30NaO14, 661.1533)；Prompting molecular weight is 638, speculates that molecular formula is in conjunction with spectral information
C32H30O14。1H and13C-NMR data are shown in Table 1, and main COSY, HMBC and NOE signal is shown in Fig. 1.
1 compound of table1H and13C-NMR data (500 MHz1H and 126 MHz 13C, in DMSO-d 6 )
The test of 2 anti tumor activity in vitro of embodiment
1 laboratory sample and experimental method
The preparation of sample solution: test sample is the pure compounds of separation and purification in above-mentioned implementation 1.Precision weighs in right amount
Sample, is configured to the mother liquor of 100 mM with DMSO, membrane filtration degerming, be stored in -20 °C it is spare.DMSO ratio is controlled 1 ‰
Below.
It is removed from liquid nitrogen the cell strain frozen, is dissolved rapidly in 37 DEG C of water-baths, 1200 rpm are centrifuged 5 min, abandon
Frozen stock solution is removed, is sucked in culture bottle after the piping and druming of 1 mL culture medium is added, the fresh DMEM of 5 mL or 1640 culture medium of RPMI is added,
Gently shaking makes cell even suspension in the medium, sets 37 DEG C, 5% CO2Incubator in cultivate.When cell density reaches
It is passed on when 90% or so, removes old culture medium, PBS is washed 2 times, is added 300 μ L pancreatin (ensuring that pancreatin can cover bottom of bottle), 37
When digestion will fall off to cell rounding in DEG C incubator, the culture medium containing 10% fetal calf serum is added and terminates digestion, piping and druming mixes
Divide afterwards into 2-3 new culture bottles, supplementing culture medium makes cell continued growth in the incubator.
Cell inhibitory effect activity test method (WST-1 method)
Anti-tumor angiogenesis evaluation uses WST-1 kit detection method, adjusts after the tumour cell digestion of logarithmic growth phase
Cell concentration is 3 × 104The single cell suspension of/mL takes 100 μ L to be inoculated in 96 orifice plates, Mei Genong after mixing cell suspension
Degree 5 multiple holes of setting.It is subsequently placed in 37 DEG C, 5% CO2Overnight incubation in incubator.Supernatant is removed, it is with culture medium that drug is dilute
It is interpreted into different concentration to be added in corresponding 96 orifice plate, the culture medium containing equal amount DMSO is added in control group.After cultivating 72 h,
After 37 DEG C of WST-1 solution 2 h of incubation of 10 μ L are added in every hole, gently oscillation is mixed, and is measured it with microplate reader and is inhaled in 450 nm
Light value.Calculate the mean OD value in 5 holes and according to formula: cell proliferation inhibition rate=(OD control group-OD blank group)/(OD experiment
Group-OD blank group) × 100% proliferation inhibition rate of the drug to tumour cell for calculating each concentration, using Graphpad Prism
5.0 softwares calculate half inhibiting rate IC50。
2 experimental results
Cell inhibitory effect active testing the results are shown in Table 2.
The inhibitory activity that 2 compound of table is proliferated people's vincristine mdr cell
3 conclusions
The compound has preferable anti-tumor activity to people's vincristine mdr cell.It can be used as that prepare vincristine drug resistance thin
Born of the same parents' Proliferation Ability drug or anti-tumor drug are used for the drug resistant research of vincristine.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, is all covered by the present invention.
Claims (3)
1. compound, it is characterised in that: the compound passes through following
Method preparation: fermentation penicillium oxalicum (Penicillium oxalicum) IBPT-6, fermentation material is obtained, then from fermentation material
It isolates and purifies to obtain the compound；Wherein the penicillium oxalicum (Penicillium oxalicum) IBPT-6, in 2013
On December 25, in is deposited in China typical culture collection center, and address: Wuhan, Wuhan University, deposit number are: CCTCC
NO:M 2013714.
2. compound described in claim 1 is preparing the application in vincristine mdr cell Proliferation Ability drug.
3. compound described in claim 1 is preparing the application in anti-vincristine medicine-resistant medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811473641.3A CN109776477A (en) | 2018-12-04 | 2018-12-04 | Iso-Penicillixanthone A and anti-vincristine drug resistance application derived from penicillium oxalicum |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811473641.3A CN109776477A (en) | 2018-12-04 | 2018-12-04 | Iso-Penicillixanthone A and anti-vincristine drug resistance application derived from penicillium oxalicum |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109776477A true CN109776477A (en) | 2019-05-21 |
Family
ID=66496555
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811473641.3A Pending CN109776477A (en) | 2018-12-04 | 2018-12-04 | Iso-Penicillixanthone A and anti-vincristine drug resistance application derived from penicillium oxalicum |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109776477A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627763A (en) * | 2018-12-04 | 2019-12-31 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | iso-Penicillium xanthone A from Penicillium oxalicum and application of anti-cisplatin drug resistance |
| CN110669800A (en) * | 2018-12-04 | 2020-01-10 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | Application of iso-Penicillium xanthone A from Penicillium oxalicum and adriamycin resistance |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107298671A (en) * | 2017-06-17 | 2017-10-27 | 福州大学 | Come from the secalonic acid H of penicillium oxalicum and prepare the application of anti-human colon cancer drug |
| CN110627763A (en) * | 2018-12-04 | 2019-12-31 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | iso-Penicillium xanthone A from Penicillium oxalicum and application of anti-cisplatin drug resistance |
| CN110669800A (en) * | 2018-12-04 | 2020-01-10 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | Application of iso-Penicillium xanthone A from Penicillium oxalicum and adriamycin resistance |
-
2018
- 2018-12-04 CN CN201811473641.3A patent/CN109776477A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107298671A (en) * | 2017-06-17 | 2017-10-27 | 福州大学 | Come from the secalonic acid H of penicillium oxalicum and prepare the application of anti-human colon cancer drug |
| CN110627763A (en) * | 2018-12-04 | 2019-12-31 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | iso-Penicillium xanthone A from Penicillium oxalicum and application of anti-cisplatin drug resistance |
| CN110669800A (en) * | 2018-12-04 | 2020-01-10 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | Application of iso-Penicillium xanthone A from Penicillium oxalicum and adriamycin resistance |
Non-Patent Citations (3)
| Title |
|---|
| GUANGWEI WU，ET AL.: "Structure-based discovery of cytotoxic dimeric tetrahydroxanthones as potential topoisomerase I inhibitors from a marine-derived fungus"" * |
| TAMAM EL-ELIMAT ET AL.: ""Biosynthetically Distinct Cytotoxic Polyketides fromSetophoma terrestris"", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| 李庆 等: ""真菌代谢产物Secalonic acid D及其药理活性研究"", 《中药材》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627763A (en) * | 2018-12-04 | 2019-12-31 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | iso-Penicillium xanthone A from Penicillium oxalicum and application of anti-cisplatin drug resistance |
| CN110669800A (en) * | 2018-12-04 | 2020-01-10 | 福建省肿瘤医院（福建省肿瘤研究所、福建省癌症防治中心） | Application of iso-Penicillium xanthone A from Penicillium oxalicum and adriamycin resistance |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107298671B (en) | Selenolonic acid H from penicillium oxalicum and application thereof in preparing medicine for resisting human colon cancer | |
| CN107353274B (en) | Selenolonic acid I from penicillium oxalicum and application thereof in preparation of human esophageal cancer resistant medicine | |
| CN107298672B (en) | Application of seclenic acid I derived from penicillium oxalicum in preparation of anti-human colon cancer drugs | |
| CN107485607B (en) | Application of seclenic acid H derived from penicillium oxalicum in preparation of human esophageal cancer resistant medicine | |
| CN107298670B (en) | Application of medicine derived from penicillium oxalicum seclenum ketonic acid H in preparation of anti-human oral epidermoid carcinoma medicines | |
| CN109776477A (en) | Iso-Penicillixanthone A and anti-vincristine drug resistance application derived from penicillium oxalicum | |
| CN107298669B (en) | Selenolonic acid I from penicillium oxalicum and application of medicine for resisting human oral epidermoid carcinoma | |
| CN109106702A (en) | Derived from application of 4-4 ' the isomerization secalonic acid D in terms of colon cancer of penicillium oxalicum | |
| CN110407792B (en) | Secalonic acid J compound derived from penicillium oxalicum and preparation method thereof | |
| CN107739362B (en) | Derived from aspergillus versicolor anthraquinone analog compound and prepare the application of anti-human oesophagus cancer drug | |
| CN107739361B (en) | Derived from aspergillus versicolor anthraquinone analog compound and prepare the application of anti-human colon cancer drug | |
| CN109134416B (en) | Application of seclenic acid H derived from penicillium oxalicum in preparation of human cervical cancer drugs | |
| CN110669800A (en) | Application of iso-Penicillium xanthone A from Penicillium oxalicum and adriamycin resistance | |
| CN110627763A (en) | iso-Penicillium xanthone A from Penicillium oxalicum and application of anti-cisplatin drug resistance | |
| CN110407794A (en) | Secalonic acid K derived from penicillium oxalicum and the application on inhibition cancer cell multiplication | |
| CN109134417B (en) | Selenolonic acid I from penicillium oxalicum and application of medicine for resisting human cervical cancer | |
| CN110407797A (en) | Derived from the secalonic acid class compound Secalonic acid K and preparation method of penicillium oxalicum | |
| CN109776478A (en) | Iso-Penicillixanthone A derived from penicillium oxalicum and the application in terms of cervical carcinoma | |
| CN110923278A (en) | iso-Penicillium xanthone A from penicillium oxalicum and application in lung cancer | |
| CN110407793A (en) | Secalonic acid J derived from penicillium oxalicum and the application on inhibition cancer cell multiplication | |
| CN110407795A (en) | Derived from penicillium oxalicum secalonic acid L and inhibiting the application in human cancer cell proliferation | |
| CN110407796A (en) | Derived from the secalonic acid class compound Secalonic acid L and preparation method of penicillium oxalicum | |
| CN110403929A (en) | Derived from the secalonic acid M of penicillium oxalicum and in the application for inhibiting human cancer cell to be proliferated | |
| CN110407798A (en) | Derived from the secalonic acid class compound Secalonic acid M and preparation method of penicillium oxalicum | |
| CN109106706A (en) | Derived from application of 4-4 ' the isomerization secalonic acid D in terms of gastric cancer of penicillium oxalicum |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190521 |
|
| RJ01 | Rejection of invention patent application after publication |