CN106420716A - Application of penemenol E1 derived from trichoderma citrinoviride in aspect of resisting intestinal cancer - Google Patents
Application of penemenol E1 derived from trichoderma citrinoviride in aspect of resisting intestinal cancer Download PDFInfo
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- CN106420716A CN106420716A CN201610820509.XA CN201610820509A CN106420716A CN 106420716 A CN106420716 A CN 106420716A CN 201610820509 A CN201610820509 A CN 201610820509A CN 106420716 A CN106420716 A CN 106420716A
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
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Abstract
The invention relates to an application of penemenol E1 derived from trichoderma citrinoviride in an aspect of resisting intestinal cancer. The compound has the following structural characteristics: the compound contains the molecular skeleton of a pentacyclic amide, the compound contains a carbonyl group which is linked to a decane saturated fat long chain, a methyl group is linked to N and two hydroxyl groups exist in molecules. Experiments prove that the alkaloid compound has a relatively good inhibitory activity on intestinal cancer cells; and the alkaloid compound can be used for preparing medicines for inhibiting proliferation of the intestinal cancer cells or medicines for resisting the intestinal cancer, and the alkaloid compound is applicable to anti-tumor researches.
Description
Technical field
The present invention relates to a kind of mould enol E1 coming from tangerine green trichoderma applies in terms of intestinal cancer.
Background technology
Alkaloid is the organic compounds containing nitrogen that a class is produced by biological cometabolism, and the alkaloid species in nature is relatively
Many, mostly derive from plant, therefore have the title of vegetable soda again.Alkaloid has important physiological action to humans and animals, including flat
Breathe heavily antibechic, hypoglycemic, reducing blood lipid, antibacterial, antitumor, analgesia etc., wherein prominent with antibacterial, antitumor activity.Natural knot
Structure alkaloid is the important sources finding lead compound in innovation drug research, has been applied to the alkaloidal drug of clinic at present
Through nearly hundred kinds.Research finds, some marine fungis can produce the biology that structure is novel, activity is good during cometabolism
Alkali, has medicinal well and industrialization prospect.
The present inventor's research is learnt, tangerine green trichoderma(Trichoderma citrinoviride.)IBPT-4 is (in 2013
On January 25, in is deposited in China typical culture collection center, address:Wuhan Wuhan University, deposit number is:CCTCC
NO:M 2013055) the CE of tunning have good tumor cell proliferation inhibition activity, then to its active component
Studied, this tangerine green trichoderma(Trichoderma citrinoviride.)IBPT-4 is in the patent No. 201310208563.5
Disclosed.Alkaloid compound shown in research discovery has antitumor activity for intestinal cancer, has not yet to see this compound
Chemical constitution and the report for colon-cancer cell proliferation inhibition activity, also there is not yet medicine related to this therefore on market.
Content of the invention
It is an object of the invention to provide a kind of application in terms of intestinal cancer for mould enol E1 coming from tangerine green trichoderma.
Present invention firstly relates to one plant of tangerine green trichoderma(Trichoderma citrinoviride.)IBPT-4, this bacterial strain
It is deposited in China typical culture collection center, address on January 25th, 2013:Wuhan Wuhan University, deposit number is:
CCTCC NO:M 2013055;This tangerine green trichoderma(Trichoderma citrinoviride.)IBPT-4 is in the patent No.
201310208563.5 in disclosed.
The purposes of described bacterial strain is, by tangerine green trichoderma(Trichoderma citrinoviride.)IBPT-4 carries out sending out
Ferment is cultivated, and mycelium and fermentation broth extract are isolated to the compound mould enol with tumor cell proliferation inhibition activity
E1.
This structural formula of compound is:
.
Its architectural feature is:Molecular skeleton containing five cyclic amides, connect ten carbon saturations containing carbonyl
One methyl is connected on fatty long-chain, N, molecule has two oh groups.
The present invention also protects application in preparation is for colon-cancer cell Proliferation Ability medicine for the described compound, and should
Application in preparing anti-bowelcancer medicine for the compound.
The remarkable advantage of the present invention:This compound shown in research is the novel alkaloid of a structure, described alkaloids
Compound has significantly anti-intestinal cancer activity, has not yet to see the chemical constitution of this compound and is directed to colon-cancer cell Proliferation Ability
The report of activity, also there is not yet medicine related to this therefore on market.
Brief description
Fig. 1 is the main COSY and HMBC signal of mould enol E1.
Specific embodiment
The chemical constitution of the compound of indication in examples below:
.
The fermenting and producing of this compound of embodiment 1 and separation and purification
1 fermenting and producing
Produce the fermented and cultured of bacterium:By the conventional method of culture microorganism, take tangerine green trichoderma(Trichoderma citrinoviride.)IBPT-4 (is deposited in China typical culture collection center, address on January 25th, 2013:Military
Chinese Wuhan University, deposit number is:CCTCC NO:M 2013055) appropriate, it is inoculated on PDA solid slope culture medium 28
Cultivate 4 days in DEG C incubator.
Take the inclined-plane culture tangerine green trichoderma of 4 days(Trichoderma citrinoviride.)Appropriate IBPT-4, is inoculated into
Equipped with 400mL nutrient solution, [nutrient solution forms (g/l):Mannitol 20.0, yeast extract 3.0, maltose 20.0, monosodium glutamate 10.0,
Glucose 10.0, KH2PO40.5, MgSO40.3, NaCL 6.0 constant volume] 1000mL conical flask in, 28 DEG C of static gas wave refrigerator
After 30 days, obtain mycelium and zymotic fluid.
The acquisition of 2 medicinal extract
With gauze by mycelium and separation of fermentative broth.By zymotic fluid and ethyl acetate 1:2(v/v)It is extracted twice, extract reduces pressure
Distill to dry, obtain the ethyl acetate extract of zymotic fluid.Mycelium then with the aqueous solution ultrasonication containing 70%-80% acetone 3 times,
Remove reduced pressure concentration after clear liquid is merged by residue and remove acetone, with being 1 by volume:2 addition ethyl acetate are extracted twice, decompression
It is concentrated to dryness to obtain mycelium medicinal extract.The total medicinal extract of extract is obtained after mycelium and zymotic fluid medicinal extract are merged.
The separation and purification of 3 compounds
This medicinal extract after 100-200 mesh silica gel mixed sample, with petroleum ether:Dichloromethane:Methyl alcohol is eluent decompression silica gel color
Spectrum post gradient elution.Eluent is followed the tracks of through activity, obtains active component B (methylene chloride-methanol v/v 50:1 eluate),
Then with petroleum ether:Dichloromethane:Methanol gradient group is divided into eluant, eluent, passes through pressurized silica gel column chromatography gradient elution further,
(methylene chloride-methanol is 20 to the active subfraction B1 obtaining:1 eluate) with chloroform-methanol (v/v1:2) carry out for solvent
Sephadex LH-20 gel filtration chromatography, finally by semi-preparative liquid chromatography (1010 types ODS-A, 10 × 250 mm, 5 μm):
Separating flow velocity is 5 mL/min, and mobile phase is that 85% acetonitrile contains 0.1% TFA, obtains shown compound(32.1 mg,t R
20.7min).
Compound pale yellow oil, high resolution mass spectrum HRESI-MS existsm/z324.2161 place provides molecular ion peak
[M – H]–, (Calcd for C18H30NO4, 324.2175), point out molecular weight to be 325, speculate molecular formula in conjunction with spectral information
For C18H31NO4.1H and13The NMR data such as C-NMR are shown in Table 1.
Table 1 compound1H and13C-NMR data (500 MHz, in CDCl3)a)
A) this table signals assignment is based on DEPT, HMQC and HMBC spectrum analysis result.The species of carbon signal utilizes DEPT method true
Fixed.
The test of embodiment 2 anti tumor activity in vitro
1 laboratory sample and experimental technique
The preparation test sample of sample solution is the pure compounds of separation and purification in above-mentioned enforcement 1.Precision weighs in right amount
Sample, is configured to the solution of desired concn with methyl alcohol, for surveying activity.
The squamous subculture of clone and cell adopts colon-cancer cell system, and cell is cultivated with the RPMI-1640 containing 10% FBS
Base, in 37 DEG C of squamous subculture in the incubator being passed through 5% carbon dioxide.
Cell inhibitory effect activity test method
Tetrazolium(MTT)Method is taken the logarithm the cell in growth period, and cell density is adjusted to every milliliter 2 × 105Individual cell, by every
200 microlitres of hole is inoculated in 96 porocyte culture plates, is passed through 5% CO in 37 DEG C2Incubator in cultivate 4 hours.Every hole adds 2
Microlitre sample liquid or blank solution, after culture 24 hours, every hole adds MTT liquid(5 milligrams of normal saline solutions of every milliliter of MTT)10
Microlitre, continue culture 4 hours, 37 DEG C, 2000 revs/min are centrifuged 8 minutes, suck supernatant.Every hole adds each 100 microlitres of DMSO,
Micro oscillator vibrates 15 minutes, after being completely dissolved to crystallization, produces SPECTRAMAX Plus type enzyme mark using MD company
Instrument measures light absorption value at 570nm for every hole(OD)Value.In same 96 orifice plate, each concentration of sample is respectively provided with three holes, separately
If three hole blanks and acellular zeroing hole(If medicine has color will do the acellular zeroing of relative medicine concentration).Each hole OD
Value first does accordingly acellular zeroing, then takes three hole mean OD value by IR (%)=(ODBlank-ODSample)/ODBlank× 100%
Formula calculates cell proliferation inhibition rate (IR%) under each concentration.
2. experimental result
Cell inhibitory effect active testing result
In mtt assay test, the colon-cancer cell proliferation inhibition rate of this compound according to variable concentrations, apply SPSS16.0 software
Carry out data processing calculation of half inhibitory concentration IC50Value.The results are shown in Table 2.
The inhibitory activity that table 2 compound is bred to colon-cancer cell
3. conclusion
Compound has obvious colon-cancer cell inhibited proliferation, can be used as preparing colon-cancer cell antiblastic or anti-intestinal cancer
Medicine is used for antineoplastic research.
The foregoing is only presently preferred embodiments of the present invention, all impartial changes done according to scope of the present invention patent with
Modify, all should belong to the covering scope of the present invention.
Claims (2)
1. a kind of application of the mould enol E1 coming from tangerine green trichoderma it is characterised in that:The structural formula of described compound is
, it is applied to the preparation of colon-cancer cell Proliferation Ability medicine.
2. a kind of application of the mould enol E1 coming from tangerine green trichoderma it is characterised in that:The structural formula of described compound is
, it is applied to the preparation of anti-bowelcancer medicine.
Priority Applications (1)
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CN201610820509.XA CN106420716B (en) | 2016-09-13 | 2016-09-13 | Derived from application of the mould enol E1 in terms of intestinal cancer of tangerine green trichoderma |
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CN201610820509.XA CN106420716B (en) | 2016-09-13 | 2016-09-13 | Derived from application of the mould enol E1 in terms of intestinal cancer of tangerine green trichoderma |
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CN106420716A true CN106420716A (en) | 2017-02-22 |
CN106420716B CN106420716B (en) | 2019-06-07 |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110136752A1 (en) * | 2009-12-04 | 2011-06-09 | Novobiotic Pharmaceuticals Llc | Novel antibiotics |
CN103865808A (en) * | 2014-03-10 | 2014-06-18 | 福州大学 | Novel anti-tumor application of penicillium enol A1 from penicillium citrinum |
-
2016
- 2016-09-13 CN CN201610820509.XA patent/CN106420716B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110136752A1 (en) * | 2009-12-04 | 2011-06-09 | Novobiotic Pharmaceuticals Llc | Novel antibiotics |
CN103865808A (en) * | 2014-03-10 | 2014-06-18 | 福州大学 | Novel anti-tumor application of penicillium enol A1 from penicillium citrinum |
Non-Patent Citations (2)
Title |
---|
LI CHEN等: "TUMONOIC ACIDS K AND L, NOVEL METABOLITES FROM THE MARINE-DERIVED FUNGUS PENICILLIUM CITRINUM", 《HETEROCYCLES》 * |
ZHEN-JIAN LIN等: "Penicillenols from Penicillium sp. GQ-7, an Endophytic Fungus Associated with Aegiceras corniculatum", 《CHEM. PHARM. BULL.》 * |
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