CN106397459A - Sulfo-diketopiperazine compound and application thereof - Google Patents
Sulfo-diketopiperazine compound and application thereof Download PDFInfo
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- CN106397459A CN106397459A CN201610788337.2A CN201610788337A CN106397459A CN 106397459 A CN106397459 A CN 106397459A CN 201610788337 A CN201610788337 A CN 201610788337A CN 106397459 A CN106397459 A CN 106397459A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
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- 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
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
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Abstract
The invention relates to the technical field of microorganism medicines, in particular to a sulfo-diketopiperazine compound, which is separated and purified from the fermentation mycelia of marine fungi Penicillium brocae, and application of the sulfo-diketopiperazine compound. The molecular formula of the sulfo-diketopiperazine compound is C18H18O5N2S1 and is as shown in a formula I; antitumor activity in vitro proves that the compound has remarkable inhibition activity on sensitive strain and cis-platinum drug-resistant strain of ovarian carcinoma cells A2780, and the median inhibitory concentrations (IC50) of the compound on the sensitive strain and the cis-platinum drug-resistant strain are respectively 664.2 and 660.6nM. In addition, an antimicrobial activity test finds that the compound has high inhibition activity on staphylococcus aureus, and the minimum inhibition concentration (MIC) of the compound is 0.25mu g/mL. The compound is expected to become a medicine for treating cancers or staphylococcus aureus infection.
Description
Technical field
The present invention relates to microorganism pharmaceutical technology field, specifically from marine fungi Penicillium brocae's
The thio diketopiperazine compound isolating and purifying in fermentation mycelium and its application.
Background technology
Marine microorganism secondary metabolite has abundant structure diversity and significant biological activity, is drug leads
The important sources of compound.Thio diketopiperazine compound is a class mainly by the mycetogenetic chemical combination with biological activity
Thing, all contains the diketopiperazine parent nucleus with sulphur bridge, has extensive biological activity in its molecular structure, as antitumor, antibacterial, resist
Virus, immunosuppressant etc..Research finds, thio diketopiperazine can stop as hypoxia inducible factor (HIF-1 α) inhibitor
HIF-1 α with transcription the co-activation factor (CBP/p300) combination, become anti-tumor drugs targeting research focus compound it
One.
Early-stage Study finds, the endogenetic fungus Penicillium brocae MA- of ocean mangrove plant Avicennia marina stem
231 in the culture of PDB culture medium standing for fermentation, can produce a series of thio Diketopiperazine derivatives with metabolism, show stronger
Anti-tumor activity, there is potential medical value, further study show that this bacterial strain can be produced with metabolism under optimum culture condition
Raw structure-rich is various, anti-tumor activity significantly thio diketopiperazine compound.
Content of the invention
It is an object of the invention to isolate and purify from the fermentation mycelium of marine fungi Penicillium brocae
Thio diketopiperazine compound and its application..
For achieving the above object, the technical solution used in the present invention is：
A kind of thio diketopiperazine compound, thio diketopiperazine compound molecular formula is C18H18O5N2S2, such as Formulas I
Shown：
A kind of application of thio diketopiperazine compound, thio diketopiperazine compound shown in described Formulas I is in preparation
Application in ovarian cancer.
A kind of application of thio diketopiperazine compound, thio diketopiperazine compound shown in described Formulas I is in system
Application in the medicine of standby suppression infection of staphylococcus aureus.
Advantage for present invention：
The present invention obtains one plant of Penicillium fungus from picking up from Hainan and be newly full of to separate Rhizophora apiculata Blume Avicennia marina stem
Penicillium brocae, this bacterium is preserved in China Committee for Culture Collection of Microorganisms's common micro-organisms center, preservation
Unit address is Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3, preservation date：On January 17th, 2014, preserving number is：CGMCC
NO.8736, carries out training systern to it, finds the novel tool of a structure from its czapek's medium shaker fermentation product
There is the thio diketopiperazine compound of notable anti-tumor activity, have not yet to see the chemical constitution to this compound and resist swollen
Tumor, the report of antibacterial activity, also there is not yet medicine related to this therefore on market.
Through anti tumor activity in vitro test, the sensitive strain of this compounds on ovarian cancerous cell A2780 and cisplatin resistance strain are equal
There is remarkable inhibiting activity, its half-inhibition concentration (IC50) it is respectively 664.2 and 660.6nM.In addition, antibacterial activity test finds
This compound also has compared with strong selectivity inhibitory activity to staphylococcus aureuses, and its minimal inhibitory concentration (MIC) is 0.25 μ g/
mL.Can be used for preparing the medicine treating the disease that above-mentioned cancer and infection of staphylococcus aureus cause.
Brief description
Figure 1A is the change of the sensitive strain inhibitory activity of compounds on ovarian cancerous cell A2780 shown in variable concentrations following formula I.
Figure 1B is the change of the cisplatin resistance strain inhibitory activity of compounds on ovarian cancerous cell A2780 shown in variable concentrations following formula I
Change.
Specific embodiment
Specific examples below is used for further illustrating the present invention, but the present invention is limited to absolutely not these examples.
In examples below, the compound chemical structure of indication is (the Arabic numerals formula chemical constitution in structural formula
In carbon atom mark)：
Embodiment 1. compound fermenting and producing and separation and purification：
Marine fungi Penicillium brocae used by the present invention is isolatable from Mangrove in Hainan plant Avicennia marina stem, pure
Cultivate after change in czapek's medium, czapek's medium formula is：Glucose 36g, Mannitol 24g, sodium nitrate 3.5g, di(2-ethylhexyl)phosphate
Hydrogen potassium 1.5g, ferrous sulfate 0.02g, magnesium sulfate 0.7g, sodium glutamate 3g, sodium tartrate 1.5g, sea salt 17.5g, distilled water
1000ml.
Using fermentation tank bulk fermentation bacterial strain Penicillium brocae MA-231, mycelium acetone-water (80-20
(v/v)) ultrasonication is extracted 3-4 days, and after united extraction liquid, revolving removes acetone, and aqueous phase is extracted with ethyl acetate 3-4 time, merges
Extract is concentrated again, obtains mycelium crude extract.
Crude extract carries out silicagel column (200-300 mesh) chromatography that reduces pressure, and is 20 with gradient:1 to 1:The petroleum ether of 1 (v/v)-
Ethyl acetate and gradient are 20:1 to 1:1 (v/v) methylene chloride-methanol carries out gradient elution (flow velocity successively as solvent
200ml/min).Collect methylene chloride-methanol 20:The elution fraction that 1 (v/v) obtains, carries out reversed phase column chromatography (with methanol-water
As eluent gradient elution, gradient scope is methanol-water 20:80 to 80:20, v/v, flow velocity is 1.5ml/min), receive
Collection methanol-water 60：The component that 40 (v/v) afford, then purified with silica gel column chromatography, with 100:1 to 10:The dichloro of 1 (v/v)
Methane-methanol eluting (flow velocity 3ml/min), collects methylene chloride-methanol 50:The component that 1 (v/v) affords obtains final product purification mesh
Mark compound.
Its Structural Identification is as shown in (I),
This compound has following physics and chemistry and spectral characteristic：
Faint yellow amorphous powder, [α]D 25- 100.0 (c 0.22, MeOH)；UV(MeOH)λmax(logε)204
(3.65),269(3.14)nm；Proton nmr spectra and carbon spectrum such as Table I；ESI mass spectrum m/z 407 [M+H]+, high-resolution ESI mass spectrum
m/z 407.0728[M+H]+, C18H19O5N2S2Value of calculation is 407.0730.
The proton nmr spectra of Table I compound and carbon spectrum (500MHz, in CDCl3) data
A) this table signals assignment be based on DEPT,1H-1H COSY, HSQC and HMBC spectrum analysis result, carbon signal multiple
Degree utilizes DEPT side
Method determines
Embodiment 2. anti-tumor activity.
It is MTT using method, tumor cell line is ovarian cancer cell A2780 sensitive strain and cisplatin resistance strain.
Operating procedure is as follows：In precise above-described embodiment, the sterling compound sample of preparation, uses dimethyl sulfoxide
(DMSO) it is configured to the solution of desired concn.
Take the logarithm the tumor cell of trophophase, cell density is adjusted to 2 × 105Individual cells/ml, by every hole, 200 microlitres connect
Plant in 96 porocyte culture plates, cultivate 4 hours in 37 DEG C of incubators being passed through 5% carbon dioxide.Sample sets 5 respectively
Concentraton gradient 10-8, 10-7, 10-6, 10-5With 10-4Mol/L, each concentration sets three Duplicate Samples, and every hole adds sample liquid or blank solution
Each 2 microlitres, cultivate 48 hours, then often hole adds 10 microlitres of the MTT liquid that concentration is 5 mg/ml, continue culture 4 hours, go out
Remove supernatant.Every hole adds each 100 microlitres of DMSO, shakes 10 minutes on micro oscillator, after being completely dissolved to crystallization, enzyme mark
Instrument measures the 570 nanometers of light absorption values (OD value) going out in every hole.Take three hole mean OD value, by IR%=(ODBlank-ODSample)/ODBlank
× 100% formula calculates the suppression ratio (IR%) of sample cell proliferation.Result is referring to Fig. 1.
Show that the sensitive strain of compounds on ovarian cancerous cell A2780 and cisplatin resistance strain all have significantly by Fig. 1 experimental result
Inhibitory activity, its half-inhibition concentration (IC50) it is respectively 664.2 and 660.6nM.Embodiment 3. antibacterial activity.
Using compound anti-Staphylococcus aureus shown in minimal inhibitory concentration (MIC) method detection Formulas I
The activity of (Staphylococcus aureus).
Experimentation is as follows：Using sterile working, the sample solution of variable concentrations after doubling dilution is added separately to aseptic
96 hole polystyrene plates in, the 1st to 11 hole adds sample solution, every hole 5 μ L, and the 12nd hole is not added with sample as growth control.
Will be equivalent to the instruction bacteria suspension of 0.5 maxwell reduced turbidity, through LB fluid medium (peptone 10g, yeast extract
5g, sodium chloride 10g, distilled water 1000ml) after 1000 times of dilution, take 95 μ L to be added sequentially in 96 orifice plates so that the 1st to 11 hole
Sample final concentration be followed successively by 128,64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/mL.After gently concussion mixes, will
96 pore plate by sealing are placed in 37 DEG C of incubators, cultivate 24 hours.
Measure the light absorption value in every hole using microplate reader under 600nm wavelength, to completely inhibit instruction bacteria growing in little in the hole
Lowest concentration of drug be MIC.When negative control in the hole indicator bacteria substantially grows, test is just meaningful.
Experimental result shows that this compound has stronger inhibitory activity to staphylococcus aureuses, and its MIC is 0.25 μ g/
mL.
Above-mentioned the results show compounds on ovarian cancerous cell involved in the present invention and staphylococcus aureuses have
Very strong inhibitory activity, can as anti-tumor agent or antibacterial, and be expected to can be connect with any acceptable salt or interpolation clinic
The adjuvant being subject to or carrier such as excipient, the form of diluent are applied in preparing related drugs.
Claims (3)
1. a kind of thio diketopiperazine compound it is characterised in that：Thio diketopiperazine compound molecular formula is
C18H18O5N2S2, shown in formula I：
2. the thio diketopiperazine compound described in a kind of claim 1 application it is characterised in that:Sulfur shown in described Formulas I
For application in preparation ovarian cancer for the diketopiperazine compound.
3. the thio diketopiperazine compound described in a kind of claim 1 application it is characterised in that:Sulfur shown in described Formulas I
For application in the medicine in preparation suppression infection of staphylococcus aureus for the diketopiperazine compound.
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| CN201610788337.2A CN106397459B (en) | 2016-08-31 | 2016-08-31 | Thio diketopiperazine compound and its application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116536239A (en) * | 2023-04-17 | 2023-08-04 | 广州市林业和园林科学研究院 | Phosphate-dissolving microbial agent, and preparation and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008112014A1 (en) * | 2006-10-05 | 2008-09-18 | Mayo Foundation For Medical Education And Research | Methods and compositions for treating cancer |
| CN102051394A (en) * | 2010-11-23 | 2011-05-11 | 沈阳药科大学 | Preparation method and application of sulfo-diketopiperazine compounds |
| CN104804020A (en) * | 2014-01-29 | 2015-07-29 | 中国科学院海洋研究所 | Sulfodionepiperazine compound, and preparation method and use thereof |
-
2016
- 2016-08-31 CN CN201610788337.2A patent/CN106397459B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008112014A1 (en) * | 2006-10-05 | 2008-09-18 | Mayo Foundation For Medical Education And Research | Methods and compositions for treating cancer |
| CN102051394A (en) * | 2010-11-23 | 2011-05-11 | 沈阳药科大学 | Preparation method and application of sulfo-diketopiperazine compounds |
| CN104804020A (en) * | 2014-01-29 | 2015-07-29 | 中国科学院海洋研究所 | Sulfodionepiperazine compound, and preparation method and use thereof |
Non-Patent Citations (4)
| Title |
|---|
| REN XIANG TAN等: "Isolation and Structure Assignments of Rostratins A-D, Cytotoxic Disulfides Produced by the Marine-Derived Fungus Exserohilum rostratum", 《J. NAT. PROD.》 * |
| 李莉媛等: "多硫代二酮哌嗪类化合物的研究进展", 《中国抗生素杂志》 * |
| 马养民等: "Spirotryprostatin 类生物碱的合成研究进展", 《有机化学》 * |
| 高艺洋等: "多硫代二酮哌嗪类化合物C87体外对肿瘤细胞生长的抑制作用及对活性氧产生的影响", 《中国药理学与毒理学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116536239A (en) * | 2023-04-17 | 2023-08-04 | 广州市林业和园林科学研究院 | Phosphate-dissolving microbial agent, and preparation and application thereof |
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