CN106397459B - Thio diketopiperazine compound and its application - Google Patents
Thio diketopiperazine compound and its application Download PDFInfo
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- CN106397459B CN106397459B CN201610788337.2A CN201610788337A CN106397459B CN 106397459 B CN106397459 B CN 106397459B CN 201610788337 A CN201610788337 A CN 201610788337A CN 106397459 B CN106397459 B CN 106397459B
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- 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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- 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 present invention relates to microorganism pharmaceutical technology fields, the thio diketopiperazine compound specifically isolated and purified from the fermentation mycelium of marine fungi Penicillium brocae and its application.Thio diketopiperazine compound molecular formula is C18H18O5N2S2, shown in formula I, anti tumor activity in vitro proves that the sensitive strain of compounds on ovarian cancer cell A2780 and cisplatin resistance strain have remarkable inhibiting activity, half-inhibition concentration (IC50) it is respectively 664.2 and 660.6nM.In addition, antibacterial activity test finds that the compound has compared with strong inhibitory activity staphylococcus aureus, minimum inhibitory concentration (MIC) is 0.25 μ g/mL, it is expected to become the drug for the treatment of cancer or infection of staphylococcus aureus.
Description
Technical field
The present invention relates to microorganism pharmaceutical technology fields, specifically from marine fungi Penicillium brocae's
The thio diketopiperazine compound isolated and purified in fermentation mycelium and its application.
Background technology
Marine microorganism secondary metabolite has abundant structure diversity and significant bioactivity, is drug leads
The important sources of compound.Thio diketopiperazine compound is one kind mainly by mycetogenetic biologically active chemical combination
Object all contains the diketopiperazine parent nucleus with sulphur bridge in molecular structure, has an extensive bioactivity, such as antitumor, antibacterial, anti-
Virus, immunosupress etc..The study found that thio diketopiperazine can be used as hypoxia inducible factor (HIF-1 α) inhibitor to prevent
HIF-1 α and transcription the co-activation factor (CBP/p300) combination, become anti-tumor drugs targeting research hot spot compound it
One.
Early-stage study discovery, the endogenetic fungus Penicillium brocae MA- of ocean mangrove plant Avicennia marina stem
231 in the standing for fermentation culture of PDB culture mediums, can be metabolized and generate a series of thio Diketopiperazine derivatives, show relatively strong
Antitumor activity, have potential medical value, further study show that the bacterial strain can be metabolized production under optimum culture condition
Raw structure-rich is various, the significant thio diketopiperazine compound of antitumor activity.
Invention content
It is an object of the invention to what is isolated and purified from the fermentation mycelium of marine fungi Penicillium brocae
Thio diketopiperazine compound and its application..
To achieve the above object, the technical solution adopted by the present invention is：
A kind of thio diketopiperazine compound, thio diketopiperazine compound molecular formula is C18H18O5N2S2, such as Formulas I
It is shown：
It is prepared by a kind of application of thio diketopiperazine compound, thio diketopiperazine compound shown in the Formulas I
Application in ovarian cancer.
A kind of application of thio diketopiperazine compound, thio diketopiperazine compound shown in the Formulas I are being made
Application in the standby drug for inhibiting infection of staphylococcus aureus.
Advantage for present invention：
The present invention obtains one plant of Penicillium fungi from picking up from Hainan and be newly full of in mangrove Avicennia marina stem separation
Penicillium brocae, the bacterium are 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 are：CGMCC
NO.8736 carries out training systern to it, and the tool of a structure novel is found from its czapek's medium shaker fermentation product
The thio diketopiperazine compound for having notable antitumor activity has not yet to see the chemical constitution to the compound and resists swollen
The report of tumor, antibacterial activity, therefore in the market also there is not yet drug related to this.
It is tested through anti tumor activity in vitro, the sensitive strain of compounds on ovarian cancer cell A2780 and cisplatin resistance strain are equal
There are remarkable inhibiting activity, half-inhibition concentration (IC50) it is respectively 664.2 and 660.6nM.In addition, antibacterial activity test is found
The compound also has staphylococcus aureus compared with strong selectivity inhibitory activity, and minimum inhibitory concentration (MIC) is 0.25 μ g/
mL.It can be used for preparing the drug of disease caused by treating above-mentioned cancer and infection of staphylococcus aureus.
Description of the drawings
Figure 1A is the variation of compounds on ovarian cancer cell A2780 sensitive strain inhibitory activity shown in various concentration following formula I.
Figure 1B is the change of compounds on ovarian cancer cell A2780 cisplatin resistance strain inhibitory activity shown in various concentration following formula I
Change.
Specific implementation mode
Following specific examples is used for further illustrating the present invention, but the present invention is limited to absolutely not these examples.
Signified compound chemical structure is (the Arabic numerals formula chemical constitution in structural formula in the following example
In carbon atom mark)：
1. compound fermenting and producing of embodiment and separation and purification：
Marine fungi Penicillium brocae used in the present invention are isolated from Mangrove in Hainan plant Avicennia marina stem, pure
In czapek's medium, czapek's medium formula is for culture after change：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 revolving removes acetone after merging extracting solution, and water phase is extracted with ethyl acetate 3-4 times, merges
Extract liquor is concentrated again, obtains mycelium crude extract.
Crude extract carries out decompression silicagel column (200-300 mesh) chromatography, and it is 20 that gradient, which is used in combination,: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) is obtained carries out reversed phase column chromatography (with methanol-water
As eluent gradient elution, gradient ranging from methanol-water 20:80 to 80:20, v/v, flow velocity 1.5ml/min), it receives
Collect methanol-water 60：The component that 40 (v/v) are afforded, then purified with silica gel column chromatography, with 100:1 to 10:The dichloro of 1 (v/v)
Methane-methanol elutes (flow velocity 3ml/min), collects methylene chloride-methanol 50:The component that 1 (v/v) is afforded purifies mesh to obtain the final product
Mark compound.
Its Structural Identification is that such as (I) is shown,
The 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；Nuclear magnetic resonance spectroscopy and carbon spectrum such as Table I；ESI mass spectrums m/z 407 [M+H]+, high-resolution ESI mass spectrums
m/z 407.0728[M+H]+, C18H19O5N2S2Calculated value is 407.0730.
The nuclear magnetic resonance spectroscopy and carbon of Table I compound compose (500MHz, in CDCl3) data
A) this table signals assignment be based on DEPT,1H-1H COSY, HSQC and HMBC spectrum analysis as a result, carbon signal it is multiple
Degree utilizes the side DEPT
Method determines
2. antitumor activity of embodiment.
Use method for MTT, tumor cell line is ovarian cancer cell A2780 sensitive strains and cisplatin resistance strain.
Operating procedure is as follows：The sterling compound sample prepared in precise above-described embodiment, uses dimethyl sulfoxide (DMSO)
(DMSO) it is configured to the solution of required concentration.
The tumour cell of logarithmic growth phase, cell density are adjusted to 2 × 105A cells/ml is connect for 200 microlitres by every hole
Kind is cultivated 4 hours in 96 porocyte culture plates in the incubator that 37 DEG C are passed through 5% carbon dioxide.Sample is set separately 5
Concentration gradient 10-8, 10-7, 10-6, 10-5With 10-4Mol/L, each concentration set three Duplicate Samples, add sample liquid or blank solution per hole
It each 2 microlitres, cultivates 48 hours, 10 microlitres of the MTT liquid of a concentration of 5 mg/ml is then added per hole, continue culture 4 hours, go out
Remove supernatant.Each 100 microlitres of DMSO is added per hole, is shaken 10 minutes on micro oscillator, until after crystallization is completely dissolved, enzyme mark
Instrument measures the light absorption value (OD values) gone out per 570 nanometers of hole.Three hole mean OD values are taken, by IR%=(ODBlank control-ODSample)/ODBlank control
× 100% formula calculates the inhibiting rate (IR%) of sample cell proliferation.As a result referring to Fig. 1.
Show that the sensitive strain of compounds on ovarian cancer cell A2780 and cisplatin resistance strain have significantly by Fig. 1 experimental results
Inhibitory activity, half-inhibition concentration (IC50) it is respectively 664.2 and 660.6nM.3. antibacterial activity of embodiment.
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 various concentration after doubling dilution is added separately to sterile
96 hole polystyrene plates in, the 1st to 11 hole adds sample solution, and per 5 μ L of hole, the 12nd hole is not added with sample as growth control.
The instruction bacteria suspension that will be equivalent to 0.5 maxwell reduced turbidity, through LB liquid medium (peptone 10g, yeast extract
5g, sodium chloride 10g, distilled water 1000ml) dilution 1000 times after, 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.It, will after gently shaking mixing
96 pore plate by sealing are placed in 37 DEG C of incubators, are cultivated 24 hours.
The light absorption value per hole is measured using microplate reader under 600nm wavelength, to completely inhibit indicator bacteria growth in aperture
Lowest concentration of drug be MIC.When indicator bacteria obviously grows in negative control hole, experiment is just significant.
It is 0.25 μ g/ that experimental result, which shows that the compound has stronger inhibitory activity, MIC to staphylococcus aureus,
mL。
Above-mentioned the results show compounds on ovarian cancer cell according to the present invention and staphylococcus aureus have
Very strong inhibitory activity can be used as anti-tumor agent or antiseptic, and be expected to connect with any acceptable salt or addition clinic
The form of the auxiliary material or carrier such as excipient, diluent received is applied in preparing related drugs.
Claims (2)
1. a kind of application of thio diketopiperazine compound, it is characterised in that:Thio diketopiperazine compound shown in Formulas I exists
Prepare the application in the drug for inhibiting infection of staphylococcus aureus；
Thio diketopiperazine compound molecular formula shown in the Formulas I is C18H18O5N2S2, structural formula is as follows：
2. a kind of application of thio diketopiperazine compound, it is characterised in that:Thio diketopiperazine compound shown in Formulas I exists
Prepare the application in ovarian cancer；
Thio diketopiperazine compound molecular formula shown in the Formulas I is C18H18O5N2S2, structural formula is as follows：
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| 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 |
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| Isolation and Structure Assignments of Rostratins A-D, Cytotoxic Disulfides Produced by the Marine-Derived Fungus Exserohilum rostratum;Ren Xiang Tan等;《J. Nat. Prod.》;20040710;第67卷(第8期);全尤其是第1375页左栏，摘要 * |
| Spirotryprostatin 类生物碱的合成研究进展;马养民等;《有机化学》;20160601(第36期);参见全文 * |
| 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;高艺洋等;《中国药理学与毒理学杂志》;20150430;第29卷(第2期);第253-259页，参见全文 * |
| 多硫代二酮哌嗪类化合物的研究进展;李莉媛等;《中国抗生素杂志》;20131231;第38卷(第3期);全文，尤其是摘要，图8 * |
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