CN102311442B - Spirolactam alkaloid compound with anti-tumor activity and preparation method as well as application thereof - Google Patents
Spirolactam alkaloid compound with anti-tumor activity and preparation method as well as application thereof Download PDFInfo
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Abstract
The invention discloses a spirolactam alkaloid compound with anti-tumor activity and a preparation method as well as application thereof. The compounds (IMCAS3308 and IMCAS3309) have structural formulas which are shown in the specification. The compound is obtained from solid leavening of aspergillus fumigatus MF330CGMCC3.10147 serving as a marine fungus. Experiments prove that the compounds IMCAS3308 and IMCAS3309 can be used as inhibitors of NFkB (Nuclear Factor-kB), have the effect of inducing apoptosis of tumor cells, can be used for developing anti-tumor medicaments and have broad application prospect.
Description
Technical field
The present invention relates to a class and there is spirolactams alkaloid compound of anti-tumor activity and preparation method thereof and application.
Background technology
Malignant tumour is serious harm human life's disease, and its mortality ratio is only second to cardiovascular and cerebrovascular diseases, and incidence has the trend rising year by year.Wherein, lung cancer is the tumour that M & M is the highest.In female tumor, breast cancer incidence and mortality ratio all occupy first.The medicine that research and development have anti-tumor activity has great importance.
Ocean is a high salt, oligotrophic, the even environment of low temperature, high pressure, and in order to adapt to special environment, marine microorganism, with its unique pathways metabolism, can produce the active metabolite of novel structure.Marine Microbial Kinds is various, provides more possibility for finding new cancer-resisting substance.Thalassiomycetes is as the important component part of marine microorganism, the research of its natural product starts from the nineties in 20th century, within 1998, enter the period of great prosperity, the new compound of separating from thalassiomycetes to 2002 has 272, is wherein no lack of the material with anti-tumor activity.
Nuclear factor К B (nclear factor-К B, NF К B) is a kind of important transcription factor protein, and several genes is raised and played a crucial role, and in various diseases, plays a significant role.Studying more is its effect in inflammation, in recent years, day by day deep due to apoptosis research, the relation of NF К B and apoptosis is also progressively elucidated.Most research shows, NF К B has the effect that prevents cell generation apoptosis, and the mechanism of action of many antitumour drugs inducing apoptosis of tumour cell just, therefore NF К B inhibitor may play an important role in the treatment of tumour.
Widely distributed at occurring in nature by tryptophane and the derivative indole alkaloid compounds of proline(Pro), biological activity is varied, about the research of this type of alkaloidal structure, chemical reaction, stereochemistry, synthetic, many important medicinal compounds etc., greatly attracting numerous organic chemists and medicine scholar.Spirocyclic lactams class Pseurotin compounds is that a class has special spirane structure and has multiple bioactive compound family, and activity relates separately to that inhibitor, Cell differentiation inducing activity and the azole drug of immunosuppression, chitinase is collaborative antimycotic, the inhibitor of apomorphine antagonist, vasculogenesis etc.
Summary of the invention
The object of the present invention is to provide a kind of snail lactam alkaloid compound with NF К B inhibitor activity that derives from thalassiomycetes and preparation method thereof.
The present invention extracts to separate and obtains two lurid snail lactam alkaloid compound (IMCAS3308 (formula I) from the fermenting culture of thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) (hereinafter to be referred as fungi Mf330), IMCAS3309 (formula II)), its chemical name is IMCAS3308: 2-[1 ' (S), 2 (S) ' dihydroxhex-3-ene-yl]-3-methyl-8 (R)-methoxy-8-benzoyl-9 (R)-hydroxy-(5S)-1-oxa-7-aza-spiro[4.4] non-2-ene-4, 6-dione (formula I) and IMCAS3309: 2-[1 ' (S), 2 (S) ' dihydroxhex-3-ene-yl]-3-methyl-8 (S)-methoxy-8-benzoyl-9 (R)-hydroxy-(5S)-1-oxa-7-aza-spiro[4.4] non-2-ene-4, 6-dione (formula II), its structural formula is as follows:
The present invention thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330 used is purchased from China Committee for Culture Collection of Microorganisms's common micro-organisms center (being called for short CGMCC), is numbered CGMCC 3.10147.
The preparation method of spirocyclic lactams compounds IMCAS3308 of the present invention and IMCAS3309, comprises the steps:
1) thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330 is carried out to solid fermentation cultivation, obtain solid fermentation thing;
2) by step 1) the solid fermentation thing vat liquor lixiviate that obtains, filter to obtain extracting solution, described extracting solution is concentrated into medicinal extract shape and obtains enriched material a; Then described enriched material a is obtained to water-soluble liquid by water dissolution, then extract by ethyl acetate, separate and obtain acetic acid ethyl acetate extract, and by the concentrated described acetic acid ethyl acetate extract crude extract that obtains; Wherein, described vat liquor is made up of ethyl acetate, methyl alcohol and Glacial acetic acid, and in described vat liquor, the volume ratio of ethyl acetate, methyl alcohol and Glacial acetic acid is 80: 15: 5-85: 10: 5;
3) by step 2) crude extract that obtains is with mixing with silica gel after acetic acid ethyl dissolution, obtaining crude extract, ethyl acetate, silica gel mass ratio is 1: (10-20): mixture (2-4), after ethyl acetate volatilization, carry out adsorption chromatography separation; First carry out wash-out with methylene dichloride, use again the mixed solution ratio of 100: 0 by volume, 98: 2,95: 5 of methylene dichloride and methyl alcohol to carry out gradient elution, each gradient elution 5-10 times column volume, collects the elution fraction that methylene dichloride and methyl alcohol volume ratio are 95: 5;
4) by step 3) collect elution fraction carry out reversed-phase silica gel column chromatography, carry out wash-out using volume ratio as the mixed solution of sherwood oil, methylene dichloride and the methyl alcohol of 5: 5: 1 as elutriant, collect eluting fraction; The sherwood oil that use volume ratio is 8: 2 and the mixed solution of acetone carry out thin-layer chromatographic analysis as developping agent to eluting fraction, obtain respectively Rf value 0.2,0.5, three cuts of 0.8;
5) cut that is 0.5 by described Rf value adopts reversed-phased high performace liquid chromatographic to separate, and carries out wash-out take the methanol aqueous solution of 60-65% as moving phase, obtains the compound shown in the compound shown in formula I and formula II.
Wherein, step 1) described in solid fermentation cultivate method be: according to 2.5% inoculum size, the seed culture fluid of thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330 CGMCC 3.10147 is inoculated in fermention medium, and 27 ℃-28 ℃ leave standstill cultivation 15-20 days; Described fermention medium is prepared as follows: sucrose 45-50g, yeast extract 0.01 gram, 8-10 gram of medicinal extract, agar 15-20 gram, 1 gram of dipotassium hydrogen phosphate, 3 grams of SODIUMNITRATE, 0.5 gram, Repone K, magnesium sulfate 0.5 and ferrous sulfate, adding distil water is settled to 1L, and adjusting pH is 6.5-7.0.
The preparation method of the seed culture fluid of described thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330 CGMCC 3.10147 is as follows: thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330CGMCC 3.10147 bacterial strains of getting-80 ℃ of preservations, after 37 ℃ of water-baths are dissolved rapidly, draw 0.1ml bacterium liquid in 100ml MHB seed culture medium, be placed on shaking table, rotating speed is 100-150rpm, cultivates 3-4 days for 27 ℃-30 ℃.
Step 2) described in extract and can carry out three times, in described extraction, the volume ratio of ethyl acetate and water-soluble liquid is 1: 1.
Step 5) described in reversed-phased high performace liquid chromatographic chromatographic column used be RP-18 reverse-phase chromatographic column, specification can be 250mm × 9.4mm × 5 μ m; Detect wavelength 254nm; Retention time is that 9.148min obtains Compound I MCAS3309, and retention time is that 10.196min obtains Compound I MCAS3308.
Another object of the present invention is to provide the application of above-mentioned spirolactams Alkaloid compound.
The application of Compound I MCAS3308 provided by the present invention and IMCAS3309 is their application in preparation NF-kB inhibitor; Or in the application of preparing in apoptosis of tumor cells inductor; Or prevent and/or treat the application in tumour medicine in preparation.
Wherein, described tumour cell can be lung carcinoma cell, specifically can be human lung cancer cell A549.
A further object of the present invention is to provide a kind of medicine that prevents and/or treats tumour.
Medicine provided by the present invention, its activeconstituents comprises the Compound I MCAS3308 and/or the IMCAS3309 that treat significant quantity.
Described medicine can be made the various ways such as injection liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
The present invention has following beneficial effect: the experiment proved that, Compound I MCAS3308 and 3309 can be served as the inhibitor of NF К B, and the effect of inducing apoptosis of tumour cell can be used for developing anti-tumor medicaments, has a extensive future.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of the prepared spirocyclic lactams compounds IMCAS3308 of the present invention and IMCAS3309 and control compound Pseurotin A thereof.
Fig. 2 is the nucleus magnetic resonance of the prepared spirocyclic lactams compounds IMCAS3308 of the present invention
1h spectrogram.
Fig. 3 is the nucleus magnetic resonance of the prepared spirocyclic lactams compounds IMCAS3308 of the present invention
13c spectrogram.
Fig. 4 is the nucleus magnetic resonance HMBC spectrogram of the prepared spirocyclic lactams compounds IMCAS3308 of the present invention.
Fig. 5 is the prepared spirocyclic lactams compounds IMCAS3308 nucleus magnetic resonance NOSEY spectrogram of the present invention.
Fig. 6 is the nucleus magnetic resonance of the prepared spirocyclic lactams compounds IMCAS3309 of the present invention
1h spectrogram.
Embodiment
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and biomaterial, if no special instructions, all can obtain from commercial channels.
The preparation of embodiment 1, Compound I MCAS3308 and IMCAS3309
(1) seed culture of fungi Aspergillus fumigatus.MF330 CGMCC3.10147:
100 milliliters of preparation MHB seed culture mediums (MHB buys in Beijing Rui Zekang Science and Technology Ltd., and by specification requires preparation), 121 ℃ of autoclavings 20 minutes.Get-80 ℃ of preservation of bacteria strains, after 37 ℃ of water-baths dissolve rapidly, be inoculated in MHB liquid seed culture medium by 5% inoculum size, be placed on shaking table, rotating speed is 100rpm-150rpm, cultivates 3-4 days for 27 ℃-28 ℃.
(2) fermentation culture of fungi Aspergillus fumigatus.MF330 CGMCC3.10147: fermention medium composition: 50 grams of sucrose, yeast extract 0.01 gram, 10 grams of medicinal extract, 15 grams, agar, 1 gram of dipotassium hydrogen phosphate, 3 grams of SODIUMNITRATE, 0.5 gram, Repone K, 0.5 gram, magnesium sulfate and ferrous sulfate, add 800ml distilled water, with 0.1M hydrochloric acid adjust pH to 6.5, and be settled to 1L, 121 ℃ of autoclavings 20 minutes.Get 1 milliliter of seed culture fluid in 40ml fermention medium, 27 ℃ leave standstill and cultivate 15 days.Ferment altogether 10 liters, 333 bottles.
(3) by 10L vat liquor (ethyl acetate: methyl alcohol: Glacial acetic acid=85: 10: 5 for 10L solid fermentation thing, v/v/v) solid fermentation thing described in lixiviate, the extracting solution that described lixiviate step is obtained is concentrated into medicinal extract shape, obtain enriched material a, add 1L distilled water, extract three times by isopyknic ethyl acetate, concentrated after combined ethyl acetate extraction liquid, obtain crude extract;
(4) crude extract is with mixing with silica gel after acetic acid ethyl dissolution, the mixture that the mass ratio of crude extract, ethyl acetate and the silica gel obtaining is 1: 10: 2, after ethyl acetate volatilization, carries out adsorption chromatography separation, first use twice of methylene dichloride wash-out, carry out successively gradient elution with the mixed solution of methylene dichloride and methyl alcohol by following volume ratio again: 100: 0,98: 2,95: 5,90: 10,80: 20,0: 100,5 times of column volumes of each gradient elution; Collect the elutriant of each gradient, totally 6 positions;
(5) 95: 5 positions of above-mentioned collection are separated with decompression reverse phase silica gel post again, the mixed solution of the sherwood oil, methylene dichloride and the methyl alcohol that are 5: 5: 1 by volume ratio carries out adsorption chromatography as elutriant and separates, use sherwood oil/acetone that volume ratio is 8: 2 to carry out thin-layer chromatographic analysis as developping agent, obtain respectively Rf value 0.2, three cuts of 0.5,0.8;
(6) cut that is 0.5 by above-mentioned Rf value separates by RP-HPLC method, methanol aqueous solution take volume content as 60% is as eluent, the reverse-phase chromatographic column adopting is the Agilent reverse-phase chromatographic column of RP-18, and chromatographic column specification is 250mm × 9.4mm × 5 μ m; Detect wavelength 254nm; Retention time is that 9.148min obtains Compound I MCAS3309, and retention time is that 10.196min obtains Compound I MCAS3308.
The structural identification of Compound I MCAS3308:
Yellow powder, ESI-MS (m/z) 432 (M+H)
+, 454 (M+Na)
+.
Optical?rotation[α]D?
25+15(MeOH)C＝0.7.
NMR data (500MHz, CD
3cOCD
3, δ, ppm, J/Hz):
13C-NMR：114.2s(C-2)，186.8s(C-3)，201.3s(C-4)，95.2s(C-5)，167.2s(C-6)，87.9s(C-8)，75.9d(C-9)，71.9d(C-10)，70.1d(C-11)，128.8d(C-12)，136.0d(C-13)，21.9t(C-14)，14.5q(C-15)，5.8q(C-16)，196.0s(C-17)，134.8s(C-18)，131.4d(C-19/23)，129.2d(C-20/22)，134.7d(C-21)，52.1q(C-8-OMe).
1H-NMR：8.32(2H?d，J＝7.5，C-19/23)，7.68(1H?t?J＝7.0，7.5，C-21)，7.53(2H?t，J＝7.6，7.5，C-20/22)，5.57(1H?td，J＝11.0，8.0，C-12)，5.45(1H?td，J＝11.0，8.0，C-13)，4.86(1H，dd?J＝14.0，6.0，C-10)，4.73(1H?d，J＝5.5，C-11)，4.32(1H?S，C-9)，3.32(3H?s，C-8-O-CH3)，1.68(3H?s，C-16)，0.99(3H?m，C-15).
The structural identification of Compound I MCAS3309:
Yellow powder, ESI-MS (m/z) 432 (M+H)
+, 454 (M+Na)
+.
Opticalrotation[α]D
25-5(MeOH)C＝0.7.
NMR data (500MHz, CD
3cOCD
3, δ, ppm, J/Hz).
13C-NMR：186.8s(C-2)，113.2s(C-3)，199.6s(C-4)，97.5s(C-5)，168.8s(C-6)，89.4s，(C-8)，77.1d(C-9)，69.8d(C-10)，72.9d(C-11)，129.2d(C-12)，136.0d(C-13)，21.9t(C-14)，14.5q(C-15)，5.8q(C-16)，194.6s(C-17)，135.8s(C-18)，131.4d(C-19/C-23)，129.6(C-20/C-22)，134.0d(C-21)，51.7d(C-8-OCH3).
1H-NMR：8.21(2H?d，J＝7.4C-19/23)，7.64(1H，t?J＝7.8，7.4，C-21)，7.53(2H，t?J＝7.6，7.7C-20/22)，5.56(1H，td，J＝7.0，11.2，C-13)，5.48(1H，td?J＝11.0，8.0，C-12)，4.85(1H，S，C-9)，4.67(1H，dd?J＝15.2，7.1，C-10)，4.51(1H，d?J＝6.7，C-11)，3.25(3H?S?C-8-OMe)，2.15(2H，m，C-14)，1.73(3H?s，C-16)，0.95(3H?s，C-15).
Table 1, Compound I MCAS3308 and IMCAS3309's
1h and
13the NMR data of C
Utilize NF-kB to shift the model screening, identify the effect of material to be detected cell death inducing on cell levels, concrete grammar is as follows:
1) in 96 orifice plates, every hole adds 90 μ l (10,000 cells) people's lung cancer A549 cell (Henan Ke Nuo Science and Technology Ltd., KG-007) suspension and cultivates 20 hours.
2) compound (IMCAS3308 or IMCAS3309) the 2 μ l that add respectively DMSO to dissolve in every hole, the final concentration of compound is 20 μ M to 0.6125 μ M totally 7 concentration, adds in hand-hole and under 37C and cultivates.The experiment of each sample repeats 3 times.
3) cell of test use all stimulates with TNF-α (Sigma-Aldrich, St.Louis, MO), and reaction terminating relies on the PBS washing of precooling, then to add the fixing 30min of paraformaldehyde room temperature in PBS of 2%, 100 μ l.
4) cell is infiltrated to 20min in the PBS that is added with 0.1%, 100 μ l Triton X-100, with PBS washing 3 times, and (1%, 100 μ l) seals 1 hour with the PBS that contains BSA.
5) add the anti-NF-kB antibody of rabbit (Santa Cruz biotechnology, Inc.), 4 ℃ of overnight incubation.Cell, with PBS washing 3 times, adds anti-(Invitrogen, Carlsbad, CA), Alexa Fluor 488 (the 50 μ l of goat anti-rabbit igg two; Molecular Probes, Inc., Eugene, OR), Hoechst 33342 (1 μ g/ml; Promega, Madison, WI) hatch together 5 hours.
6), after PBS washing, cell detects for 500 times at ImageXpress, filter system be adjusted to FITC (excite: 490nm, transmitting: 525nm dichroscope 505nm) and DAPI (excite: 350nm; Transmitting: 479nm dichroscope: 400nm) (Molecular Devices, Sunnyvale, CA).
7) with MetaXpress software (Molecular Devices) quantitative analysis image.Nucleus relies on Hoechst33342 dyeing, and NF-kB consideration convey moves by the difference of fluorescence average intensity in nucleus and tenuigenin and calculates and obtain.
The IC50 of Compound I MCAS3308 is 2.6 μ M, and the IC50 of Compound I MCAS3309 is 6.6 μ M.
Claims (7)
1. the compound shown in formula I:
2. the preparation method of the compound shown in the compound shown in formula I or formula II, comprises the steps:
1) thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330CGMCC3.10147 is carried out to solid fermentation cultivation, obtain solid fermentation thing; The condition that described solid fermentation is cultivated is as follows: thalassiomycetes Aspergillus fumigatus (Aspergillus fumigatus) MF330CGMCC3.10147 is left standstill and cultivates 15-20 days in 27 ℃-28 ℃ in fermention medium; Described fermention medium is prepared as follows: sucrose 45-50g, yeast extract 0.01 gram, 8-10 gram of medicinal extract, agar 15-20 gram, 1 gram of dipotassium hydrogen phosphate, 3 grams of SODIUMNITRATE, 0.5 gram, Repone K, magnesium sulfate 0.5 and ferrous sulfate, adding distil water is settled to 1L, and adjusting pH is 6.5-7.0;
2) solid fermentation thing vat liquor lixiviate step 1) being obtained, filters to obtain extracting solution, described extracting solution is concentrated into medicinal extract shape and obtains enriched material a; Then described enriched material a is obtained to water-soluble liquid by water dissolution, then extract by ethyl acetate, separate and obtain acetic acid ethyl acetate extract, and by the concentrated described acetic acid ethyl acetate extract crude extract that obtains; Wherein, described vat liquor is made up of ethyl acetate, methyl alcohol and Glacial acetic acid, and in described vat liquor, the volume ratio of ethyl acetate, methyl alcohol and Glacial acetic acid is 80:15:5-85:10:5; Described extraction is carried out three times, and in described extraction, the volume ratio of ethyl acetate and water-soluble liquid is 1:1;
3) by step 2) crude extract that obtains is with mixing with silica gel after acetic acid ethyl dissolution, and the mixture that to obtain crude extract, ethyl acetate, silica gel mass ratio be 1:10-20:2-4, after ethyl acetate volatilization, carries out adsorption chromatography separation; First carry out wash-out with methylene dichloride, again with the mixed solution of methylene dichloride and methyl alcohol by volume the ratio of 100:0,98:2,95:5 carry out gradient elution, each gradient elution 5-10 times column volume, collects the elution fraction that methylene dichloride and methyl alcohol volume ratio are 95:5;
4) elution fraction of step 3) being collected carries out reversed-phase silica gel column chromatography, and the mixed solution of sherwood oil, methylene dichloride and methyl alcohol using volume ratio as 5:5:1 carries out wash-out as elutriant, collects eluting fraction; The sherwood oil that use volume ratio is 8:2 and the mixed solution of acetone carry out thin-layer chromatographic analysis as developping agent to eluting fraction, obtain respectively Rf value 0.2,0.5, three cuts of 0.8;
5) cut that is 0.5 by described Rf value adopts reversed-phased high performace liquid chromatographic to separate, and the methanol aqueous solution take volume content as 60%-65% carries out wash-out as moving phase, obtains the compound shown in the compound shown in formula I and formula II; In described reversed-phased high performace liquid chromatographic, chromatographic column used is RP-18 reverse-phase chromatographic column, and specification is 250mm × 9.4mm × 5 μ m; Detect wavelength 254nm; Retention time is that 9.148min obtains the compound shown in formula II, and retention time is that 10.196min obtains the compound shown in formula I;
3. compound claimed in claim 1 is following 1)-3) in the application of any one:
1) application in preparation NFkB inhibitor;
2) in the application of preparing in apoptosis of tumor cells inductor;
3) prevent and/or treat the application in tumour medicine in preparation.
4. application according to claim 3, is characterized in that: described tumour cell is lung carcinoma cell; Described tumour is lung cancer.
5. application according to claim 4, is characterized in that: described tumour cell is human lung cancer cell A549.
6. prevent and/or treat a medicine for tumour, its activeconstituents is the compound shown in the formula I in claim 1.
7. medicine according to claim 6, is characterized in that: described tumour is lung cancer.
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