CN102643765A - Streptomyces, anti-tumor compound (Spiro-Indimycin A-D) as well as preparation method and application thereof - Google Patents
Streptomyces, anti-tumor compound (Spiro-Indimycin A-D) as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a streptomyces, anti-tumor compound (Spiro-Indimycin A-D) as well as preparation and application thereof. The streptomyces sp. SCSIO 03032 is preserved in China Center for Type Culture Collection (CCTCC) on July 18, 2011, the address is Wuhan University, Wuhan, China, and the preservation number is CCTCC NO: M 2011258. The invention provides a new streptomyces sp. SCSIO 03032, which can be used for producing the compound Spiro-Indimycin A, B, C and D with novel structure and antineoplastic activity; and the compound Spiro-Indimycin A, B, C and D not only has a rare spiral structure, but also has selective and efficient activity for tumour cells, and is an ideal candidate compound for being developed to be the efficient and anti-tumor compound with low toxicity.
Description
Technical field:
The invention belongs to the industrial microorganism field; Be specifically related to a kind of new streptomycete (Streptomyces sp.) SCSIO 03032 that can produce multiple antineoplastic compound, and the antineoplastic compound Spiro-Indimycin A-D of this bacterium production.
Background technology:
In recent years, find novel sea actinomycetes resource, and therefrom screen novel active secondary metabolite and become the important directions of marine microorganism research in the world.From marine actinomycete, seek novel structure, meta-bolites efficient, low toxicity becomes the new source that medicine is sought gradually.
Summary of the invention:
First purpose of the present invention provides a kind of new streptomycete (Streptomyces sp.) SCSIO 03032; This bacterium is preserved in Chinese typical culture collection center (CCTCC) on July 18th, 2011; The address: Chinese Wuhan City Wuhan University, its deposit number is CCTCC NO:M 2011258.
New streptomycete of the present invention (Streptomyces sp.) SCSIO 03032 separates in the marine bottom sediment of 3412 meters of (87 ° 59.7 of E ', 9 ° 59.3 of N ') depth of waters from the Indian Ocean to obtain.
1, morphological feature and physiological and biochemical analysis
Streptomycete (Streptomyces sp.) SCSIO 03032 belongs to Gram-positive, aerobic actinomycetes, and the little yellow branch of base silk, gas silk pearl branch also is divided into curling spore chain; Spore ellipsoid shape (Fig. 2), long 0.4-0.7 μ m, smooth surface.Growing way on the PDA substratum a little less than, growth has soluble pigment to produce on ISP5.Catalase, urase, milk solidify and the trunk reacting positive, and gelatine liquefication, melanochrome produce and the oxydase reaction feminine gender.Ability hydrolyzed starch, Mierocrystalline cellulose, polysorbas20,40,80; H
2S produces and the nitrate reduction reaction negative; Can utilize the D-pectinose, the D-cellobiose, fructose, inositol, Sodium.alpha.-ketopropionate, the D-raffinose, the L-rhamnosyl, D-N.F,USP MANNITOL, D-glucose, D-sorbose and Xylitol are sole carbon source and energy growth.And can not utilize the D-semi-lactosi, D-lactose, D-seminose, D-ribose, D-trehalose and D-wood sugar; Responsive to Sulfamonomethoxine and lincomycin.The tolerance range of pH, salt concn and temperature is respectively pH 6.0-9.0,0-9% and 15-40 ℃.Cell walls contains L-DAP.The advantage quinone is MK-9 (H6) and MK-11; Main lipid acid is i-C
15:0(8%), i-C
16:0(24%), i-C
16:1G (14%), ai-C
17:0(15%) and ai-C
17:1A (12%).The G+C molar content is 71.6 (± 0.5) %.
2, molecular biology identification
The 16S rDNA of conventional pcr amplification bacterial strain SCSIO 03032 and order-checking; Its sequence then is submitted among the GenBank shown in SEQ ID NO.1,16S rDNA nucleotide sequence is carried out BLAST analyze; The result shows, this bacterial strain and Streptomyces specialis GW41-1564
TSimilarity be 97%, rebuild this genus phylogenetic tree and show that bacterial strain SCSIO 03032 gathers at this monoid, explain that this bacterial strain SCSIO 03032 is streptomyces.As shown in Figure 1, clearly disclosed the phyletic evolution relation of this bacterial strain and one group of streptomyces species through adjacent method, show a kind of in streptomyces of this Pseudomonas.
According to analyses such as above morphology, physiology, chemistry, itself and known immediate bacterial strain and Streptomyces specialis GW41-1564
TBigger difference is arranged; And genomic hybridization shows that its hybridization value is 23%; 70% (Stackebrandt far below the intraspecies variation standard; E.& Ebers, J.Taxonomic parameters revisited:tarnished gold standards.Microbiol Today. (2006) .33,152-155.); Therefore; The multinomial grouped data of analysis-by-synthesis; Identify that this bacterial strain is a novel species of streptomyces (Streptomyces), called after: streptomycete (Streptomyces sp.) SCSIO 03032, this bacterium is preserved in Chinese typical culture collection center (CCTCC) on July 18th, 2011; The address: Chinese Wuhan City Wuhan University, its deposit number is CCTCC NO:M 2011258.
Streptomycete of the present invention (Streptomyces sp.) SCSIO 03032 can produce 4 kinds of antineoplastic compound Spiro-Indimycin A-D with novel structure.
Therefore second purpose of the present invention provides compound S piro-Indimycin A-D, and its structural formula is suc as formula shown in (I):
The inventor finds through experiment; Compound S piro-Indimycin A-D comprises mammary cancer MCF-7 to human cancer cell, human pancreas cancer 1990, people's liver cancer HepG2; Human cervical carcinoma Hale; Humanmachine tumour B16, people's lung cancer H460 and the selective cytotoxic activity of people's acute lymphoblastic leukemia T lymphocyte CCRF-CEM, wherein Spiro-Indimycin B is to the IC of Humanmachine tumour B16 cell, people's lung cancer H460 cell and people's acute lymphoblastic leukemia T lymphocyte CCRF-CEM
50Be respectively 11 μ M, 36.6 μ M and 4.5 μ M, and other subject cell strain is not had obvious GIA; Spiro-Indimycin C is to the IC of human liver cancer cell HepG2 and people's lung cancer H460 cell
50Be respectively 14.1 μ M and 35.4 μ M, and other subject cell strain is not had obvious GIA; Spiro-Indimycin D is to the IC of human liver cancer cell HepG2, Humanmachine tumour B16 cell and people's lung cancer H460 cell
50Be respectively 44.4 μ M, 40.4 μ M and 36.3 μ M, and other subject cell strain is not had obvious GIA, Spiro-Indimycin A is to the IC of people's acute lymphoblastic leukemia T lymphocyte CCRF-CEM
50Be 44.4 μ M, and other subject cell strain is not had obvious GIA (table 3).
The 3rd purpose of the present invention provides the application of compound S piro-Indimycin A-D in the preparation antitumor drug.
Preferably, the application of described compound S piro-Indimycin A in preparation treatment people acute lymphoblastic leukemia medicine.
Preferably, the application of described compound S piro-Indimycin B in preparation treatment Humanmachine tumour, people's lung cancer or people's acute lymphoblastic leukemia medicine.
Preferably, the application of described compound S piro-Indimycin C in preparation treatment people's liver cancer or people's lung-cancer medicament.
Preferably, the application of described compound S piro-Indimycin D in preparation treatment Humanmachine tumour, people's liver cancer or people's lung-cancer medicament.
The 4th purpose of the present invention provides streptomycete (Streptomyces sp.) SCSIO 03032 in the application that is used to prepare compound S piro-Indimycin A, B, C or D.
The 5th purpose of the present invention provides the preparation method of Spiro-Indimycin A, B, C or D; It is characterized in that described compound S piro-Indimycin A, B, C or D are that the preparation separation obtains from the fermenting culture of streptomycete (Streptomyces sp.) SCSIO 03032.
Preferably, be from the fermenting culture of streptomycete (Streptomyces sp.) SCSIO 03032, to prepare compound S piro-Indimycin A, B, C or D through following method, concrete steps are following:
A) fermenting culture of preparation streptomycete (Streptomyces sp.) SCSIO 03032; The fermented liquid and the mycelium of this fermenting culture are separated; Fermented liquid is through macroporous resin adsorption; The back is with acetone wash-out macroporous resin, and the remainder water mixed solution was used ethyl acetate extraction after elutriant reclaimed acetone, and ethyl acetate layer obtains extractum A through distilling after concentrated; Mycelium use earlier acetone extraction, and the remainder water mixed solution was used ethyl acetate extraction again after leaching liquid reclaimed acetone, and ethyl acetate layer obtains medicinal extract B through distilling after concentrated;
B) crude extract that extractum A and medicinal extract B is merged as eluent, carried out gradient elution in 100: 0～0: 100 from volume ratio with chloroform/methanol through silica gel column chromatography; Collect the cut Fr.1 that 95: 5 gradient elutions of chloroform/methanol volume ratio get off, after ODS anti-phase medium pressure liquid chromatography, water/methyl alcohol is as eluent; Carried out gradient elution in 100: 0～0: 100 from volume ratio, collect the cut Fr.1-1 that 30: 70 gradient elutions of water/methyl alcohol volume ratio get off, after the LH-20 gel column; With chloroform/methanol volume ratio 1: 1 as the moving phase wash-out; Follow the trail of to separate with thin-layer chromatography, collecting and using the chloroform/acetone volume ratio on the thin layer plate is that 9: 1 values of Rf during as developping agent are 0.8 cut, is Spiro-Indimycin B; The Rf value is 0.6 cut, is Spiro-Indimycin A; Collecting and using the petrol ether/ethyl acetate volume ratio on the thin layer plate is that 40: 60 values of Rf during as developping agent are 0.8 cut, is Spiro-Indimycin C; Collecting and using the petrol ether/ethyl acetate volume ratio on the thin layer plate is that 50: 50 values of Rf during as developping agent are 0.8 cut, is Spiro-Indimycin D.
The fermenting culture of the preparation streptomycete of described a) step (Streptomyces sp.) SCSIO 03032 is preferably through following method preparation: activatory streptomycete (Streptomyces sp.) SCSIO 03032 is inserted seed culture medium, 28 ℃, 200rpm; Cultivate 48h and get seed liquor, seed liquor is linked in the fermention medium 28 ℃ with 10% inoculum size; 200rpm, shaking culture 120h, and make fermenting culture; The prescription of described seed culture medium and fermention medium all is to contain in every liter of substratum: starch 10g; Yeast powder 5g, peptone 4g, CaCO
32g, thick sea salt 30g, surplus is a water, pH 7.2.
The invention provides a kind of new streptomycete (Streptomyces sp.) SCSIO 03032; This bacterium can production structure novel compound S piro-Indimycin A, B, C and D with anti-tumor activity; Compound S piro-Indimycin A, B, C and D are except that having rare spirane structure; Also to tumour cell selectively, active efficiently, the antineoplastic compound ideal candidate compound efficient, low toxicity that is that exploitation becomes.
Streptomycete of the present invention (Streptomyces sp.) SCSIO 03032 is preserved in Chinese typical culture collection center (CCTCC), address on July 18th, 2011: Chinese Wuhan City Wuhan University, its deposit number is CCTCC NO:M 2011258.
Description of drawings:
The phylogenetic tree that concerns between the nearest kind of Fig. 1 sibship with it that to be streptomycete (Streptomyces sp.) SCSIO 03032 rebuild based on the adjacent method of 16S rDNA sequence;
Fig. 2 is the ESEM microscopic morphology of streptomycete (Streptomyces sp.) SCSIO 03032;
Fig. 3 is the extract-extractum A of supernatant and the high-efficient liquid phase chromatogram of mycelial extract-medicinal extract B;
Performance liquid chromatography (HPLC) condition: chromatographic column is phenomex 150 * 4.6mm (SphereClone SAX); Moving phase comprise flow A mutually with mobile B mutually; Mobile phase A phase: the trifluoroacetic acid of the acetonitrile of 10% (volume(tric)fraction)+0.08% (volume(tric)fraction); Solvent is a water, and the B phase flows: the acetonitrile of 90% (volume(tric)fraction), solvent are water; Sample introduction program: 0-20min, the moving phase ratio is A phase/B phase (volume ratio): 95: 5-0: 100,20-21min, the moving phase ratio is A phase/B phase (volume ratio): 0: 100; 21-22min, the moving phase ratio is A phase/B phase (volume ratio): 0: 100-95: 5,22-30min; The moving phase ratio is A phase/B phase (volume ratio): 95: 5, detect wavelength 254nm, flow velocity 1ml/min; 1 representation compound 1,2 representation compound, 2,3 representation compounds 3 and 4 representation compounds 4 wherein.
Fig. 4 is the X-ray structure iron of compound 1;
Fig. 5 is the X-ray structure iron of compound 2.
Embodiment:
Following examples are to further specify of the present invention, rather than limitation of the present invention.
Embodiment 1:
One, separation and the evaluation of streptomycete (Streptomyces sp.) SCSIO 03032
Streptomycete of the present invention (Streptomyces sp.) SCSIO 03032 is from the Indian Ocean: separate to obtain in the marine bottom sediment that (87 ° 59.7 of E ', 9 ° 59.3 of N ') depth of water is 3412 meters.Isolation medium is the ISP2 substratum of optimizing in the prior art, and every liter contains yeast extract powder 2.0g, and Fructus Hordei Germinatus extracts powder 2.0g, glucose 1.0g, and agar 20.0g, zero(ppm) water 500ml, natural sea-water 500ml, pH 7.2.The separation and Culture condition is: 28 ℃, and 14 days.Obtain a bacterial strain SCSIO 03032 (streptomycete Streptomyces sp.SCSIO 03032) from the marine bottom sediment separation and purification thus.
1, morphological feature and physiological and biochemical analysis
This Pseudomonas is in Gram-positive, aerobic actinomycetes, and the little yellow branch of base silk, gas silk pearl branch also is divided into curling spore chain; Spore ellipsoid shape (Fig. 2), long 0.4-0.7 μ m, smooth surface.Growing way on the PDA substratum a little less than, growth has soluble pigment to produce on ISP5.Catalase, urase, milk solidify and the trunk reacting positive, and gelatine liquefication, melanochrome produce and the oxydase reaction feminine gender.Ability hydrolyzed starch, Mierocrystalline cellulose, polysorbas20,40,80; H
2S produces and the nitrate reduction reaction negative; Can utilize the D-pectinose, the D-cellobiose, fructose, inositol, Sodium.alpha.-ketopropionate, the D-raffinose, the L-rhamnosyl, D-N.F,USP MANNITOL, D-glucose, D-sorbose and Xylitol are sole carbon source and energy growth.And can not utilize the D-semi-lactosi, D-lactose, D-seminose, D-ribose, D-trehalose and D-wood sugar; Responsive to Sulfamonomethoxine and lincomycin.The tolerance range of pH, salt concn and temperature is respectively pH 6.0-9.0,0-9% and 15-40 ℃.Cell walls contains L-DAP.The advantage quinone is MK-9 (H6) and MK-11; Main lipid acid is i-C
15:0(8%), i-C
16:0(24%), i-C
16:1G (14%), ai-C
17:0(15%) and ai-C
17:1A (12%).The G+C molar content is 71.6 (± 0.5) %.
2, molecular biology identification
The extraction of the genomic dna that relates to during streptomycete (Streptomyces sp.) SCSIO 03032 identifies, the pcr amplification of 16S rDNA, the structure of sequence alignment and systematic evolution tree and physiology, chemistry and morphology evaluation etc., all reference [Tian, X.P.; Zhi, X.Y., Qiu, Y.Q., Zhang; Y.Q., Tang, S.K., Xu, L.H.; Zhang, S., Li, W.J.Sciscionella marina gen.nov.; Sp.nov., a marine actinomycete isolated from a sediment in the northern South China Sea.Int J Syst Evol Microbiol, 2009,59 (Pt 2): 222-228].
Extract the genomic dna of bacterial strain SCSIO 03032 according to the method in the reference; The 16S rDNA of this bacterial strain of pcr amplification and order-checking obtain 1430 bases, and its sequence is shown in SEQ ID NO.1; Then be submitted among the GenBank; 16S rDNA nucleotide sequence is carried out BLAST analyze, the result shows, this bacterial strain and Streptomyces specialis GW41-1564
TSimilarity be 97%, rebuild this genus phylogenetic tree and show that bacterial strain SCSIO 03032 gathers at this monoid, explain that this bacterial strain SCSIO 03032 is streptomyces.As shown in Figure 1; Clearly disclosed the phyletic evolution relation of this bacterial strain SCSIO03032 and one group of streptomyces species through adjacent method; Show a kind of in streptomyces of this Pseudomonas, show bacterial strain SCSIO 03032 and the most similar bacterial classification Streptomyces specialis GW41-1564 through the genomic hybridization methods and results
TThe hybridization value be 23%; This hybridization value is far below 70% (Stackebrandt of intraspecies variation standard; E.& Ebers, J.Taxonomic parameters revisited:tarnished gold standards.Microbiol Today. (2006) .33,152-155.); Simultaneously with the most similar known bacterial strain bigger difference is arranged all at aspects such as morphology, physiology, cytochemistries; Therefore, the multinomial grouped data of analysis-by-synthesis identifies that this bacterial strain is a novel species of streptomyces (Streptomyces); Called after: streptomycete (Streptomyces sp.) SCSIO 03032; This bacterium is preserved in Chinese typical culture collection center (CCTCC), address on July 18th, 2011: Chinese Wuhan City Wuhan University, its deposit number is CCTCC NO:M 2011258.
Two, the separation of active metabolite Spiro-Indimycin A-D and preparation
1, substratum (seed culture and fermention medium): every liter contains starch 10g, yeast powder 5g, peptone 4g, CaCO
32g, sea salt 30g, surplus is a water, pH 7.2.121 ℃, sterilization 30min;
2, fermentation
2.1, seed culture: single bacterium colony of activatory streptomycete on the petridish (Streptomyces sp.) SCSIO 03032 is inserted 18 bottles respectively, in the taper culturing bottle of every bottle of 250mL that contains the 50mL substratum, 28 ℃, 200rmin
-1, cultivate 48h, make seed liquor 900mL.
2.2, fermentation culture: seed liquor is linked in the 9L fermention medium (place the taper culturing bottle of 250mL, every bottle contains the 50ml substratum, 180 bottles) with 10% inoculum size (volume percent) totally, 28 ℃, 200rmin
-1, shaking culture 120h obtains the 9L fermenting culture.
3, extraction: fermenting culture carries out spinning (3500rmin earlier
-1, 8min), obtain the supernatant (fermented liquid) and the mycelium of 9L volume.Fermented liquid is through macroporous resin XAD16 SPE, and the back is with acetone wash-out macroporous resin 3 times, and elutriant reclaims behind the acetone remainder water mixed solution with ethyl acetate extraction 3 times, and ethyl acetate layer obtains supernatant extract-extractum A (4.1g) through distilling after concentrated; Mycelium is with 2L acetone lixiviate at room temperature 3 times, and each 3 hours, united extraction liquid, the surplus water mixed solution is used the 6L ethyl acetate extraction behind the reclaim under reduced pressure acetone, and the ethyl acetate layer underpressure distillation gets mycelium extract-medicinal extract B (0.9g).
4, the extraction separation of active compound and evaluation
4.1 extraction separation and the evaluation of compound S piro-Indimycin A-D: the sample of the extractum A that takes a morsel respectively and medicinal extract B is dissolved in the 100 μ l methyl alcohol; Centrifuging and taking supernatant 10 μ l; Through the HPLC sample detection, show, contain compound 1 (1) and 2 (2) in the extractum A; Contain compound 3 (3) and 4 (4) among the medicinal extract B (Fig. 3), extractum A and medicinal extract B are merged.The crude extract of this merging through silicagel column (300-400 order) chromatography, as eluent, 100: 0～0: 100 is carried out gradient elution from volume ratio with chloroform/methanol; Collect the cut Fr.1 (3.03g) that 95: 5 gradient elutions of chloroform/methanol volume ratio get off, evaporate to dryness is through ODS anti-phase medium pressure liquid chromatography (YMC*GEL ODS-A ball-type filler; The 120A aperture, 50um particle diameter, 240 * 4.0cm I.D.); Flow velocity is 25ml/min, and water/methyl alcohol carried out gradient elution as eluent in 100: 0～0: 100 from volume ratio; Collect the cut Fr.1-1 (1.57g) that 30: 70 gradient elutions of water/methyl alcohol volume ratio get off, after LH-20 gel column (2.5*100cm), with chloroform/methanol volume ratio 1: 1 as the moving phase wash-out; Flow velocity is 1ml/min, and every 100ml collects and merges into portion, and order obtains Fr.1-1-A-G 7 duplicate samples; Fr.1-1-C (331mg) wherein, Fr.1-1-D (626mg), Fr.1-1-E (27mg).Fr.1-1-C use the chloroform/acetone volume ratio be 9: 1 as developping agent, through the thin layer preparation, scraping and getting the Rf value is 0.8 band, eluent ethyl acetate obtains compound 2 (18.0mg) (Spiro-Indimycin B); Scraping and getting the Rf value is 0.6 band, and eluent ethyl acetate obtains compound 1 (5.0mg) (Spiro-Indimycin A); Fr.1-1-D use the petrol ether/ethyl acetate volume ratio be 40: 60 as developping agent, through the thin layer preparation, scraping and getting the Rf value is 0.8 band, eluent ethyl acetate obtains compound 3 (22.0mg) (Spiro-Indimycin C); Fr.1-1-E use the petrol ether/ethyl acetate volume ratio be 50: 50 as developping agent, through the thin layer preparation, scraping and getting the Rf value is 0.8 band, eluent ethyl acetate obtains compound 4 (6.6mg) (Spiro-Indimycin D).
Through structural analysis, 4 the compound 1-4-compound S piro-Indimycin A-D (formula (II)) that from the fermenting culture of streptomycete (Streptomyces sp.) SCSIO 03032, prepare of the present invention are identified that to it its qualification result is following:
Compound 1: white crystal, its nuclear magnetic data ownership is as shown in table 1,
UV (MeOH) λ
Max(log ε) 272nm (4.05); 227nm (4.40); IR (KBr) λ
Max3443,1725,1229cm
-1 1H NMR (500MHz, CD
3OD) see table 1,
13C NMR (125MHz, CD
3OD) see table 2.High resolution mass spectrum HRESIMS m/z C
24H
15Cl
2N
3O
3(measured value [M-H]
-478.0353 calculated value is 478.0361), degree of unsaturation is 18.The hydrogen of compound 1 spectrum show 2 methoxyl groups [δ H 3.53 (and 3H, s), 4.00 (3H, s)], 7 fragrant protons, 2 reactive hydrogens [δ H 11.47 (1H, s), 12.20 (1H, brs)].
13C NMR and DEPT NMR show 2 carbonyl carbon [δ C 159.6 (s), 160.3 (s)], 13 quaternary carbons, 7 methine carbons, 2 methyl carbon.The hydrogen spectrum C spectrum of compound 1 is compared [McArthur, K.A. with known compound Lynamicin D; Mitchell, S.S.; Tsueng, G.; Rheingold, A.; White, D.J.; Grodberg, J.; Lam, K.S.; Potts, B.C.Lynamicins A-E, chlorinated bisindole pyrrole antibiotics from a novel marine actinomycete; J Nat Prod, 2008,71; 1732-7.]; Find that the two is extremely similar, difference is: compound 1 is few 2 hydrogen in molecular formula, simultaneously more degrees of unsaturation; Many 1 sp in the carbon spectrum of compound 1
3Hydridization quaternary carbon, few sp among the Lynamicin D simultaneously
2The quaternary carbon of hydridization; The chemical shift of C-2 ' in the compound 1 is the low (δ of deflection obviously
C169.2).Infer the C-3 ' of compound 1 and C-5 " linking to each other is connected into ring, and the conjugation of former C-2 ' and between C-3 ' existence shifts simultaneously, becomes a conjugation of between C-2 ' and N-1 ' according to above evidence.Infer that more than the X-ray (Fig. 4) through compound 1 further proves.And the chlorine atom that exists in the molecule makes X-ray clearly the absolute configuration of compound 1 to be confirmed as C-3 ' S configuration.The structure of compound 1 is suc as formula shown in (II), called after Spiro-Indimycin A.
Compound 2: white crystal.[α]
20 D+169.2(c?0.67，MeOH)；UV(MeOH)λ
max(logε)252nm(4.77)；209nm(4.66)；IR(KBr)λ
max3418，1695，1284cm
-1。The negative ion high resolution mass spectrum provides [M-H] at 436.0602 places
-The peak, (calculated value is 436.0620), the molecular formula that combined carbon spectrum, hydrogen spectrum draw this compound is C
23H
16Cl
2N
3O
2, include 16 degrees of unsaturation.The 1D NMR of compound (
1HNMR (500MHz, CD
3OD) see table 1,
13C NMR (125MHz, CD
3OD) see table 2.) there is following signal in the prompting hydrogen spectrum: 1 n-formyl sarcolysine base [δ
H2.88 (1H, s)], 1 oxygen methyl [δ
H3.36 (3H, s)], 7 methine protons, 1 methene proton [δ
Ha3.63 (1H, d, J=8.5Hz) and δ
Hb4.06 (1H, d, J=8.5Hz)] and 2 tradable protons; There is following signal in the carbon spectrum: 1 carbonyl carbon, 13 quaternary carbons (comprising the quaternary carbon of 12 sp2 hydridization and the quaternary carbon of 1 sp3 hydridization), 7 methine carbons, 1 mesomethylene carbon, 1 oxygen methyl carbon and 1 n-formyl sarcolysine base carbon.Comparative compound 2 and known compound Lynamicins A [McArthur, K.A.; Mitchell, S.S.; Tsueng, G.; Rheingold, A.; White, D.J.; Grodberg, J.; Lam, K.S.; Potts, B.C.Lynamicins A-E, chlorinated bisindole pyrrole antibiotics from a novel marine actinomycete; J Nat Prod, 2008,71; 1732-7.] hydrogen spectrum carbon spectrum data; Find that the two is similar, prompting compound 2 and compound L ynamicins A similar also belong to bisindole alkaloid.Exist in the hydrogen of compound 2 spectrum two ABX coupling systems (H-5 '/H-7 '/H-8 '; H-5 "/H-7 "/H-8 "), similar with Lynamicins A, be illustrated in and exist two 1,2 in the compound 2,4-trisubstituted benzene ring is 1a and 1b (formula (III)) with its ownership respectively.Further, the 1a fragment is set up through following HMBC is relevant: from H-5 ' to C-6 '/and C-7 '/C-9 '; From H-7 ' to C-5 '/C-9 '; From H-8 ' to C-6 '/C-4 (the above relevant chlorine that shows simultaneously replaces in C-6 ' position) and from H-2 ' to C-3 '/C-4 '/C-9 '.The n-formyl sarcolysine matrix of H-10 ' position [δ H 2.88 (s)] navigates to the segmental N-1 ' of 1a to this n-formyl sarcolysine base to the HMBC of C-2 ' [δ C 64.3 (t)] and C-9 ' [δ C 151.9 (s)] is relevant.The 1b fragment obtains through following HMBC: from H-5 " to C-3 "/C-7 "/C-6 "/C-9 ", from H-7 " to C-5 "/C-6 "/and from H-8 " to C-3 "/C-5 "/C-4 "/C-6 "/C-9 ".The 1c fragment is relevant by following HMBC: H-2 is to relevant the obtaining of COSY of C-3/C-4/C-5 and H-2/NH-1.Remove this, from H-2 to C-3 " the relevant prompting of weak HMBC methoxy acyl group replace in the C-5 position.Different with known compound Lynamicins A is; Compound 2 forms 5/5 a rare volution; Crucial HMBC is relevant: H-2 ' [δ H 3.63 (d)] is to C-3 [δ C 140.1 (s)], and H-2 ' [δ H 4.06 (d)] supports the formation of spirane structure to C-2 " [δ C 154.5 (s)] and H-2 [δ H6.91 (d)] are to C-3 " [δ C 112.1 (s)].More than the structure of compound 2 is inferred the further proof by X-ray (Fig. 5), and the chlorine atom that exists in the molecule makes X-ray clearly the absolute configuration of compound 2C-3 ' to be confirmed as the R configuration.The structure of compound 2 is suc as formula shown in (II), called after Spiro-Indimycin B.
Compound 3: white solid, its nuclear magnetic data ownership is as shown in table 1.
UV (MeOH) λ
Max(log ε) 251nm (4.44); 210nm (4.63); IR (KBr) λ
Max3417,1701,1285cm
-1 1H NMR (500MHz, CD
3OD) see table 1,
13C NMR (125MHz, CD
3OD) see table 2.HRESIMS m/z [M-H]
-422.0499 (calcd for C
22H
14Cl
2N
3O
2422.0463), its molecular formula and compound 2 differ a methyl, anatomize H-spectrum, the C-spectrum, HSQC and HMBC spectrum, draw compound 3 and be compound 2 disappearances 1 '-homologue of N methyl, its structure is suc as formula shown in (II), called after Spiro-Indimycin C.
Compound 4: white solid, its nuclear magnetic data ownership is as shown in table 1.
UV (MeOH) λ
Max(ε) 266nm (4.23); 243nm (26373); 208nm (4.48); IR (KBr) λ
Max3307,1718,1268cm
-1 1H NMR (500MHz, CD
3OD) see table 1,
13C NMR (125MHz, CD
3OD) see table 2.HRESIMS?m/z[M-H]
-494.0661，(calcd?for?C
25H
18Cl
2N
3O
4，494.0674)。The hydrogen spectrum of compound 4 is compared with compound 2 with the carbon spectrum, found also to find the sp of the C-2 position in 2 than more than 2 methyl esters groups of compound
2The methine carbon of hydridization [δ H 6.91 (d, J=3.0Hz, H-2); δ C 110.3 (d, C-2)] by sp
2The quaternary carbon of hydridization [δ C 111.5 (s, C-2)] replaces, and 2 methyl esters that this explanation compound 4 is compounds 2 replace analogs, and its structure is suc as formula shown in (II), called after Spiro-Indimycin D.
Table 1: compound 1-4's
1H-NMR nuclear magnetic data ownership (data are measured in 500MHz, are coupling constant (Hz) in the bracket)
aSample is dissolved in DMSO and detects;
bSample is dissolved in CDCl
3Detect
Table 2: compound 1-4's
13C-NMR nuclear magnetic data ownership (data are measured in 125MHz)
aSample is dissolved in DMSO and detects;
bSample is dissolved in CDCl
3Detect
The determination of cytotoxic activity of embodiment 3:Spiro-Indimycin A-D
Spiro-Indimycin A-D is directed against seven kinds of tumor cell lines: human breast carcinoma MCF-7 cell; Human pancreas cancer 1990, human liver cancer cell HepG2, human cervical carcinoma Hale; Humanmachine tumour B16 cell; People's lung cancer H460 cell and people's acute lymphoblastic leukemia T lymphocyte CCRF-CEM have carried out determination of activity, experimental technique reference [Wu, Z.C.; Li, D.L.; Chen, Y.C.; Zhang; W.M.; A new isofuranonaphthalenone and benzopyrans from the endophytic fungus Nodulisporium sp.A4 from Aquilaria sinensis.Helv.Chim.Acta 2010,93, (5); 920-924.], with Staurosporine as contrast.
Its result is as shown in table 3; The result shows the selective cytotoxic activity of Spiro-Indimycin A-D, and wherein Spiro-Indimycin B is to the IC of Humanmachine tumour B16 cell, people's lung cancer H460 cell and people's acute lymphoblastic leukemia T lymphocyte CCRF-CEM
50Be respectively 11 μ M, 36.6 μ M and 4.5 μ M, and other subject cell strain is not had obvious GIA; Spiro-Indimycin C is to the IC of human liver cancer cell HepG2 and people's lung cancer H460 cell
50Be respectively 14.1 μ M and 35.4 μ M, and other subject cell strain is not had obvious GIA; Spiro-Indimycin D is to human liver cancer cell HepG2, the IC of Humanmachine tumour B16 cell and people's lung cancer H460 cell
50Be respectively 44.4 μ M, 40.4 μ M and 36.3 μ M, and other subject cell strain is not had obvious GIA; Spiro-IndimycinA is to the IC of people's acute lymphoblastic leukemia T lymphocyte CCRF-CEM
50Be 44.4 μ M, other subject cell strain is not had obvious GIA; Staurosporine compares with positive control, and Spiro-Indimycin A-D is to the optionally restraining effect that shows as of seven kinds of cells being surveyed, and its activity is stronger, and being expected exploitation through biotechnology or chemically modified becomes anti-cancer agent.
The CTA of table 3:Spiro-Indimycin A-D
Annotate :-IC
50＞100 μ g/ml
Claims (10)
1. streptomycete (Streptomyces sp.) SCSIO 03032, its deposit number is CCTCC NO:M 2011258.
2. compound S piro-Indimycin A-D, its structural formula is suc as formula shown in (I):
3. the application of the described compound S piro-Indimycin of claim 2 A-D in the preparation antitumor drug.
4. application according to claim 3 is characterized in that, the application of described compound S piro-Indimycin A in preparation treatment people acute lymphoblastic leukemia medicine.
5. application according to claim 3 is characterized in that, the application of described compound S piro-Indimycin B in preparation treatment Humanmachine tumour, people's lung cancer or people's acute lymphoblastic leukemia medicine.
6. application according to claim 3 is characterized in that, the application of described compound S piro-Indimycin C in preparation treatment people's liver cancer or people's lung-cancer medicament.
7. application according to claim 3 is characterized in that, the application of described compound S piro-Indimycin D in preparation treatment Humanmachine tumour, people's liver cancer or people's lung-cancer medicament.
8. the described streptomycete of claim 1 (Streptomyces sp.) SCSIO 03032 is in the application that is used to prepare compound S piro-Indimycin A, B, C or D.
9. the preparation method of a compound S piro-Indimycin A, B, C or D; It is characterized in that described compound S piro-Indimycin A, B, C or D are that preparation separates and obtains in the fermenting culture of Accessory Right requirement 1 described streptomycete (Streptomyces sp.) SCSIO 03032.
10. preparation method according to claim 9 is characterized in that concrete steps are following:
A) fermenting culture of preparation streptomycete (Streptomyces sp.) SCSIO 03032; The fermented liquid and the mycelium of this fermenting culture are separated; Fermented liquid is through macroporous resin adsorption; The back is with acetone wash-out macroporous resin, and the remainder water mixed solution was used ethyl acetate extraction after elutriant reclaimed acetone, and ethyl acetate layer obtains extractum A through distilling after concentrated; Mycelium use earlier acetone extraction, and the remainder water mixed solution was used ethyl acetate extraction again after leaching liquid reclaimed acetone, and ethyl acetate layer obtains medicinal extract B through distilling after concentrated;
B) crude extract that extractum A and medicinal extract B is merged as eluent, carried out gradient elution in 100: 0～0: 100 from volume ratio with chloroform/methanol through silica gel column chromatography; Collect the cut Fr.1 that 95: 5 gradient elutions of chloroform/methanol volume ratio get off, after ODS anti-phase medium pressure liquid chromatography, water/methyl alcohol is as eluent; Carried out gradient elution in 100: 0～0: 100 from volume ratio, collect the cut Fr.1-1 that 30: 70 gradient elutions of water/methyl alcohol volume ratio get off, after the LH-20 gel column; With chloroform/methanol volume ratio 1: 1 as the moving phase wash-out; Follow the trail of to separate with thin-layer chromatography, collecting and using the chloroform/acetone volume ratio on the thin layer plate is that 9: 1 values of Rf during as developping agent are 0.8 cut, is Spiro-Indimycin B; The Rf value is 0.6 cut, is Spiro-Indimycin A; Collecting and using the petrol ether/ethyl acetate volume ratio on the thin layer plate is that 40: 60 values of Rf during as developping agent are 0.8 cut, is Spiro-Indimycin C; Collecting and using the petrol ether/ethyl acetate volume ratio on the thin layer plate is that 50: 50 values of Rf during as developping agent are 0.8 cut, is Spiro-Indimycin D.
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| PCT/CN2012/074013 WO2013143184A1 (en) | 2012-03-28 | 2012-04-13 | Streptomyces, and anti-tumor compounds spiro-indimycin a-d and preparation method and application thereof |
| JP2014541509A JP5826406B2 (en) | 2012-03-28 | 2012-04-13 | Streptomyces, antitumor compound Spiro-Indymycin AD, production method and use thereof, and antitumor agent and drug containing spiroindimycin |
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| CN116199695B (en) * | 2022-08-30 | 2024-05-28 | 浙江大学 | Citrinin derivative, and preparation method and application thereof |
| CN115177616B (en) * | 2022-09-13 | 2022-11-11 | 中国农业科学院农产品加工研究所 | Application of streptomyces bricorubidus extract in preparation of anti-aging product |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101126074A (en) * | 2007-07-13 | 2008-02-20 | 东南大学 | Marine streptomycete with antineoplastic activity and culture method thereof |
| CN102295562A (en) * | 2011-07-01 | 2011-12-28 | 中国科学院微生物研究所 | Antineoplastic compound, its preparation method and applications |
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| CN101126074A (en) * | 2007-07-13 | 2008-02-20 | 东南大学 | Marine streptomycete with antineoplastic activity and culture method thereof |
| CN102295562A (en) * | 2011-07-01 | 2011-12-28 | 中国科学院微生物研究所 | Antineoplastic compound, its preparation method and applications |
Non-Patent Citations (4)
| Title |
|---|
| KATHERINE A. MCARTHUR ET AL.: "Lynamicins A-E, Chlorinated Bisindole Pyrrole Antibiotics from a Novel Marine Actinomycete", 《J. NAT. PROD》 * |
| XIN-PENG TIAN ET AL.: "Streptomyces nanshensis sp. nov., isolated from the Nansha Islands in the South China Sea", 《INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY》 * |
| XUHUA MO ET AL.: "Cloning and characterization of the biosynthetic gene cluster of the bacterial RNA polymerase inhibitor tirandamycin from marine-derived Streptomyces sp.SCSIO1666", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
| 谷晓辉 等: "新型海洋双吲哚类生物碱的研究进展", 《有机化学》 * |
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| CN111732579A (en) * | 2020-06-04 | 2020-10-02 | 中国科学院南海海洋研究所 | Polyether polyketone compound polydecaminmycin and preparation method and application thereof |
| CN111732579B (en) * | 2020-06-04 | 2021-06-29 | 中国科学院南海海洋研究所 | Polyether polyketone compound polydecaminmycin and preparation method and application thereof |
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