CN1298722C - Indole carbazole alkaloid and its preparing method and use - Google Patents
Indole carbazole alkaloid and its preparing method and use Download PDFInfo
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- CN1298722C CN1298722C CNB2005100514379A CN200510051437A CN1298722C CN 1298722 C CN1298722 C CN 1298722C CN B2005100514379 A CNB2005100514379 A CN B2005100514379A CN 200510051437 A CN200510051437 A CN 200510051437A CN 1298722 C CN1298722 C CN 1298722C
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Abstract
The present invention relates to novel indole carbazole alkaloid, a preparation method and an application thereof. The present invention prepares an indole carbazole alkaloid compound with a novel chemical structure by fermenting Actinomycesa lmadurae of a sea source. By the experiment verification, the indole carbazole alkaloid compound can be used as a cell cycle inhibitor or a tumor cell proliferation inhibitor or an antineoplastic agent.
Description
Technical field:
The present invention relates to novel indole carbazole alkaloid compounds, by the method for this indole carbazole alkaloid compounds of Actinomycesa lmadurae Actinomadurasp.007 fermentative preparation of marine source, and the purposes of this compounds in preparation cell cycle inhibitor, tumor cell proliferation inhibitor or antineoplastic agent.
Background technology:
Indole carbazole Alkaloid Staurosporine (staurosporine) separates report (S.Omura, Y.Iwai, A.Nalagawa, et al., J.Antibiot., 1977,30,275 in streptomycete AM-2282 product; A.Furusaki, N.Hashiba, T.Matsumoto, et al., J.Chem.Soc.Chem.Comm., 1978, found to have multiple important biological 800-801) successively, as antibiotic, vasodilation, cytotoxic activity and inhibition platelet aggregation and arrestin kinase c etc.Because the Staurosporine aglycon is to the significant (D.Meksurriyen of its associated biomolecule activity, G.A.Cordell, J.Nat.Prod.1988,51,884-892), thereby with the Staurosporine aglycon is that the indole carbazole alkaloid compounds of parent receives very big concern as the important biological molecule.
The indole carbazole alkaloid compounds that contains Staurosporine aglycon skeleton is main in addition with Staurosporine, K-252a (H.Kase, K.Iwahashi, Y.Matsuda except non-glycoside derivative, J.Antibiot., 1986,39,1059-1065) and K-252d (T.Yasuzawa, T.Iida, M.Yoshida, et al., J.Antibiot., 1986,39,1072-1078) be the glycosides compound of three types of representative.This four big indole carbazole alkaloid compounds has all separated from nature and has obtained, and hundreds of glycoside derivatives also by synthetic (a golden well literary composition man of virtue and ability, Net city a surname is kind, the male will in northern village, etc., WO01/004125, international open day January 18 calendar year 2001; マ イ ケ Le イ one Le イ ス, コ ラ ネ Off, ジ Le ロ バ one Star-Le イ ス waits ， Te Open 2003-113184).But do not see as yet that so far relevant sugar encircles the report of going up and the similar thing of the natural Staurosporine of heterocyclic being arranged.In addition, analyze (A.Furusaki, N.Hashiba, T.Matsumoto, et al., J.Chem.Soc.Chem.Commun., 1978,800-801 through X-line single crystal diffraction; N.Funato, H.Takayanagi, Y.Konda, et al., Tetreahedron Lett., 1994,35,1251-1254) and nuclear magnetic resonance research (P.D.Davis, C.H.Hill, W.A.Thomas, et al., J.Chem.Soc.Chem.Commun., 1991,182-184), determined the configuration of pyranoid ring in solid-state and solution state of Staurosporine and analogue thereof, be that free alkali is got the chair form configuration, 4 '-N then got boat conformation (wherein O-1 ' and C-4 ' they are forward andor aft) by protonated salt.But do not see as yet that so far pyranoid ring is got C-2 ' and C-5 ' is the compound of the boat conformation of forward andor aft.
Summary of the invention:
The present invention aims to provide the compound with anti-tumor activities such as cell cycle inhibition, tumor cell proliferation inhibition of the new chemical structure of a class, particularly, be to provide a kind of in sugar ring 3 ' and 4 ' position and oxaza, sugared pyranoid ring get C-2 ' and the C-5 ' Staurosporine compounds for the boat conformation of forward andor aft.
The present invention also aims to provide the preparation method of such new compound.
Another object of the present invention is to provide the purposes of such new compound in preparation cell cycle inhibitor, cell death inducer, tumor cytotoxicity agent, tumor cell proliferation inhibitor or antineoplastic agent.
The present invention has found a kind of new indole carbazole alkaloid class formula I compound first from the nature microorganism fermented product:
Formula I
Among the formula I, R
1, R
2, R
4, R
5, R
6, R
7All can be hydrogen, hydroxyl,-oxyl, acyloxy, amino, amido; R
3And R
8Can be hydrogen, alkyl, hydroxyl, acyl group.
Preferred The compounds of this invention is R
1, R
2, R
3, R
4, R
5, R
6, R
7Be hydrogen, R
8Formula I compound for methyl.
Its most significant constructional feature of compound provided by the present invention is: in sugar ring 3 ' and 4 ' and position and oxaza and pyranoid ring get C-2 ' and the C-5 ' boat conformation for forward andor aft.
The preparation method of formula I compound of the present invention is, can produce the microorganism of indole carbazole alkaloid compounds by fermentation culture, as actinomycetes 007 strain, at first obtain the tunning that contains formula I compound, the separating and purifying technology that utilizes the relevant speciality technician to know again, as liquid-liquid extraction, column chromatography, high performance liquid phase etc., purifying preparation and the formula of acquisition I compound.
Enumerated in the embodiments of the invention and utilized actinomycetes 007 strain to prepare preferred formula I examples for compounds of the present invention.
This actinomycetes 007 strain is by separating from the ooze sample of coastal waters, Qingdao, and is accredited as a strain microorganism Actinomadura sp.007 of actinomadura through means of taxonomic research.This bacterial strain has been deposited in Chinese typical culture collection center (deposit number: CCTCC M204076) on December 13rd, 2004.This Actinomycesa lmadurae Actinomadura sp.007CCTCCM204076 strain has following microorganism mycology feature (seeing Table 1):
The microorganism mycology feature of table 1 007 bacterial strain
| Test item | The result | Test item | The result |
| Colony diameter (um) surface color matrix pigment aerial hyphae fibrillae of spores forms the spore chain sporangiocyst and forms spore surface Tween 80 adonitol PEARLITOL 25C D-MANNOSE D-R D-arabitol D-cellobiose galactolipin D-galacturonic acid m-inositol N-ACETYL-D-GLUCOSAMINE gentiobiose | 2.0 the light brown luxuriant slightly straight song of～3.1 whites++ smooth++++++++-+-+ | Starch D-wood sugar maltose alpha-D-glucose L-rhamnose wheat tooth trisaccharide melibiose D-Fructose D-lactose D-gossypose D-Ah tyrosol sugar D-melezitose trehalose bromination butanedioic acid decanedioic acid butanedioic acid methyl succinate glycerine altheine D-L-alpha-phosphate glycerine | + + + + + + + + + + + + + - - + + - - - |
Of particular note, the method of producing formula I compound of the present invention through organism of fermentation can adopt other any microorganism that can produce the indole carbazole alkaloid compounds, all can be used as and produces plain bacterium and be used for preparation I compound as long as can produce the microorganism of this compounds.
The present invention adopts lissamine rhodamine B (sulforhodamine B, SRB) method, tetrazolium (MTT) reduction method and flow cytometry detect the method for cell morphological characteristic in conjunction with microscopically, test evaluation formula I compound of the present invention to cell inhibitory effect, cell cycle inhibition and the apoptosis-inducing of mouse breast cancer tsFT210 cell, people's lung cancer A549 cell, human hepatocellular carcinoma BEL-7402 cell, mouse leukemia P388 cell, human leukemia HL60 cell and to the effects such as direct killing of tumour cell.Experiment confirm, formula I compound can be by suppressing the cell cycle turnover, bring out cancer cell-apoptosis or mode such as directly killing and wounding to tumour cell, show the biologic activity that suppresses tumor cell proliferation, thereby bring into play its antitumor action, especially people's lung cancer A549 cell is had very strong anti-tumor activity.
The acceptable various carriers of formula I compound of the present invention and medicine, vehicle or supplementary product compatibility can be made into antitumor drugs such as doing cell cycle inhibitor or tumor cytotoxicity agent, are used for tumor treatment.
Formula I compound of the present invention also can be used as the low molecular biosciences probe that suppresses the cell cycle and is used for life science.When wushu I compound is used for life science as cell cycle inhibitor, dissolve in methyl alcohol or the aqueous methanol, also dissolve in the aqueous solution of dimethyl sulfoxide (DMSO) and be applied.
Embodiment:
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The chemical structure of the Compound I of indication is in following embodiment: formula I compound, wherein R
1, R
2, R
3, R
4, R
5, R
6, R
7Be hydrogen, R
8Be methyl, pyranoid ring gets C-2 ' and C-5 ' is the boat conformation of forward andor aft:
Formula I
The fermentative production and the separation and purification of embodiment 1 Compound I
1 fermentative production
Produce the ordinary method of the fermentation culture of plain bacterium by culturing micro-organisms, it is an amount of to get Actinomycesa lmadurae Actinomadura sp.007 CCTCC M204076, is inoculated on the synthetic No. 1 agar solid slant culture base of Gao Shi, cultivates 7 days in 28 degrees centigrade of incubators.
It is an amount of to get 7 days Actinomycesa lmadurae Actinomadura sp.007 CCTCC M204076 of slant culture, is inoculated into one and contains 100 milliliters of seed culture fluids (substratum composition: glucose 20.0 grams, K
2HPO
40.5 gram, MgSO
40.5 gram, extractum carnis 3.0 grams, corn steep liquor 3.0 grams, yeast extract paste 10.0 grams, starch 10.0 grams, CaCO
32.0 gram, 1 liter of artificial seawater is transferred pH 7.0) Erlenmeyer flask in, shaking table was cultivated 48 hours under 28 ℃, 120 rev/mins conditions, obtained seed culture fluid.Get this seed culture fluid, be inoculated in respectively in the Erlenmeyer flask of adorning 100 milliliters of production nutrient solutions (substratum is formed the same) in 100 by 5% inoculum size, be loaded into the production fermentation of 28 ℃, 120 rev/mins 7 days enterprising behavior phases of shaking table, obtain to contain the fermented product of indole carbazole alkaloid class target compound.The same terms bottom fermentation twice obtains about 20 liters of fermented product altogether.
2 contain the preparation of the thalline crude extract of Compound I
Fermented product (about 20 liters) suction filtration with above-mentioned Actinomycesa lmadurae Actinomadura sp.007 CCTCC M204076, leaching thalline part, also at room temperature stir the extraction of spending the night with 1.5 liter of 80% aqueous acetone solution immersion, 4000 rev/mins centrifugal 15 minutes, get supernatant liquor, be evaporated to and do not contain acetone, the gained water layer is with equal-volume ethyl acetate extraction three times, combined ethyl acetate extraction liquid concentrating under reduced pressure must contain the thalline crude extract (4.8 gram) of Compound I.
The separation and purification of 3 Compound I
Get the thalline crude extract (4.8 gram) of the Actinomadura sp.007 CCTCC M204076 that contains Compound I, mix sample with adding 20 gram 200-300 order silica gel Hs (Qingdao Haiyang Chemical Industry Group Corp.'s product) after the dissolving of chloroform-methanol mixed solvent, add to and be filled with on the glass decompression post of 50 gram Qingdao Haiyang Chemical Industry Group Corp. product thin-layer chromatographies with silica gel H, with chloroform → chloroform-methanol mixed solution is eluent, and column chromatography reduces pressure.The polarity of eluting solvent comes gradient to increase progressively by the consumption that improves methyl alcohol in the chloroform, each wash-out stream share receives 150 milliliters respectively, according to thin-layer chromatography and active detected result, merge, obtain containing the active constituent Fr-3 (520 milligrams, 98: 2 → 85: 15 eluates of chloroform-methanol) of Compound I.With Fr-3 with silica gel H decompression post on the method, with sherwood oil-acetone mixed solution is eluent, column chromatography reduces pressure, through thin-layer chromatography and active the detection, merge related streams part, obtain target compound part,, obtain containing the target components Fr-3-6 of Compound I again through SephadexLH-20 column chromatography for separation (5: 5 wash-outs of chloroform-methanol) with sherwood oil-acetone (5: 5) wash-out.With reverse phase silica gel RP-18 decompression post on this component Fr-3-6 dry method, with methanol-water mixed solvent wash-out, detect merging through HPLC, obtain the Compound I crude product, again through partly preparing HPLC (Capcell Pak C
18Post, 5 μ m, 20 * 250mm; Moving phase 40% acetonitrile-water, flow velocity 4 ml/min detect wavelength 288 nanometers) the purifying preparation, get the pure product of Compound I (15 milligrams, retention time 15 minutes).
The faint yellow crystallization of Compound I (chloroform-methanol), mp 283.4-285.5 ℃, [α]
D 20+ 83.2 (c 0.10, MeOH), and molecular formula C
28H
22N
4O
4Positive ion TOF-MS m/z:479[M+H]
+Positive ion HR-TOF-MS: measured value 479.1704, C
28H
23N
4O
4[M+H]
+Calculated value 479.1719.UVλ
max MeOHnm(ε)：232(19613)，243(19020)，275(19720)，290(33212)，318(9936)，332(9636)。IR (KBr) v
MaxCm
-1: 3377 (NH), 2924,2935 (CH
2), 1739 (oxazolone C=O), 1677 (lactan C=O), 1589,1458,1399,1354,1321,1275,1228,1150,1133,1105,1030,774,751.
1H reaches
13C NMR data see Table 2.
Table 2 Compound I at deuterium for the 600MHz among the DMSO
1H and 150MHz
13C NMR data
| No. | δ H(Jin Hz) | COSY | NOE’s | δc | HMBC |
| 1 2 | 7.79br d(8.4) 7.53ddd(8.4，7.6，1.1) | H-2 H-1，H-3 | 108.74d 125.51d | C-2，C-3，C-4a C-1，C-3，C-4， C-13a |
| 3 4 4a 4b 4c 5 NH 7 7a 7b 7c 8 9 10 11 11a 12a 12b 13a 2′ 3′ 4′ 5′ 6′ 2′-CH 3 N-CH 3 1″ | 7.32br t(7.6) 9.25br d(7.6) - - - - 8.71br s Ha 5.03d(17.2) Hb 4.99d(17.2) - - - 8.05br d(7.4) 7.39br t(7.4) 7.52ddd(8.5，7.4，1.1) 8.07br d(8.5) - - - - - 5.30d(8.8) 4.34ddd(12.0，8.8，5.3) Ha 2.01ddd(13.6，12.0，10.0) He 2.93ddd(13.6，6.0，5.3) 6.97dd(10.0，6.0) 2.03s 2.59s - | H-2，H-4 H-3 Hb-7 Ha-7 H-9 H-8，H-10 H-9，H-11 H-11 H-4′ H-3′，Ha-5′，He-5′ H-4′，He-5′ H-4′，Ha-5′ Ha-5′，He-5′ | H-4′ H-3′，H-6′ H-4′，Ha-5′， H-6′，N-CH 3 H-1，H-4′，He-5′ | 119.62d 125.79d 122.39s 115.81s 120.31s 171.62s - 45.51t 132.98s 115.44s 124.61s 121.24d 120.98d 124.98d 116.65d 140.36s 128.60s 124.61s 136.43s 92.52s 75.41d 52.07d 28.75t 79.18d 29.56q 28.25q 155.66s | C-1，C-2，C-4， C-4a，C-13a C-1，C-2，C-3， C-4b，C-13a C-4b，C-4c，C-5， C-7，C-7a，C-7b C-4，C-5，C-7a，C-7b C-4，C-5，C-7a，C-7b C-7b，C-10，C-11a C-7c，C-8，C-11，C-11a C-8，C-9，C-11，C-11a C-7c，C-9，C-10 C-2′，2′-CH 3，C-4′， C-5′，C-1″ C-2′，C-3′，C-1″ C-3′，C-4′，C-6′ C-3′，C-4′，C-6′ C-2′，C-5′，C-12b， C-13a C-2′，C-3′ C-4′，C-1″ |
The anti tumor activity in vitro test of embodiment 2 Compound I
1 laboratory sample and experimental technique
The preparation specimen of sample solution is the pure product of Compound I of separation and purification in the foregoing description 1.Precision takes by weighing an amount of sample, is mixed with the solution of desired concn with methyl alcohol, and is active for surveying.
The succeeding transfer culture of clone and cell adopts cancerous cell lines such as people's lung cancer A549 cell, human hepatocellular carcinoma BEL-7402 cell, human leukemia HL60 cell, mouse breast cancer tsFT210 cell and mouse leukemia P388 cell.Various cells are all with the RPMI-1640 substratum that contains 10%FBS, at 32 ℃ (tsFT210 and P388 cells) or at 37 ℃ (A549, HL60 and BEL-7402 cells) succeeding transfer culture in the incubator that feeds 5% carbonic acid gas.
The cell inhibitory effect activity test method
People's lung cancer A549 cell that lissamine rhodamine B (SRB) method is taken the logarithm vegetative period, human hepatocellular carcinoma BEL-7402 cell or mouse breast cancer tsFT210 cell, being mixed with density with fresh RPMI-1640 substratum is every milliliter 2 * 10
5The cell suspension of individual cell is inoculated in 96 orifice plates by every hole 200 microlitres, and every hole adds the sample or the blank solution of 2 microlitre different concns, 32 ℃ of following 17 hours (tsFT210 cell) or 24 hours (A549 or BEL-7402 cells) of 37 ℃ of following cultivations cultivated.Get it filled under the thing effect cell after cultivating, at first under opticmicroscope, observe the morphological change that drug treating causes, judge to have or not the cell cycle to suppress the morphological feature of apoptosis or necrocytosis, then 4 ℃, 3000 rev/mins centrifugal 3 minutes, inhale and to remove supernatant.Add 20% Tricholroacetic Acid, 50 microlitres in every porocyte, place 4 ℃ to fix 1 hour, water flushing 5 times and dry air.Every hole adds acetum 50 microlitres of 0.4%SRB and left standstill 30 minutes in room temperature.Clean 4 times with 1% acetic acid water, remove unconjugated free SRB dyestuff.Every hole adds 150 microlitre Tris damping fluids (10mmol/L, pH 10.5) soluble protein combination dye and utilizes MD company to produce SPECTRA MAX Plus type microplate reader and measure optical density(OD) (OD) value of every hole at the 520nm place.Each concentration of sample all is provided with three holes in same 96 orifice plate, and other establishes three hole blanks and acellular zeroing hole (if medicine has color will do the acellular zeroing of relative medicine concentration).Each hole OD value is done corresponding acellular zeroing earlier, gets the average OD value in three holes again by IR%=(OD
Blank-OD
Sample)/OD
Blank* 100% formula is calculated the cell proliferation inhibition rate (IR%) under each concentration.
Human leukemia HL60 cell that tetrazolium (MTT) method is taken the logarithm vegetative period and mouse leukemia P388 cell transfer to every milliliter 2 * 10 with cell density
5Individual cell is inoculated in the 96 porocyte culture plates by every hole 200 microlitres, feeds 5%CO in 37 ℃
2Incubator in cultivated 4 hours.Every hole adds each 2 microlitre of sample liquid or blank solution, cultivates after 24 hours, and every hole adds MTT liquid (every milliliter of 5 milligrams of normal saline solutions of MTT) 10 microlitres, continue to cultivate 4 hours, 37 ℃, 2000 rev/mins centrifugal 8 minutes, supernatant is removed in suction.Every hole adds each 100 microlitre of DMSO, and vibration is 15 minutes on micro oscillator, after dissolving fully to crystallization, utilizes MD company to produce SPECTRA MAX Plus type microplate reader and measures the light absorption value (OD value) of every hole at the 570nm place.Each concentration of sample all is provided with three holes in same 96 orifice plate, and other establishes three hole blanks and acellular zeroing hole (if medicine has color will do the acellular zeroing of relative medicine concentration).Each hole OD value is done corresponding acellular zeroing earlier, gets the average OD value in three holes again by IR%=(OD
Blank-OD
Sample)/OD
Blank* 100% formula is calculated the cell proliferation inhibition rate (IR%) under each concentration.
Flow cytometry
The tsFT210 cell of taking the logarithm vegetative period, being mixed with density with fresh RPMI-1640 substratum is every milliliter 2 * 10
5The cell suspension of individual cell is inoculated in 24 orifice plates by 0.5 milliliter in every hole, and every hole adds the sample solution of 5 microlitre different concns, cultivates 17 hours down for 32 ℃.Get it filled under the thing effect cell after cultivating is at first observed the morphological change that drug treating causes under opticmicroscope, judge to have or not the cell cycle to suppress that the morphological feature of apoptosis or necrocytosis is taken pictures in case of necessity.Then cell is transferred to 1.5 milliliters of Eppendorf centrifuge tubes from 24 orifice plates respectively, 4 ℃ following 3000 rev/mins centrifugal 3 minutes, supernatant liquor is removed in suction, add 0.5 milliliter of phosphate buffer solution (PBS) concussion washing once, centrifugal collecting cell under the same terms, add 150 microlitre propidium iodide (PI) aqueous solution (in 100 ml waters, contain 5 milligrams of PI, 100 milligrams of citric acids are received and 200 milligrams of NP-40), dyeing is after 30 minutes under 4 ℃, add 150 microlitre PBS dilution, measure the content distribution of DNA in the cell with flow cytometry analysis.Cell the cell cycle each the time distribution in mutually utilize Coulter Corporation to produce computer software WinCycle to carry out analytical calculation.
2 experimental results
Compound I is to the inhibition activity of cancer cell multiplication
In the srb assay test, Compound I is respectively 28.3% and 21% to the inhibiting rate of mouse breast cancer tsFT210 cell proliferation under 21 and 2.1 micromolar concentration.
In srb assay or mtt assay test, the Compound I of different concns suppresses to the results are shown in Table 3 to the propagation of people's lung cancer A549 cell, human hepatocellular carcinoma BEL-7402 cell, human leukemia HL60 cell and mouse leukemia P388 cell.
The Compound I of table 3 different concns is to the inhibiting rate (%) of cancer cell multiplication
| Cell strain | Compound I | ||||
| 1×10 -4M | 1×10 -5M | 1×10 -6M | 1×10 -7M | 1×10 -8M | |
| A549 BEL-7402 HL60 P388 | 92.2％ 85.4％ 100.0％ 87.9％ | 86.8％ 70.0％ 100.0％ 72.5％ | 82.6％ 57.3％ 76.1％ 62.2％ | 64.2％ 13.5％ 18.2％ 14.3％ | 46.4％ 4.5％ 0％ 12.5％ |
The Flow cytometry analytical results
The flow cytometry that the tsFT210 cell records after Compound I is handled 17 hours the results are shown in Table 4.As shown in table 4, Compound I can significantly be arrested in the G2/M phase with the cell cycle of tsFT210 cell when the every milliliter 10 above concentration of microgram, also shown more weak apoptosis-inducing activity when every milliliter 100 microgram.
Table 4 tsFT210 cell after Compound I is handled 17 hours the cell cycle each the time relative distribution in mutually
| Concentration (μ g/ml) | sub-G0/G1％ | G0/G1％ | S％ | G2/M％ |
| Blank 1.0 10.0 100.0 | 0.0 0.0 0.0 0.51 | 33.8 44.2 13.3 1.2 | 59.0 55.7 34.3 43.5 | 7.2 2.0 52.4 55.4 |
Annotate: this table data system records result with flow cytometry with the tsFT210 cell after propidium iodide dyeing.
Morphologic detection result
Under the optics inverted microscope, observe, after the Compound I of high density is handled, various cancer cells are the morphological feature of typical gangrenosum acne cell in various degree, show that Compound I has certain direct killing sexual cell cytotoxic activity to mammalian cancer cells when high density.
3 conclusions
The G2/M phase that Compound I has inhibition, a cell cycle of direct killing effect and on cell proliferation to various human cancer cells and mammalian cancer cells suppresses and anti-tumor activity such as apoptosis-inducing, especially people's lung cancer A549 cell is had very strong inhibited proliferation.These results show that Compound I can be made into antitumor drugs such as cell cycle inhibitor or tumor cytotoxicity agent, are used for tumor treatment, also can be used as the low molecular biosciences probe that suppresses the cell cycle and are used for life science.
Claims (6)
1. formula I compound, wherein, R
1, R
2, R
4, R
5, R
6, R
7Be hydrogen, hydroxyl,-oxyl, acyloxy, amino or amido; R
3And R
8Be hydrogen, alkyl, hydroxyl or acyl group; Pyranoid ring gets C-2 ' and C-5 ' is the boat conformation of forward andor aft.
Formula I
2. the described formula I compound of claim 1, wherein R
1, R
2, R
3, R
4, R
5, R
6, R
7Be hydrogen; R
8Be methyl.
3. the preparation method of the described formula I compound of claim 2, it is characterized in that fermentation culture Actinomycesa lmadurae Actinomadura sp.007CCTCC M204076, obtain the fermented product that contains formula I compound, separation and purification and prepare formula I compound from this fermented product again.
4. the described formula I compound of claim 1 is in the purposes of preparation in the antitumor drug.
5. purposes according to claim 4, wherein said antitumor drug are meant cell cycle inhibitor, cell death inducer or tumor cytotoxicity agent.
6. purposes according to claim 4, wherein said antitumor drug is meant tumor cell proliferation inhibitor.
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| CN103980266B (en) * | 2014-04-02 | 2016-01-20 | 浙江大学 | A kind of compound with anti-microbial activity and preparation method thereof |
| CN110218206B (en) * | 2016-06-01 | 2022-03-04 | 中国海洋大学 | Bisindolylmaleimide derivative and preparation method and application thereof |
| CN106146475B (en) * | 2016-06-01 | 2019-05-17 | 中国海洋大学 | Bisindole maleimide derivative and its preparation method and application |
| CN107674105B (en) * | 2017-09-27 | 2020-05-22 | 杭州科兴生物化工有限公司 | Indole carbazole compound and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001004125A1 (en) * | 1999-07-13 | 2001-01-18 | Kyowa Hakko Kogyo Co., Ltd. | Staurosporin derivatives |
| CN1332157A (en) * | 2001-08-10 | 2002-01-23 | 崔承彬 | Carbazole alkaloid derivative and its prepn and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001004125A1 (en) * | 1999-07-13 | 2001-01-18 | Kyowa Hakko Kogyo Co., Ltd. | Staurosporin derivatives |
| CN1332157A (en) * | 2001-08-10 | 2002-01-23 | 崔承彬 | Carbazole alkaloid derivative and its prepn and use |
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