CN1309964A - Carbazole-alkoloid cell cycle inhibitor, cell death inducer and their preparation - Google Patents
Carbazole-alkoloid cell cycle inhibitor, cell death inducer and their preparation Download PDFInfo
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Abstract
Four carbazole-alkaloids in different structure are discovered, which may be used as cell cycle inhibitor and cell death inducer as reagent in life science research. The compounds can be used to inhibit the cell cycle of cancer, to induce cancer cell to die or kill cancer cell directly. They are prepared through ethanol extraction of Chinese wampee bark to obtain coarse concrete, organic solvent extraction, repeated column chromatography, repeated silica gel chromatography and recrystallization to separate the active components in the concrete.
Description
The present invention relates to compositions and preparation thereof that a class new compositions, particularly a class that are used for cell cycle inhibition and apoptosis-inducing contain the carbazole alkaloid derivant.
Though Bicyclomahanimbine. has some chemical compounds synthetic, but also be mainly derived from natural product mostly, and the existing people of the carbazole compound of some structure type carried out the active research of part biological, as document Tian-Shung Wu, et al, Carbazole alkaloids from Clausena excavata and their biological activity:Phytochemistry, Vol.43.No.1.pp133-140,1996 and document A.Chakraborty, et al, Carbazole alkaloid with antimicrobial activity from Clausena heptaphylla:Phytochemistry, Vol.38.No.3.pp787-789,1995 reported once that this compounds had antibacterial action and anticoagulant effect.But the biological activity of relevant natural carbazole alkaloid compounds is not seen the research report of antitumaous effects such as cell cycle inhibition and apoptosis-inducing are arranged so far.
Natural Bicyclomahanimbine. much all derives from Rutaceae (Rutaceae) Clausena (Clausena) plant.This platymiscium The Chemical Constituents report is a lot of so far, and main component is Bicyclomahanimbine. and coumarin kind compound.Congener Radix osteomelis schwerinais Clausena lansium (Lour.) Skeels Clausena dunniana Levl is the cancer that is used for the treatment of among the people in China some areas, but its chemical constituent is not particularly appeared in the newspapers so far about the research of this botanical anticancer active component.
Cell cycle suppresses and the material, particularly a class carbazole alkaloid derivant and a preparation thereof of apoptosis-inducing to the objective of the invention is to develop new being used for of a class.
The present invention finds that first the crude extract of Radix osteomelis schwerinais Clausena lansium (Lour.) Skeels has good cell cycle inhibition, apoptosis-inducing and certain active anticancers such as cell toxicant, then its relevant anticancer active constituent has been carried out systematic research, and found the Bicyclomahanimbine. of following four kinds of structure types, have cell cycle and suppress and the apoptosis-inducing effect, its structure is as follows:
With above-claimed cpd as main active, join with the acceptable adjuvant of medicine, excipient, can make novel cell cycle inhibitor of a class and cell death inducer.
The preparation method of above-claimed cpd is to extract the dry fragment of Radix osteomelis schwerinais Clausena lansium (Lour.) Skeels peel of stem with an amount of ethanol or aquiferous ethanol solution, gets crude extract, and the gained crude extract is used organic solvent extraction successively, obtains extract.Above-mentioned extractive with organic solvent is separated purification process through repeatedly silica gel and Sephadex LH20 column chromatography, repeatedly preparation silica gel thin-layer chromatography with recrystallization etc., isolate the active component in the extractum, obtain the Bicyclomahanimbine. activated monomer of above-mentioned four kinds of structure types.
The present invention adopts flow cytometry and is equipped with cell microscopic morphology observation of characteristics, fluorescence microscopy morphological characteristic observation and grain graininess analytic process, being screening and the test job that leading indicator has been carried out active anticancer to the cell cycle inhibition of tsFT210 mouse mastopathy cell, apoptosis-inducing and to the lethal effect of this cancerous cell.Simultaneously, adopt human carcinoma cell lines such as HT-1080, K562, detected the lethal effect of active component human cancer cell with mtt assay.The result shows that the Bicyclomahanimbine. of above-mentioned four kinds of structure types that this patent provided all has good related activity in the active anticancer model of being tested.
The function Characteristics of carbazolyl alkaloid of the present invention is: perhaps the cell cycle by anticancer has enough to meet the need, or by inducing cancer cell generation apoptosis, perhaps play a role by the direct killing cancerous cell, research reagent～cell cycle inhibitor or cell death inducer that above-mentioned carbazolyl alkaloid reactive compound also can be used as life sciences are used to explore biosis.
Embodiment 1 separates the extraction of preparation 1. medical materials and the preparation of active site
5 kilograms in the dry fragment of Radix osteomelis schwerinais Clausena lansium (Lour.) Skeels peel of stem with 70% ethanol 15L backflow lixiviate, extracts each 4 hours three times at every turn altogether.Merge extractive liquid,, concentrating under reduced pressure gets crude extract 300 grams.
With the 2500ml aqueous dispersion of this extractum, use equivalent petroleum ether, chloroform, ethyl acetate and n-butanol extraction three times successively, collect each extract respectively and concentrate.Getting ligroin extraction 25 grams, chloroform extract 30 grams, ethyl acetate extract 35 grams, n-butanol extract 60 grams and water-soluble part 150 respectively restrains.2. the tracking of active component separates in the ligroin extraction
Get ligroin extraction 25 grams, mix sample with 30 gram silica gel G, last decompression post (250 gram silica gel H dry column-packing) chromatography, with petroleum ether (PE)-ethyl acetate (EA) gradient elution segmentation, by the polarity rough segmentation is 20 stream parts, after active testing and thin layer detection, merge, obtain 6 components: A component 1.5g (PE eluting), B component 6.35g[PE-EA (99: 1～97: 3) eluting], C component 6.25g[PE-EA (96: 4～95: 5) eluting], D component 1.25g[PE-EA (95: 5～93: 7) eluting], E component 0.35g[PE-EA (93: 7～92: 8) eluting], F component 9g[PE-EA (90: 10～50: 50) eluting].Wherein B, C composition activity be based on apoptosis-induced and cell toxicant, and D, E component activity be based on the cell cycle inhibition, A and F component non-activity.
B, C component go up the normal pressure post with silica gel G (1: 50), and 95: 5 eluting of n-hexane/acetone obtain chemical compound 7 and 8 crude product 5g and 4.0g.
D component LH-20 (1: 50) column chromatography for separation, sample on the normal pressure wet method, methanol-eluted fractions obtains chemical compound 1 and 2 crude product 0.6g and 25mg.
The E component is got active constituent through the LH-20 column chromatography for separation, separates obtaining chemical compound 9 crude product 35mg again through the preparation thin layer chromatography.
Get the reactive compound crude product that B～E component obtains through above-mentioned column chromatography for separation,, obtain pure product chemical compound 1 (0.7g), 2 (15mg), 7 (4.5g), 8 (3.5g), 9 (25mg) through ODS column chromatography (70% acetonitrile/water eluting) is refining repeatedly.3. the tracking of active component separates in the chloroform extract
Get chloroform extract 30 grams, mix sample with 36 gram silica gel G, last decompression post (300 gram silica gel H dry column-packing), with petroleum ether (PE)-ethyl acetate (EA) gradient elution segmentation, by the polarity rough segmentation is 20 stream parts, after active testing and thin layer detection, merge, obtain 6 components: G component 1g (PE eluting), H component 5.0g[PE-AE (97: 3) eluting], I component 4.0g[PE-AE (93: 7) eluting], J component 0.65g[PE-AE (9: 1) eluting], K component 1.35g[PE-AE (9: 1～8: 2) eluting], L component 16g[PE-EA (7: 3～1: 1) eluting].Wherein H, I component mainly contain the composition identical with petroleum ether layer, and J, K component contain new active component, G and L component non-activity.
H, I component are separated with reference to the method for separating ligroin extraction, obtain chemical compound 1 (0.5g), 7 (2.7g), 8 (2g) respectively.
J, K component go up the LH-20 post respectively, behind the methanol-eluted fractions chromatography, get active stream part, check that through thin layer similar person merges, and obtains 12 active components.From these active components, LH-20 column chromatography, preparation thin layer chromatography separation and purification through repeatedly obtain chemical compound 3 (25mg), 4 (12mg), 5 (8mg) and 6 (10mg) respectively.
4. the physicochemical constant of reactive compound 1～9 and spectroscopic data
Chemical compound 1 faint yellow oily thing.ESI-MS(m/z):212[M+H]
+.UVλ
max?nm(logε)in?MeOH:341(3.67),328(3.71),291(4.19),250(4.57),241(4.75),228(4.64).IR?ν
max?cm
-1(KBr):3422,3056,2918,2852,1588,1503,1394,828。
1H?NMRδ(CDCl
3):8.30(brs,NH),8.20(d,J=8Hz),7.66(s),7.55(t,J=8Hz),7.49(d,J=8Hz),7.37(t,J=8Hz),6.87(s),4.07(s,3H),2.70(s,3H)。
13C?NMRδ(CDCl
3):145.4,139.5,129.5,128.1,125.5,124.4,123.6,120.4,119.2,112.5,110.9,107.7,55.5,21.9。Chemical compound 2 colourless column crystallizations, mp178-179 ℃ of .ESI-MS (m/z): 264[M+H]
+.UV λ
MaxNm (log ε) in MeOH:342 (3.70), 328 (3.74), 295 (4.46), 258 (4.42), 246 (4.53), 235 (4.80), 229 (4.78) .IR ν
MaxCm
-1(KBr): 3405,3050,2917,2858,1607,1460,1243,847.
13CNMRδ(CDCl
3):139.9,137.8,128.8,127.2,125.7,123.6,123.3,120.2,120.2,119.3,110.6,110.2,21.4。Chemical compound 3 colourless fine needle column crystallizations, mp236-237 ℃ of .ESI-MS (m/z): 212.3[M+H]
+.UV λ
MaxNm (log ε) in MeOH:344 (4.06), 333 (4.06), 287 (4.31), 274 (4.49), 250 (4.28), 239 (4.38), 221 (4.25) .IR ν
MaxCm
-1(KBr): 3400,3047,2917,2815,1670,1473,1251,851.
1H?NMRδ(Acetone):9.98(s),8.24(d,J=1.5),8.17(d,J=8Hz),7.63(d,J=8Hz),7.45(dd,J=8.0,8.0Hz),7.42(t,J=1.5Hz),7.24(dd,J=8.0,8.0Hz),
13C?NMRδ(CDCl
3):191.4,143.7,140.3,134.0,130.2,126.2,124.1,123.6,120.4,119.9,118.2,111.8,107.5。Chemical compound 4 colourless acicular crystals, mp165-166 ℃ of .ESI-MS (m/z): 224[M-H] .UV λ
MaxNm (log ε) in MeOH:339 (4.10), 330 (4.10), 386 (4.31), 273 (4.50), 248 (4.25), 237 (4.46), 222 (4.24) .IR ν
MaxCm
-1(KBr): 3177,3103,2918,1661,1501,1344,1141,846.
1HNMRδ(CDCl
3):10.06(s,CHO),8.19(brs),8.11(d,J=8Hz),7.51(d,J=8Hz),7.48(dd,J=8.0,8.0Hz),7.46(d,J=1.0Hz),7.32(dd,J=8.0,8.0Hz),4.06(s,3H)。
13C?NMRδ(CDCl
3):191.8,146.1,139.4,134.1,130.2,126.6,123.7,123.6,120.7,120.7,120.3,111.5,103.6,55.8。Chemical compound 5 white particulate crystallizations, mp229-230 ℃ of .ESI-MS (m/z): 242[M+H]
+.UV λ
MaxNm (log ε) in MeOH:353 (3.95), 340 (3.91), 296 (4.27), 278 (4.32), 255 (4.14), 242 (4.18), 223 (4.19) .IR ν
MaxCm
-1(KBr): 3391,3360,2927,2829,1670,1459,1216,842.
1HNMRδ(CDCl
3):9.96(s,CHO),8.23(s),7.75(d,J=2Hz)7.54(d,J=9Hz),7.39(s),7.09(dd,J=9.0,2.0Hz),3.88(s,3H)。
13C?NMRδ(CDCl
3):191.3,154.5,143.7,135.0,134.6,129.8,124.1,124.0,118.7,115.8,112.5,106.9,102.7,55.2。Chemical compound 6 Chinese red needles.ESI-MS(m/z):211[M-1]
+.UVλ
max?nm(logε)?in?MeOH:286(3.84),258(4.19),224(4.39).IRν
max?cm
-1(KBr):3220,2921,2853,1664,1637,1468,887,747。
1H?NMRδ(CDCl
3):8.04(d,J=8Hz),7.52(d,J=8Hz),7.38(dd,J=8,8Hz),7.30(dd,J=8,8Hz),6.62(d,J=1Hz),2.06(d,J=1Hz)。
13C?NMRδ(CDCl
3):183.1,180.1,148.0,137.4,135.9,131.6,126.2,123.8,123.6,121.6,115.4,113.8,15.6。Chemical compound 7 colourless flaky crystals, mp176-177 ℃ of .ESI-MS (m/z): 264[M+H]
+.UV λ
MaxNm (log ε) in MeOH:357 (4.04), 342 (4.10), 327 (4.07), 287 (4.80), 236 (4.84) .IR ν max cm
-1(KBr): 3320,2975,2931,1642,1460,1146,1058,882.
1H?NMRδ(CDCl
3):7.83(brs,NH),7.93(d,J=8Hz),7.69(s),7.37(d,J=8Hz),7.33(t,J=8Hz),7.20(t,J=8Hz),6.60(d,J=10Hz),5.69(d,J=10Hz),2.36(s,3H)1.51(s,3H)。
13C?NMRδ(CDCl
3):149.9,139.6,134.9,129.4,124.3,124.0,121.2,19.6,119.3,118.7,118.7,117.2,116.8,110.4,104.5,75.9,27.7,27.7,16.0。The cotton-shaped crystallization of chemical compound 8 white pins, mp95.5-96.5 ℃ of .[α]
D 25+ 55.9 ° (c1.8, MeOH) .ESI-MS (m/z): 332[M+H]
+.UV λ
MaxNm (log ε) in MeOH:357 (4.18), 342 (4.22), 329 (4.19), 287 (4.94), 238 (4.97) .IR ν
MaxCm
-1(KBr): 3325,2965,2926,2856,1647,1460,1218,846.
1H NMR δ (CDCl
3): 7.93 (brd, J=8Hz), 7.81 (brs, NH), 7.67 (m), 7.37 (brd, J=8Hz), 7.32 (td, J=8,1Hz), 7.19 (td, J=8,1Hz), 6.63 (d, J=10Hz), 5.66 (d, J=10Hz), 5.14 (brt, J=7Hz), 2.36 (s, 3H), 2.20 (m, 2H), 1.79 (m, 2H), 1.69 (s, 3H), 1.61 (s, 3H), 1.47 (s, 3H).
13C?NMRδ(CDCl
3):150.0,139.5,134.9,131.7,128.5,124.3,124.2,124.0,121.2,119.5,119.3,118.5,117.5,116.7,110.4,104.2,78.2,40.9,25.9,25.6,22.8,17.6,16.0。Chemical compound 9 colourless column crystallizations, mp146.5-147.5 ℃ of .[α]
D 25+ 9.0 ° (c1.0, MeOH) .ESI-MS (m/z): 332[M+H]
+.UV λ
MaxNm (log ε) in MeOH:332 (3.85), 304 (4.44), 254 (4.66), 241 (4.85), 218 (4.76) .IR ν
MaxCm
-1(KBr): 3478,3062,2953,2859,1613,1458,1145,873.
1H NMR δ (CD
3OD): 7.88 (brd, J=8Hz), 7.65 (s), 7.4 (brd, J=8Hz), 7.23 (td, J=8Hz), 7.08 (rd, J=8,0.5Hz), 3.46 (d, J=9.5Hz), 2.71 (t, J=9Hz), 2.54 (m), 2.33 (s, 3H), 2.09 (m), 1.80 (m), 1.74 (m), 1.66 (m), 1.59 (s, 3H), 1.38 (s, 3H).
13C?NMRδ(CD
3OD):151.7,141.7,139.5,125.1,124.7,120.4,119.8,119.7,119.6,117.5,111.8,108.7,85.0,48.1,40.9,40.8,40.5,38.1,34.9,26.7,26.2,19.1,16.8。
Embodiment 2 active testings, 1. cell culture and active testing
1) cell cycle suppresses and the apoptosis-inducing activity
Temperature sensitive type mouse breast cancer tsFT210 cell is with containing the RPMI-1640 culture medium of 10%FBS, 32 ℃, feed successive transfer culture in the incubator of 5% carbon dioxide.During active testing, the tsFT210 cell of the trophophase of taking the logarithm, being mixed with density with fresh culture medium is 2 * 10
5The cell suspension of cells/ml adds in 24 orifice plates by 0.5ml/well respectively, and every hole adds the sample methanol solution of 5 μ l variable concentrations, cultivates 17h down for 32 ℃.Get it filled under the thing effect cell after cultivating, at first under optical microscope, observe the morphological change that drug treating causes, judge the morphological feature that has or not apoptosis or necrocytosis, then cell is transferred to the 1.5ml Eppendorf centrifuge tube from 24 orifice plates respectively, 4 ℃ of centrifugal 3min of following 3000rpm, supernatant is removed in suction, add 0.5 μ l phosphate buffer solution concussion washing once, collecting cell under the same terms, add 150 μ l propidium iodide (PI) aqueous solutions (5mg PI, 100mg Sodium citrate and 200mg NP-40in 100ml H
2O), behind 4 ℃ of 30min that dye down, measure the content distribution of DNA in the cell with flow cytometry analysis.In addition, cell after the thing of getting it filled is in case of necessity handled, with cell dyeing, the morphological feature of observation of cell nuclear chromatin changes under fluorescence microscope with Hoechst 33258 fluorometric reagents, judges to have or not apoptotic morphological feature or cell cycle to be suppressed in the G2 phase or in the M phase.
2) to the killing activity of human cancer cell
Human fibrosarcoma cell HT-1080 and people's chronic myeloid leukemia cells K562 be all with the RPMI-1640 culture medium that contains 10%FBS, 37 ℃, feed successive transfer culture in the incubator of 5% carbon dioxide.The trophophase cell of taking the logarithm, being diluted to density with fresh RPMI-1640 culture fluid is 2 * 10
5The Cell sap of individual cells/ml is inoculated into this Cell sap in 96 orifice plates, and dispensing 100 μ l in every hole place 5%CO
2In the incubator, cultivated 4 hours for 37 ℃, every hole adds given the test agent liquid or each 5 μ l of positive control cisplatin solution of variable concentrations, and every kind of sample or cisplatin are all established three holes, establish three hole blanks simultaneously, cultivate 24 hours for 37 ℃ in CO2 gas incubator.Every hole adds the MTT liquid 10 μ l of 5mg/ml, in CO2 gas incubator, cultivated 4 hours for 37 ℃, centrifugal 5 minutes of 4 ℃, 2000rpm, after supernatant is removed in suction, every hole adds 100 μ l DMSO, hatches about 10 minutes for 37 ℃, after the dissolving to be crystallized fully, vibrated about 1 minute with the timing micro oscillator, utilize microplate reader to measure optical density (the to call OD) value of each hole in the 570nm place.
Get the meansigma methods of three hole OD values, be calculated as follows cell proliferation inhibition rate:
Suppression ratio=(OD
Blank-OD
Sample)/OD
Blank* 100%
Get the suppression ratio of each sample under variable concentrations, draw amount effect curve, calculate half by this opisometer and suppress valid density.
2. biological activity test result
1) cell cycle suppresses and the apoptosis-inducing activity
Chemical compound 1 has very strong apoptosis-inducing effect to the tsFT210 cell when concentration is high, weaken gradually along with concentration reduces apoptosis-induced effect, and the very strong M phase of cell cycle that presents gradually in generation suppresses active; Chemical compound 3,4,5 cell cycle have very strong G2/M inhibitory action; 6 pairs of tsFT210 cells of chemical compound present very strong lethal effect; 7,8,9 pairs of tsFT210 cells of chemical compound all have very strong apoptosis-induced effect and lethal effect; And chemical compound 2 does not have obvious activity to the tsFT210 cell in the test concentrations scope less than 400/ μ g/ml.These chemical compounds are respectively the minimum effective drug concentration (MEC) of tsFT210 cell: 1,1.25 μ g/ml (0.85 μ g/ml＜MEC＜=1.25 μ g/ml); 2, MEC＞400 μ g/ml; 3,9.38 μ g/ml (4.69 μ g/ml＜MEC＜=9.38 μ g/ml); 4,16.50 μ g/ml (8.25 μ g/ml＜MEC＜=16.50 μ g/ml); 5,8.25 μ g/ml (4.12 μ g/ml＜MEC＜=8.25 μ g/ml); 6,30.0 μ g/ml (15.0 μ g/ml＜MEC＜=30.0 μ g/ml); 7,25.0 μ g/ml (12.5 μ g/ml＜MEC＜=25.0 μ g/ml); 8,15.0 μ g/ml (12.5 μ g/ml＜MEC＜=15.0 μ g/ml); 9,20.0 μ g/ml (12.5 μ g/ml＜MEC＜=20.0 μ g/ml).2) killing activity to human cancer cell adopts mtt assay, and the part of detecting chemical compound is to the lethal effect of human cancer cell, and the result is as shown in table 1.
Table 1 part of compounds is to the lethal effect (IC that mtt assay records of human cancer cell
50Value, μ g/ml)
| Chemical compound | The HT-1080 cell | The K562 cell |
| ?1 ?2 ?7 ?8 ?9 | ?33.5 ?25.0 ?39.5 ?22.7 ?40.0 | 27.6 undetermined 8.9 17.1＜1.0 |
Above-mentioned biological activity test result shows, carbazole alkaloid compounds provided by the present invention can be used as cell cycle inhibitor or cell death inducer is used to explore biosis, also can by join with the acceptable adjuvant of medicine, excipient, make the new anticancer therapy medicine of a class, the feature of such medicine is the carbazole alkaloid active component by the cell cycle turnover of anticancer or by inducing cancer cell generation apoptosis or the drug effect by direct killing cancerous cell performance anticancer therapy.
Claims (3)
1. compositions that can be used as cell cycle inhibitor and cell death inducer, the active component that it is characterized in that said composition is a kind of carbazole alkaloid derivative or its salt, and the structure of described carbazole alkaloid derivative comprises the structure shown in following formula I, formula II, formula III and the formula IV.
2. the described carbazole alkaloid derivative of claim 1, wherein preferred chemical compound is R
1=OCH
3, R
2=CH
3, R
3=H, R=CH
2CH
2CH=C (CH
3)
2
3. the preparation method of the described Bicyclomahanimbine. of claim 2 is the dry fragment with the ethanol extraction Radix osteomelis schwerinais Clausena lansium (Lour.) Skeels peel of stem of ethanol or 60-70%, gets crude extract; With this extractum of organic solvent extraction, obtain extract; This extract through repeatedly silica gel and Sephadex LH20 column chromatography, repeatedly preparation silica gel thin-layer chromatography and recrystallization, is isolated the active component in the extractum.
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| CN 01123988 CN1209107C (en) | 2001-02-09 | 2001-08-10 | Carbazolyl alkaloid anticarcinogen and its prepn |
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| CN102491972A (en) * | 2011-12-05 | 2012-06-13 | 中山大学 | Carbazole derivative, preparation method thereof, and application of carbazole derivative serving as anticancer drug |
| JP2013014530A (en) * | 2011-07-01 | 2013-01-24 | Nippon Yakuyo Shokuhin Kenkyusho:Kk | Whitening composition |
| CN102988356A (en) * | 2013-01-08 | 2013-03-27 | 中国科学院昆明植物研究所 | Medicine composition with carbazole alkaloid in clausena plants as antineoplastic activity ingredient and preparation method and application thereof |
| CN103012417A (en) * | 2013-01-08 | 2013-04-03 | 中国科学院昆明植物研究所 | Carbazole alkaloids in clausena plants, medicine composition with carbazole alkaloids as anti-tumor active component, and preparation method and application of carbazole alkaloids |
| CN117582507A (en) * | 2024-01-18 | 2024-02-23 | 北京大学 | Application of LAMTOR1 inhibitor in preparation of antitumor drugs |
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2001
- 2001-02-09 CN CN 01103675 patent/CN1309964A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013014530A (en) * | 2011-07-01 | 2013-01-24 | Nippon Yakuyo Shokuhin Kenkyusho:Kk | Whitening composition |
| CN102491972A (en) * | 2011-12-05 | 2012-06-13 | 中山大学 | Carbazole derivative, preparation method thereof, and application of carbazole derivative serving as anticancer drug |
| CN102491972B (en) * | 2011-12-05 | 2014-01-22 | 中山大学 | Carbazole derivative, preparation method thereof, and application of carbazole derivative serving as anticancer drug |
| CN102988356A (en) * | 2013-01-08 | 2013-03-27 | 中国科学院昆明植物研究所 | Medicine composition with carbazole alkaloid in clausena plants as antineoplastic activity ingredient and preparation method and application thereof |
| CN103012417A (en) * | 2013-01-08 | 2013-04-03 | 中国科学院昆明植物研究所 | Carbazole alkaloids in clausena plants, medicine composition with carbazole alkaloids as anti-tumor active component, and preparation method and application of carbazole alkaloids |
| CN103012417B (en) * | 2013-01-08 | 2015-01-07 | 中国科学院昆明植物研究所 | Carbazole alkaloids in clausena plants, medicine composition with carbazole alkaloids as anti-tumor active component, and preparation method and application of carbazole alkaloids |
| CN117582507A (en) * | 2024-01-18 | 2024-02-23 | 北京大学 | Application of LAMTOR1 inhibitor in preparation of antitumor drugs |
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