CN1275959C - Pterocarya stenoptera extract, its preparation and use - Google Patents
Pterocarya stenoptera extract, its preparation and use Download PDFInfo
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- CN1275959C CN1275959C CN 200310115556 CN200310115556A CN1275959C CN 1275959 C CN1275959 C CN 1275959C CN 200310115556 CN200310115556 CN 200310115556 CN 200310115556 A CN200310115556 A CN 200310115556A CN 1275959 C CN1275959 C CN 1275959C
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Abstract
The present invention relates to a Pterocarya stenoptera extract, a preparation method thereof and a purpose thereof. A new compound of diphenyl epoxy heptane is extracted from a Tokyo pterocarya stenoptera tree. The tests show that the compound can be used as an inhibitor of mitotic cycle, an inducer of apoptosis or an antineoplastic agent.
Description
Technical field:
The present invention relates to Chinese ash element (Pterocarine) and its production and use.Be specifically related to the phenylbenzene epoxy iieptanes new compound, this compounds and the preparation method that from the Chinese ash of Tokyo, extract, and this class material is the purposes of antineoplastic agent as cell cycle inhibitor, cell death inducer or tumor cytotoxicity agent.
Background technology:
Phenylbenzene epoxy iieptanes compound has some bibliographical informations, as document [Motohiko Morihara, e.al., Twonovel diarylheptanoid glucosides from Myrica gale var.tomentosa and absolute structure ofplane-chiral galleon.Chem.Pharm.Bull., 1997,45 (5): 820-823] and document [Gabriela IslasGonzalez, et al., A unified strategy toward the synthesis of acerogenin-type macrocycles:Totalsyntheses of acerogenina A, B, C, and L and aceroside IV.J Org.Chem., 1999,64,914-924] once reported the compound of the natural and synthetic of phenylbenzene epoxy iieptanes respectively, but having a cell cycle, suppresses and the active report of apoptosis-inducing this compounds of Shang Weijian.
Tokyo Chinese ash Pterocarya tonkinesis (Franch.) Dode. is a kind of Juglandaceae Chinese ash platymiscium, is used for the treatment of cancer in China some areas as folk medicine, but the chemistry of its extract and pharmacological research do not see as yet that so far report is arranged.Do not see yet and from the Chinese ash of Tokyo, separate the bibliographical information that obtains natural phenylbenzene epoxy iieptanes compound.
Summary of the invention:
The present invention aims to provide a class and has the new compound that suppresses the cell cycle turnover, brings out anti-tumor activities such as cancer cell-apoptosis and anticancer propagation.
The present invention finds that first the crude extract of Tokyo Chinese ash has good apoptosis-inducing, cell cycle inhibition to reach the anti-tumor activities such as propagation inhibition to cancer cells, studies its activeconstituents then.Find that the new Chinese ash chlorins compound of phenylbenzene epoxy iieptanes has anti-tumor activity shown in the following general formula I:
Formula I
Among the formula I, R
1Be hydroxyl, alkoxyl group, acyloxy or hydrogen atom; R
2Be hydroxyl, alkoxyl group, acyloxy or hydrogen atom.
The preparation method of above-mentioned formula I compound is, with the dry stem skin of alcohol or hydrous alcohol extraction Tokyo Chinese ash, crude extract, separation and purification and obtaining from crude extract then.
Described alcohol is methyl alcohol, ethanol; Described aqueous alcohol is 60～70% aqueous ethanol; Described separation and purification comprises the ordinary method of utilizing Separation of Natural Products purifying well known to those skilled in the art, as liquid-liquid extraction, column chromatography, thin-layer chromatography and recrystallization etc.Wherein column chromatography and recrystallizing and refining can carry out repeatedly repeatedly.
Through experiment confirm, the formula I compound that the present invention finds has effects such as the cell cycle of inhibition, inducing apoptosis and inhibition propagation to tumour cell, therefore can be used as cell cycle inhibitor, cell death inducer or tumor proliferation inhibitor.
The present invention adopts lissamine rhodamine B (sulforhodamine B, SRB) method and flow cytometry detect the method for cell morphological characteristic in conjunction with microscopically, have tested formula I compound to the cell cycle inhibition of mouse breast cancer tsFT210 cell, people's chronic myelogenous leukemia K562 cell and human large intestine cancer HCT-15 cell and apoptosis-inducing and to the effects such as propagation inhibition of this cell.
Chinese ash chlorins compound of the present invention to the biological action feature of tumour cell is: under different concns or the condition of different action times, to cancer cells can by or the turnover of cell cycle of anticancer, or bring out cancer cell-apoptosis, show the biologic activity that suppresses tumor cell proliferation, thereby bring into play its antitumor action.
Chinese ash chlorins compound of the present invention can be made antineoplastic agent or cell cycle inhibitor and cell death inducer by adding medicine or reagent acceptable auxiliary or solvent, is used for tumor treatment or life science.When suppressing the cell cycle or bringing out apoptotic low molecular biosciences probe to be used, compound of the present invention dissolves in methyl alcohol, aqueous methanol or the water and uses, and also can use with the aqueous solution dissolving of dimethyl sulfoxide (DMSO) in life science.
Description of drawings:
Fig. 1 is the ultra-violet absorption spectrum of Compound I in methyl alcohol;
Fig. 2 is the infrared absorption spectrum (KBr) of Compound I;
Fig. 3 is that Compound I is in deuterated pyridine
1The H nuclear magnetic resonance spectrum;
Fig. 4 is that Compound I is in deuterated pyridine
13The C nuclear magnetic resonance spectrum;
Fig. 5 is the flow cytometry histogram that people's chronic myelogenous leukemia K562 cell records after the Compound I of different concns is handled 24 hours.The picture left above is the blank group, and all the other are the Compound I of different concns (concentration is seen each figure upper right side) treatment group, and curve part is a measured data among the figure, and the black filling part is a calculated value.
Embodiment:
The separation and purification of embodiment 1 Compound I
Compound I
In the formula, Arabic numerals are marks of carbon atom in the chemical structure.
Getting the dry stem skin (3.5 kilograms) of Tokyo Chinese ash pulverizes, with 10 liter 60% ethanol soaking at room temperature 6 days, leaching aqueous ethanol solution (same extraction is carried out 8 times altogether), united extraction liquid, be evaporated to and do not contain ethanol (about 2 liters), with isopyknic chloroform extraction 4 times, the combined chloroform extraction liquid, concentrate drying obtains chloroform extract 10.4 grams.
Get chloroform extract (10.4 gram), mix sample,, separate, obtain 34 and flow part with chloroform → methyl alcohol gradient elution chromatography with the post that reduces pressure on the 194 gram silica gel H dry method with adding 10 gram tlc silica gel G after an amount of chloroform dissolving.Each stream part is carried out thin layer inspection and the active testing under every milliliter 50 microgram concentration, and merge related streams part, obtain active constituent Fr-5 (2.1 grams, chloroform wash-out part) according to the result.Fr-5 is all gone up Sephadex-LH 20 posts,, obtain 130 stream parts altogether,, get active ingredient Fr-5-4 totally 1.6 grams through merging the related streams branch with chloroform-methanol (1: 1) elution chromatography.With an amount of chloroform dissolved constituents Fr-5-4 (1.6 gram), and add 5 gram tlc silica gel G and mix sample, with the post that reduces pressure on the 35 gram silica gel Hs, sherwood oil-chloroform gradient elution chromatography obtains active constituent Fr-5-4-14 (25 milligrams) from sherwood oil-chloroform (30: 70) wash-out stream part.This component Fr-5-4-14 separates through preparation silica gel thin-layer chromatography (chloroform-methanol launches at 95: 5), scrape and get big (Rf=0.2) band of polarity, with chloroform-methanol (90: 10) wash-out and the Compound I crude product that obtains is refining by ODS dropper pillar (methanol-eluted fractions), get 5.8 milligrams of the pure product of Compound I.
Compound I white amorphous powder, [α]
D 27+ 60.5 (c1.0, CHCl
3), molecular formula C
19H
20O
4, TOF-MS m/z:313[M+H]
+Positive HR-TOF-MS m/z: measured value 313.1452[M+H]
+, calculated value 313.1440 (C
19H
21O
4[M+H]
+).UV λ
MaxNm (log ε) in MeOH:281.5 (3.42), 222.5 sh (3.95), 204.5 (4.37, end absorption).IRν
max cm
-1(KBr)：3404(OH)，3032(olefin protons)，293，28581(methyleneprotons)，1708(ketocarbonyl)，1597，1517，1503(aromatic rings)，1439，1368，1343，1288，1269，1225(C-O)，1187，1116，953(m)，887(vs)，828(s)，743(w)，645(w)，600(w)，452(w)。
1H reaches
13C NMR data see Table 1.
The 600MHz of table 1 Compound I in deuterochloroform
1H and 150MHz
13C NMR data
A)
| Location label | δ H(Jin Hz) | 1H- 1H COSY b) | δ C | HMBC c) |
| 1 2 3 4 5 6 7 1′ 2′ 3′ 4′ 5′ 6′ 1″ 2″ 3″ 4″ 5″ | 2.82 d)AB type 2.87 d)AB type 2.28ddd(16.7，8.3，2.7) 2.36ddd(16.7，8.8，2.8) 1.82 e)AB type 1.89 e)AB type 1.56(2H)m 1.64m 1.68m 2.67 f)AB type 2.71 f)AB type —— 5.57 g)d(2.2) —— —— 6.83d(8.0) 6.64dd(8.0，2.2) —— 6.94d(1.9) —— —— 6.89d(8.0) | 1(δ2.87)，2 1(δ2.82) 1，2(δ2.36) 4(δ1.89)，5 4，6 5，6(δ1.68)，7 6，7(δ2.71) 6，7(δ2.67) 6′ 6′ 2′，5′ 6″ 6″ | 27.26t 41.12t 210.47s 46.43t 18.99t 27.22t 35.60t 133.95s 112.51d 146.77s 142.87s 115.57d 122.75d 140.58s 117.95d 148.79s 140.61s 123.41 | 2，2′，6′ 1 1，2，4 5，6 4，6，7 4，5，7 6，2″，5，6″ 1，2，2′，5′ 1，6′ 2′，5′ 2′，6′ 6′ 1，2′ 2″，5″，6，7 6″，7 2″，5″ 2″，6″ |
| 6″ 4′-O H 3″-O H | 6.82dd(8.0，1.9) 5.79br s 5.71
h) |
2″，5″ | 122.88d —— —— | 2″，7 |
A) this table signal ownership is based on DEPT, PFG
1H-
1H COSY, PFG HMQC and PFG HMBC spectrum analysis result.The multiple degree of carbon signal utilizes the DEPT method to determine and uses s (singlet), d (doublet), t (triplet) and q (quartet) to represent respectively.B) numeral and the code name in this hurdle represented at PFG respectively
1H-
1In the H COSY spectrum with corresponding line in
1H provides the coupling coherent signal
1H nuclear.C) numeral in this hurdle and code name represent respectively PFGHMBC (
1J
CH=8Hz) in corresponding line in carbon signal provide long-range heteronuclear relevant (HMBC) signal
1H nuclear.D) from PFG
1H-
1In the H COSY spectrum 2 '-detect the long-range coherent signal of four keys of being separated by between H and 6 '-H.E) at PFG
1H-
1Detect the long-range coherent signal of W-type between this hydrogen and the 6-H (δ 1.68) in the H COSY spectrum.F) this hydrogen and " between the H at PFG
1H-
1Provide long-range coherent signal in the H COSY spectrum.G) in PFG NOESY spectrum, 2 '-detect NOE respectively between H and " between the H and 2 '-H and the 3 "-OH.H) in PFG NOESY spectrum, 3 " OH and 2 '-H between and 3 "-detect NOE respectively between OH and 4 '-OH.
2 pairs of cancer cells cell proliferations of embodiment and the inhibition activity of cell cycle and apoptosis-inducing active testing 1 laboratory sample and experimental technique
The pure product Compound I of separation and purification in the foregoing description 1 is got in the preparation of sample solution, and precision takes by weighing in right amount, is mixed with the solution of desired concn with methyl alcohol, and is active for surveying.
Clone and cell cultures active testing adopt mammiferous cancerous cell lines such as mouse breast cancer tsFT210 cell, people's chronic myelogenous leukemia K562 cell and human large intestine cancer HCT-15 cell.Various cells are all with the RPMI-1640 substratum that contains 10%FBS, at 32 ℃ (tsFT210 cells) or at 37 ℃ (K562 cell and HCT-15 cells) succeeding transfer culture in the incubator that feeds 5% carbonic acid gas.
Cell inhibitory effect activity test method (srb assay)
The bright employing of this law SRB (sulforhodamine B, lissamine rhodamine B) method, test evaluation the inhibition activity of tested sample to cancer cell multiplication.
The tsFT210 that takes the logarithm vegetative period, K562 or HCT-15 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 solution of 2 microlitre different concns, 32 ℃ of following 17 hours (tsFT210 cell) or 24 hours (K562 cell and HCT-15 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 following centrifugal 3 minutes of 4 ℃, 3000 rev/mins conditions, inhale and 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 holes as blank.Get the average OD value in three holes by IR%=(OD
Blank-OD
Sample)/OD
BlankThe X100% formula is calculated the cell proliferation inhibition rate (IR%) under each concentration, utilizes the Bliss method again, tries to achieve half-inhibition concentration (IC by the inhibiting rate (IR%) of various concentration
50).Same test and calculating are carried out respectively three times, try to achieve IC
50Mean value and standard deviation.
Cell cycle suppresses and the active flow cytometry testing method of apoptosis-inducing
The tsFT210 that takes the logarithm vegetative period, K562 or HCT-15 cell, 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, 32 ℃ of following 17 hours (tsFT210 cell) or 24 hours (K562 cell and HCT-15 cells) of 37 ℃ of following cultivations cultivated.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
The srb assay test result: Compound I is 20.2 ± 2.4% to the proliferation inhibition rate of mouse breast cancer tsFT210 cell under the concentration of every milliliter 100 microgram, is 23.8 ± 2.4% to the proliferation inhibition rate of human large intestine cancer HCT-15 cell; Compound I is stronger to people's chronic myelogenous leukemia K562 cell activity, its half-inhibition concentration (IC
50) be 81.8 ± 15.6%.
Flow cytometry result: with the Compound I of different concns handle the tsFT210 cell respectively 17 hours, K562 and HCT-15 cell each 24 little after, the cell cycle of the Compound I that records with flow cytometry suppresses and the apoptosis-inducing active testing the results are shown in Table 2.
The flow cytometry result of table 2 Compound I cell cycle effect (mean+SD, n=3)
| Clone | Concentration (μ g/ml) | sub-G0/G1％ | G0/G1％ | S％ | G2/M％ |
| tsFT210 | Blank | 0.2±0.02 | 35.7±1.0 | 47.8±0.6 | 16.4±0.8 |
| 100.0 | 0.2±0.03 | 46.4±1.7 | 41.5±1.0 | 12.1±0.8 | |
| HCT-15 | Blank 100.0 | 6.8±0.8 18.8±4.4 | 36.9±2.2 51.2±2.4 | 47.1±0.2 30.1±2.7 | 16.0±2.1 12.4±0.7 |
| K562 | Blank 60.0 80.0 100.0 | 2.2±0.5 3.3±0.7 9.0±3.3 11.3±0.3 | 30.5±0.6 49.4±0.6 44.0±4.8 34.9±3.0 | 53.3±0.9 43.1±3.0 40.0±0.1 50.8±3.2 | 15.8±0.6 7.5±2.4 15.5±5.1 13.9±0.2 |
Annotate: this table data system records result with flow cytometry with the cell after the drug treating after propidium iodide dyeing.
Table 2 data show, Compound I is suppressed at the G0/G1 phase with the cell cycle of tsFT210 and HCT-15 cell and K562 cell respectively when every milliliter 100 microgram and every milliliter 60 microgram are above, and also brought out K562 simultaneously when 80 micrograms are above remarkable apoptosis takes place.
Compound is to the morphologic detection result of cancer cells effect:
Observe under the optics inverted microscope, the K562 cell is when handling with the Compound I of every milliliter of concentration more than 80 milligrams, and it is that snowflake flap cell or film are being wrapped up in cell debris that significant apoptotic cell is arranged in the visual field.Can detect the apoptotic cell of highly significant in the HCT-15 cell after 100 milligrams every milliliter Compound I is handled, then do not observe than the more significant apoptosis phenomenon of blank in the tsFT210 cell after 100 milligrams every milliliter Compound I is handled, the little cell count of volume significantly increases in the full visual field, is typical little and morphological specificity that the uniform G0/G1 phase suppresses.
3 conclusions
Above-mentioned experimental result shows that Compound I is brought into play its antitumor action to cancer cell multiplications such as tsFT210, K562, HCT-15 by suppressing the cell cycle turnover and bringing out cell generation apoptosis.Therefore, Chinese ash chlorins compound of the present invention can be used as antineoplastic agent (being antitumor drug) and is used for tumor treatment, also can be used as to suppress the cell cycle turnover or bring out the Life Science Experiment research that apoptotic low molecular biosciences probe is used for exploring biological phenomena essence.
Claims (5)
1. formula I compound
2. the preparation method of the described formula I compound of claim 1, with the dry stem skin of hydrous alcohol extraction Tokyo Chinese ash, crude extract, separation and purification and getting from crude extract then; The step of described separation and purification is as follows:
With isopyknic chloroform extraction 4 times, combined chloroform extraction liquid, concentrate drying obtains chloroform extract;
Get chloroform extract and add tlc silica gel G after with the dissolving of an amount of chloroform and mix sample,, separate, obtain 34 stream parts with chloroform → methyl alcohol gradient elution chromatography with the post that reduces pressure on the silica gel H dry method; Each stream part is carried out thin layer inspection and active testing, obtain active constituent Fr-5; Fr-5 is all gone up Sephadex-LH 20 posts, with chloroform-methanol 1: 1 elution chromatography in proportion, obtain 130 stream parts altogether, merge related streams part according to the result, get active ingredient Fr-5-4, with an amount of chloroform dissolved constituents Fr-5-4, and adding tlc silica gel G mixes sample, with the post that reduces pressure on the silica gel H, sherwood oil-chloroform gradient elution chromatography; Wash-out stream part obtain active constituent Fr-5-4-14 at 30: 70 in proportion from sherwood oil-chloroform; Fr-5-4-14 separates through the preparation silica gel thin-layer chromatography, launches at 95: 5 in proportion with chloroform-methanol, and scraping and getting Rf is 0.2 the big band of polarity, with chloroform-methanol 90: 10 wash-outs in proportion; And with the formula I compound crude product that obtains by ODS dropper pillar, refining with methanol-eluted fractions, the pure product of formula I compound.
3. the preparation method of the described formula I compound of claim 2, described aqueous alcohol is 60% aqueous ethanol.
4. the described formula I compound of claim 1 is used to prepare the purposes of cell cycle inhibitor, cell death inducer and tumor cytotoxicity agent.
5. the described formula I compound of claim 1 is used to prepare the purposes of antitumor drug.
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| CN 200310115556 CN1275959C (en) | 2003-12-01 | 2003-12-01 | Pterocarya stenoptera extract, its preparation and use |
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|---|---|---|---|
| CN 200310115556 CN1275959C (en) | 2003-12-01 | 2003-12-01 | Pterocarya stenoptera extract, its preparation and use |
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| CN1275959C true CN1275959C (en) | 2006-09-20 |
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| CN103356735A (en) * | 2012-03-31 | 2013-10-23 | 广西中医学院 | Preparation method and application of anti-microbial substance site drug of Pterocarya stenoptera |
| CN109045107B (en) * | 2018-09-07 | 2021-07-30 | 湖北民族学院 | Medicine for treating rheumatoid arthritis and preparation method thereof |
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