CN101845032B - Phenolic compound and uses - Google Patents
Phenolic compound and uses Download PDFInfo
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- CN101845032B CN101845032B CN2010101900292A CN201010190029A CN101845032B CN 101845032 B CN101845032 B CN 101845032B CN 2010101900292 A CN2010101900292 A CN 2010101900292A CN 201010190029 A CN201010190029 A CN 201010190029A CN 101845032 B CN101845032 B CN 101845032B
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Abstract
The invention belongs to the field of medical technology, and discloses a novel phenolic compound and uses. The physical and chemical constants and spectroscopic means are utilized to identify the chemical structure of the compound. The compound not only has good anti-aging effect, but also has good anti-tumor effect, has the advantages of high efficiency and low toxicity, and becomes a novel anti-tumor drug on the market.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of new phenolic compound and uses thereof.
Background technology
Malignant tumour is the principal disease of harm humans health and lives, and the mankind's threat is increased day by day.In recent years, the sickness rate of tumour obviously increases, because the minimizing of transmissible disease, tumour and cardiovascular and cerebrovascular disease rise to first and second disease, if but cardiovascular diseases and cerebro-vascular diseases are separated the first place of just steady seat sickness rate of tumour and case fatality rate.Based on such reality, national governments, research institution and drugmaker are paid much attention to and huge investment tumor research and antitumor drug exploitation for a long time always, thereby make oncotherapy constantly developed.China is universally acknowledged natural drug (herbal medicine) big country, and Chinese people use the herbal medicine long history of curing the disease, thus in herbal medicine the screening anti-cancer agent approach that gets twice the result with half the effort of can yet be regarded as.In recent years, people begin the plant Chinese fan palm is studied, and find that the Chinese fan palm fruit extract has the composition of prevention and treatment cancer, are a kind of efficient, nontoxic more satisfactory cancer therapy drugs.
Tumour threatens huge to human health, utilize various means to seek effective cancer therapy drug, has become the hot subject of life science in the world wide.Be used at present the chemical synthetic drug of oncotherapy clinically, though play crucial effect for oncotherapy, its toxicity greatly, has easily produced side effects limit such as resistance their being extensive use of.The medical scientific research worker is less relatively in unremitting effort searching toxic side effect always, action principle is unique, the outstanding effect medicine, how to invent the new compound with function of tumor, is one of their primary study direction always.
Summary of the invention
For these reasons, the scientific research personnel of our company passes through long term studies, obtained 1 new compound, this compounds is except having good antidotal effect, also has good antineoplastic action, this compounds has efficiently, the advantage of low toxicity, will become antitumor drug new on the market.
The present invention is achieved through the following technical solutions.
Compound:
The wherein application of compound in the old and feeble medicine of preparation treatment.
The wherein application of compound in preparation medicine for treating tumor thing.
Wherein compound is the pharmaceutical preparation of feedstock production.
Wherein said tumour is a cancer.
Wherein said tumour is a liver cancer.
Wherein said tumour is a leukemia.
Wherein said tumour is a nasopharyngeal carcinoma.
Compound of the present invention, can be by including but not limited to that following method obtains:
The Chinese fan palm seed, use extraction using alcohol, reclaim ethanol and get concentrated extract (LC), (LC) uses water-dispersion with concentrated extract, use sherwood oil, chloroform, ethyl acetate and n-butanol extraction successively, collect each extraction liquid respectively and concentrate acquisition petroleum ether extract (LCP), chloroform extract (LCC), acetic acid ethyl ester extract (LCE) and n-butyl alcohol extract (LCB).
Get acetic acid ethyl ester extract (LCE), with chloroform and dissolve with methanol, chromatographic silica gel (100-200 order) is mixed sample.Silica gel (200-300 order) is with chloroform dissolves silicon mucilage binding post, and no longer descends sample on the dry method with chloroform balance pillar to silica gel face.Use chloroform, chloroform-methanol (100: 1), chloroform-methanol (50: 1), chloroform-methanol (25: 1), chloroform-methanol (15: 1), chloroform-methanol (10: 1), chloroform-methanol (5: 1), chloroform-methanol (2: 1), methyl alcohol gradient elution successively.Utilize thin layer to detect merging and obtain 23 components (LCE1-LCE23).
Get the 11st cut LCE21 (obtaining), carry out silicagel column and separate, take by weighing 100～200 order silica gel and mix sample by 50: 1 wash-outs of chloroform-methanol.200～300 order silica gel dissolve silica gel with chloroform, fill out post, and till no longer descending with chloroform balance pillar to silica gel, last sample.With chloroform and methyl alcohol is that eluent carries out gradient elution, its gradient is set to chloroform, chloroform-methanol (100: 1), chloroform-methanol (50: 1), chloroform-methanol (25: 1), chloroform-methanol (15: 1), chloroform-methanol (10: 1), chloroform-methanol (5: 1), methyl alcohol, the volume of each gradient elution is respectively 10L, 10L, 5L, 5L, 3L, 3L, 3L, 0.5L, and concentrate about every part of 500ml, utilize thin layer to detect and instruct merging to obtain 7 components (LCE11-1-LCE11-7).Component LCE11-2 dissolve with methanol, (2 * 43cm) separate, and are eluent with chloroform-methanol (7: 3), utilize thin layer to detect and instruct merging to obtain 3 components (LCE11-2-1-LCE11-2-3) by Sephadex LH-20 post.Component LCE11-2-1 is through Rp-18 high performance liquid phase Waters XTerra series, 19 * 250mm i.d. preparative chromatography post separates, moving phase is methyl alcohol: water (42: 58) pH is 2.5, ultraviolet detection, wavelength is 205nm, and flow velocity is that 6ml/min is that 32.407min obtains The compounds of this invention in retention time.
New compound of the present invention can obtain by the method for chemosynthesis.
One, the structure of The compounds of this invention is identified
White indefiniteness powder, [α]
25 D=+8.2 (c0.20, MeOH).ESI-MS (positive) provides quasi-molecular ion peak [M+Na]
+M/z 369, and the prompting molecular weight is 346.HRESIMS m/z:369.094[M+Na]
+(C
18Hx
18AO
7Theoretical value is 369.0945), calculating degree of unsaturation is 10.
1On the H NMR spectrum, δ
HThree aryl hydrogen evolution 1,3 of (6.78 2H, s, H-2 ', 6 ') and 6.93 (1H, s, H-4 '), 5-trisubstituted benzene ring, δ
H7.55 (1H, s is H-2) with 7.44 (1H, s, two aryl hydrogen evolution 1,3,4 H-6), 5-four substituted benzene rings;
13On the C NMR spectrum, chemical shift in the 110.5-151.6 zone 12 and judge wherein to have 4 to contain that quaternary carbon that oxygen replaces and 3 are non-to contain quaternary carbon and 5 methine carbons that oxygen replaces according to its chemical shift and DEPT spectrum.In addition, there is a carboxyl in chemical shift in the prompting of the peak at 167.1 places.δ 88.1 and 62.6 shows oxidized a methyne peak and a methylene peak respectively, and a methyne peak is contained at δ 2 methoxy base peaks of 55.6 demonstrations and δ 52.2 places.According to
1H-
1In the H COSY spectrum, δ
H3.55 (1H, br s, H-3) and δ
H3.70 (2H, br s, H-9) and δ
H5.56 (1H, d, J=6.6Hz, H-2) relevant, can infer that this compound contains (OCHCHCH
2OH) fragment, again in conjunction with among the HMBC, it is long-range relevant that H-2 (5.56) and C-7a (151.6) have, and points out this compound to contain a cumarone structure fragment.In addition, in HMBC, H-2 (5.56) is also relevant with C-4 ' (110.5) with C-1 ' (131.6), and the skeleton structure that can infer this compound is 2-phenyl-3-(methylol-1)-2,3-dihydro benzofuran.In HMBC spectrum, the hydrogen on two oxygen methyl is relevant with C-7 with C-3 ' respectively, and H-4 is relevant with carboxyl carbon with H-7, can be from above being correlated with definite substituent position.Thereby determine that this compound is 2-(3 '-hydroxyl-5 '-methoxyphenyl)-3-(methylol-1)-7-methoxyl group-2,3-dihydro benzofuran-5-carboxylic acid.
Table 1 compound
1HNMR,
13C NMR,
1H-
1H COSY and HMBC data [δ in ppm, mult. (J in Hz)]
| position | 1H-NMR | 13C-NMR | 1H- 1H-COSY | HMBC |
| 1 | ||||
| 2 | 5.56，d(6.6) | 88.1 | H-3 | 1’，4’，4，7a，9 |
| 3 | 3.55br，s | 52.2 | H-2，H-9 | 1’ |
| 4 | 7.55，s | 119.1 | H-6 | 3，6，7，7a，8 |
| 5 | 123.7 | |||
| 6 | 7.44br，s | 113.2 | H-4 | 4，5，7，7a，8 |
| 7 | 143.3 | |||
| 8 | 167.1 | |||
| 9 | 3.70br，s | 62.6 | H-3 | |
| 3a | 129.6 | |||
| 7a | 151.6 | |||
| 1’ | 131.6 | |||
| 2’ | 6.78，s | 115.4 | H-4 | 1’，3’，4’ |
| 3’ | 147.6 | |||
| 4’ | 6.93，s | 110.5 | H-2，H-6 | 2，5’，6’ |
| 5’ | 146.6 | |||
| 6’ | 6.78，s | 119.0 | H-4 | |
| 3’-OCH 3 | 3.83，s | 55.6 | 3’ | |
| 7-OCH 3 | 3.75，s | 55.6 | 7 |
Measured?in?DMSO-d
6
Two, remove O
2 -Ability test
(1) preparation of each storing solution
NADH storing solution: claim 20.7mg NADH, be dissolved in the 40ml pH 8.150mmol/L Tris-HCl damping fluid.
PMS storing solution: claim 1.84mg PMS, be dissolved in the 40ml pH 8.150mmol/L Tris-HCl damping fluid.
NBT storing solution: claim 12.3mg NBT, be dissolved in the 30ml pH 8.150mmol/L Tris-HCl damping fluid.
Sample: be dissolved into different concns with DMSO.
(2) experimentation
445 μ l pH 8.150mmol/L Tris-HCl → 250 μ l NADH storing solutions → 250 μ l NBT storing solutions → 5 μ l samples → 50 μ l PMS storing solutions, mixing, room temperature is put 5min, and 570nm surveys the OD value.
Attention: the zeroing group replaces sample+PMS with the DMSO+Tris-HCl damping fluid
Blank group replaces PMS with the Tris-HCl damping fluid
Control group replaces sample with DMSO
Superoxide anion clearance rate=[1-(the blank group of OD mensuration group-OD)/(OD control group-OD zeroing group)] * 100%
(3) experimental result: see Table 2.
Table 2 The compounds of this invention is removed O
2 -The result
| The sample title | IC 50(μM) |
| Coffic acid | 3.51 |
| The compounds of this invention | 2.70 |
Three, to alkane free radical DPPH influence test
(1) DPPH storing solution: claim 5mg DPPH, with dissolve with methanol to the about 100mg/L of concentration.
Sample: be dissolved into different concns with DMSO
(2) experimentation: 995 μ l DPPH storing solutions → 5 μ l medicines
Mixing, 546nm surveys the OD value behind the room temperature lucifuge 20min.
The zeroing group replaces the DPPH+ medicine with methyl alcohol+DMSO
Blank group replaces DPPH with methyl alcohol
Control group replaces medicine with DMSO
Remove per-cent=[1-(OD
Measure-OD
Blank)/(OD
Contrast-OD
Zeroing)] * 100%
(3) experimental result: see Table 3.
Table 3 The compounds of this invention is to alkane free radical DPPH test-results
| The sample title | IC 50(μM) |
| Coffic acid | 2.87 |
| The compounds of this invention | 2.05 |
Four, The compounds of this invention inhibition test
The compounds of this invention is to the external antitumor activity experiment of 4 knurl strains of human body, and these 4 knurl strains comprise leukemia HL-60 cell, leukemia Mata cell, nasopharyngeal carcinoma CNE-1 cell and liver cancer HepG2 cell.
(1) mtt assay
Every hole adds 200ul and (contains 2.5 * 10 in 96 well culture plates
4Individual tumour cell) contains the cell suspension of RPMI 1640 substratum of 10%FBS, put 37 ℃ of 5%CO
2After cultivating 24h in the incubator, experimental group adds the compound described in ultimate density 100,50,25,12.5 and the 6.25 μ g/ml claims 1 respectively, and control group then adds the equal-volume solvent, and repeat 4 times in every group 4 hole.Put 37 ℃, 5%CO
2Incubator was cultivated after 2 days, and abandoning supernatant adds the serum-free medium of the freshly prepared 50mg/ml of the containing MTT in 200 μ l/ holes, and 37 ℃ are continued to cultivate 4h.Abandoning supernatant adds 200 μ l DMSO, behind the concussion mixing, is 550nm with the wavelength on microplate reader, and reference wavelength is that 450nm measures the OD value.Calculation result also utilizes the CalcuSyn computed in software to go out IC
50Value.
Be calculated as follows medicine growth of tumour cell got inhibiting rate:
Growth of tumour cell inhibiting rate %=(the average OD value of the average OD value/control group of 1-experimental group) * 100%
(2) experimental result: see Table 4.
The different compound function of tumor inhibition of table 4
Experimental result shows: above-mentioned test shows, new compound of the present invention has antidotal effect, antineoplastic action, particularly to cancer, include but not limited to that liver cancer, leukemia, nasopharyngeal carcinoma have good therapeutic action, testing data shows that The compounds of this invention is better than the positive drug cis-platinum to leukemia HL-60 cell, leukemia Mata cell and the effect of HepG-2 cells in vitro inhibition of proliferation.
Embodiment
Embodiment 1
Get the Chinese fan palm seed 20kg of dried and crushed, with 70% ethanol (150L) refluxing extraction 3 times, each 3 hours, united extraction liquid.Get concentrated extract (LC) 3.0kg at 55 ℃ of following decompression recycling ethanols.(LC) uses the 4.0L water-dispersion with the 3.0kg concentrated extract, uses equal-volume sherwood oil, chloroform, ethyl acetate and n-butanol extraction three times successively.Collect each extraction liquid respectively and concentrate and obtain petroleum ether extract (LCP) 90.21g, chloroform extract (LCC) 91.72g, acetic acid ethyl ester extract (LCE) 55.05g and n-butyl alcohol extract (LCB) 554.35g.
Get acetic acid ethyl ester extract (LCE) 55.05g,, claim 80g column chromatography silica gel (100-200 order) to mix sample with chloroform and dissolve with methanol.Take by weighing silica gel (200-300 order) 1200g, use chloroform dissolves silicon mucilage binding post, and no longer descend with chloroform balance pillar to silica gel face, sample on the dry method, pillar height are 10 * 80cm.Use successively chloroform (48L), chloroform-methanol (100: 1) (80L), chloroform-methanol (50: 1) (47L), chloroform-methanol (25: 1) (53L), chloroform-methanol (15: 1) (116L), chloroform-methanol (10: 1) (41L), chloroform-methanol (5: 1) (45L), chloroform-methanol (2: 1) (5.1L), methyl alcohol (3L) gradient elution.The control flow velocity is at 1500ml/h, and whenever meeting 1000ml is that a cut concentrates.And utilize thin layer to detect merging and obtain 23 component (LCE
1-LCE
23).
Get the 11st cut LCE21 (1.60g) (obtaining), carry out silicagel column and separate, take by weighing about 100～200 order silica gel 2g and mix sample by 50: 1 wash-outs of chloroform-methanol.Take by weighing 200～300 order silica gel 50g then, dissolve silica gel with chloroform, fill out post, and till no longer descending with chloroform balance pillar to silica gel, last sample is measured the diameter of pillar and highly is (2.5 * 35cm).With chloroform and methyl alcohol is that eluent carries out gradient elution, its gradient is set to chloroform, chloroform-methanol (100: 1), chloroform-methanol (50: 1), chloroform-methanol (25: 1), chloroform-methanol (15: 1), chloroform-methanol (10: 1), chloroform-methanol (5: 1), methyl alcohol, the volume of each gradient elution is respectively 10L, 10L, 5L, 5L, 3L, 3L, 3L, 0.5L, and concentrate about every part of 500ml, utilize thin layer to detect and instruct merging to obtain 7 components (LCE11-1-LCE11-7).Component LCE11-2 (750mg) uses the 2ml dissolve with methanol, (2 * 43cm) separate by Sephadex LH-20 post, with chloroform-methanol (7: 3) is eluent, flow velocity is 1 droplet/second, every 5ml concentrates as a cut, and utilizes thin layer to detect and instruct merging to obtain 3 components (LCE11-2-1-LCE11-2-3).Component LCE11-2-1 (100mg) is through Rp-18 high performance liquid phase Waters XTerra series, 19 * 250mm i.d. preparative chromatography post separates, moving phase is methyl alcohol: water (42: 58) pH is 2.5, ultraviolet detection, wavelength is 205nm, and flow velocity is that 6ml/min is that 32.407min obtains The compounds of this invention (10mg) in retention time.Identify structure by physicochemical constant and modern Wave Spectrum means (MS, NMR), compound is 2-(3 '-hydroxyl-5 '-methoxyphenyl)-3-(methylol-1)-7-methoxyl group-2,3-dihydro benzofuran-5-carboxylic acid.
The foregoing description includes but not limited to above-mentioned.
Claims (7)
1. compound:
2. the application of compound according to claim 1 in the old and feeble medicine of preparation treatment.
3. the application of compound according to claim 1 in preparation medicine for treating tumor thing.
4. application according to claim 3, wherein said tumour are cancer.
5. application according to claim 3, wherein said tumour are liver cancer.
6. application according to claim 3, wherein said tumour are leukemia.
7. application according to claim 3, wherein said tumour are nasopharyngeal carcinoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101900292A CN101845032B (en) | 2010-06-03 | 2010-06-03 | Phenolic compound and uses |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101900292A CN101845032B (en) | 2010-06-03 | 2010-06-03 | Phenolic compound and uses |
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| Publication Number | Publication Date |
|---|---|
| CN101845032A CN101845032A (en) | 2010-09-29 |
| CN101845032B true CN101845032B (en) | 2011-11-30 |
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| RU2328495C2 (en) * | 2003-03-07 | 2008-07-10 | Кова Ко., Лтд. | Benzofuran derivatives |
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