CN101434525B - 4-(4-hydroxy3-methoxybenzene methyl) curcumin and use thereof in preparing anti-tumor medicament - Google Patents
4-(4-hydroxy3-methoxybenzene methyl) curcumin and use thereof in preparing anti-tumor medicament Download PDFInfo
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- CN101434525B CN101434525B CN 200810071179 CN200810071179A CN101434525B CN 101434525 B CN101434525 B CN 101434525B CN 200810071179 CN200810071179 CN 200810071179 CN 200810071179 A CN200810071179 A CN 200810071179A CN 101434525 B CN101434525 B CN 101434525B
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- 0 COc(cc(C*)cc1)c1O Chemical compound COc(cc(C*)cc1)c1O 0.000 description 2
- YYKIPSPMJXEHDD-LUZURFALSA-N COc1cc(CC(C(/C=C/c(cc2OC)ccc2O)=O)C(/C=C/c(cc2OC)ccc2O)=O)ccc1O Chemical compound COc1cc(CC(C(/C=C/c(cc2OC)ccc2O)=O)C(/C=C/c(cc2OC)ccc2O)=O)ccc1O YYKIPSPMJXEHDD-LUZURFALSA-N 0.000 description 1
Abstract
The invention relates to a synthetic antineoplastic, in particular to the synthesis of 4-(4-hydroxy-3-methoxyl benzyl) curcumin and an application thereof for the preparation of the antineoplastic. After 2, 4-pentanedione and vanillin are condensed by Knovenagel, the compound is subjected to catalytic hydrogenation to obtain 3-(4-hydroxy-3-methoxyl benzyl)-2, 4-pentanedione and then the 3-(4-hydroxy-3-methoxyl benzyl)-2, 4-pentanedione and the vanillin are condensed by hydroxyaldehyde to obtain the 4-(4-hydroxy-3-methoxyl benzyl) curcumin. The compound is applied to the preparation of medicaments for the treatment of leukemia, skin cancer, gastric cancer, carcinoma of colon, hepatic carcinoma, breast cancer, prostatic carcinoma or other malignant tumors.
Description
Technical field
The present invention relates to synthesizing antineoplastic medicament, the application that is specifically related to synthetic 4-(4-hydroxy 3-methoxybenzene methyl) curcumine and is used to prepare antitumor drug.
Background technology
Curcumine has the edible and medicinal record of more than one thousand years on India, China, Japan, Korea S and other places.Discover both at home and abroad that at present curcumine has various active such as antitumor, anti-inflammatory, angiogenesis inhibitor, anti-oxidant and neuroprotective.But the curcumine poorly water-soluble, its aqueous solution is unstable, and especially more unstable under neutrality to alkaline pH value condition, metabolism was fast in vivo after curcumine was oral, and bioavailability is low, and Plasma Concentration is lower, has become the principal element that limits its clinical application.Through the synthetic curcumin derivate of structure of modification, enhanced activity, water-soluble significant.Curcumin analogue anti-tumor aspect research at present mainly concentrates on and suppresses the NF-κ B and the AP-1 factor; The in vitro study of anti-angiogenesis activity and androgen antagonist; Having of curcumin analogue anti-tumor aspect foreign patent mandate: Vander Jagt etc. uses the NF-κ B and the AP-1 factor is suppressed; Screening anti-tumor activity curcumin analogue (US20070060644); The androgen receptor antagonists of Lee etc. (US006790979), the antitumor and anti-angiogenesis activity curcumin analogue (US006664272) of Snyder etc.
Both at home and abroad the structure of modification route to curcumine mainly contains: change substituting group kind and position on the phenyl ring, beta-diketon condensation or unsaturatedly for single ketones, in the middle of changing grip connection chain altogether, reduce unsaturated double-bond, 4 active methylene radical replacements etc., activity research still is in the experiment in vitro stage.
The present invention is through introducing active structure unit 34 of curcumine parents, and 4-disubstituted benzenes methyl synthesizes new curcumin analogue, and estimates its anti-tumor activity.
Summary of the invention
One of the object of the invention is to provide 4-(4-hydroxy 3-methoxybenzene methyl) curcumine, and its structural formula is:
Two of the object of the invention is to provide 4-(4-hydroxy 3-methoxybenzene methyl) preparation method of curcumine.The compounds of this invention 4-(4-hydroxy 3-methoxybenzene methyl) curcumine can be by 2; 4-diacetylmethane and Vanillin obtain earlier 3-(4-hydroxy 3-methoxybenzene methylene radical)-2 after the Knovenagel condensation; 4-diacetylmethane (intermediate A); Catalytic hydrogenation 3-(4-hydroxy 3-methoxybenzene methylene radical)-2 obtains 3-(4-hydroxy 3-methoxybenzene methyl)-2,4-diacetylmethane (intermediate B) behind the 4-diacetylmethane; 3-(4-hydroxy 3-methoxybenzene methyl)-2,4-diacetylmethane make 4-(4-hydroxy 3-methoxybenzene methyl) curcumine with Vanillin through aldol condensation again.Its reaction signal formula is as follows:
Three of the object of the invention is to provide 4-(4-hydroxy 3-methoxybenzene methyl) curcumine to be used to prepare the application of antitumor drug.
4-(4-hydroxy 3-methoxybenzene methyl) curcumine can be used for but be not limited to preparation treating white blood disease, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer or prostate cancer medicine.
4-(4-hydroxy 3-methoxybenzene methyl) curcumine can significantly suppress the propagation of various human tumour cell.Can see according to table two; This compound all shows the restraining effect stronger than parent curcumine to seven kinds of cell strains in this experiment; Especially K562, this two strains cell strain of B16; This compound is obviously better than the curcumine to their inhibited proliferation, and its half-inhibition concentration is about 1/4 and 1/7 of curcumine.Above result shows that 4-(4-hydroxy 3-methoxybenzene methyl) curcumine tumor cell in vitro inhibited proliferation is stronger than the restraining effect of its parent curcumine.
Embodiment
Synthesizing of embodiment 1 4-(4-hydroxy 3-methoxybenzene methyl) curcumine.
Synthesis material 3-hydroxyl-4-methoxybenzaldehyde (Vanillin), 2,4-diacetylmethane, boron trioxide, tri-n-butyl borate, n-Butyl Amine 99, piperidines are Chemical Reagent Co., Ltd., Sinopharm Group.Catalytic hydrogenation device (U.S. Parr 1100), and nuclear magnetic resonance spectrometer (Unity 500, U.S. Varian company, 500MHz), ion trap mass spectrometer (DECAX-30000, U.S. Thermo Finnigan company); Micro-fusing point appearance (X-4, Shanghai precision instrument factory).
Add 2 in the 250ml single port flask, 4-diacetylmethane 10g (0.1mol), ethanol 100ml adds the catalytic amount piperidines, Vanillin 15g (0.1mol), stirring reaction is 48 hours under the room temperature, concentrates and removes solvent, and recrystallization gets buff powder intermediate A 12.0g.
Add acetone 100ml in the 250ml catalytic hydrogenation bottle, intermediate A 10g, 10% palladium carbon 1g, the pressurized catalysis hydrogenation is 1 hour under the 25PSI, reacting liquid filtering, filtrating concentrates the back recrystallization and gets light brown oily solid intermediate B8.8g.
Intermediate B 2.36g (10mmol) and boron trioxide 0.49g (7mmol) are dissolved among the ETHYLE ACETATE 10ml, 40 ℃ of stirring reactions 0.5 hour; Adding Vanillin 3.04g (20mmol),, tri-n-butyl borate 11ml (40.5mmol), stirring reaction is 0.5 hour under the room temperature, splashes into the mixed solution of n-Butyl Amine 99 0.2ml (2mmol) and ETHYLE ACETATE 10ml; 0.5 hour drip, stirring reaction is 48 hours under the room temperature, adds 0.5M hydrochloric acid 15ml; Be warming up to 60 ℃ of reactions 1 hour, reaction solution is used ethyl acetate extraction, the saturated common salt washing; Anhydrous magnesium sulfate drying concentrates the back and uses ethyl alcohol recrystallization, gets orange powder 2.50 grams (productive rate 50%).Mp203-205 ℃, molecular formula C
29H
28O
8,
1H NMR (DMSO) δ (ppm) 3.69 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 3.99 (s, 2H), 6.78 (d, 2H, J=7.5Hz), 6.60-7.27 (m, 9H), 7.58 (d, 2H, J=15.0Hz), 17.9 (s, 1H); ESI-MS (M-H) 503.5.
Embodiment 2 4-(4-hydroxy 3-methoxybenzene methyl) curcumine suppresses tumour cell K562, HL-60, and B-16, SW480, HepG2, MGC80-3, the growth in vitro of SH-SY5Y is active:
2.1. clone
K562: human acute transformation of chronic myelocytic leukemia clone
HL-60: human acute myeloid leukemia cell is
B16: murine melanoma B16 cell strain.
SW480: human colon cancer cell
HepG2: human liver tumor cell
MGC80-3: gastric carcinoma cells
SH-SY5Y: HNB's cell
Above cell all derives from Chinese Academy of Sciences's Shanghai cell bank.
2.2 cell cultures
The cell cultures liquid formula is seen table 1, and cell is at 37 ℃, 5%CO
2Cultivate in the incubator, the vegetative period cell of taking the logarithm is used for propagation, apoptosis experiment.
Table 1 nutrient solution prescription
The cell strain nutrient solution
K562 RPM11640 nutrient solution+10% calf serum
HL60 RPM11640 nutrient solution+10% calf serum
B16 RPM11640 nutrient solution+10% calf serum
SW480 DMEM+10% foetal calf serum
HepG2 RPM11640 nutrient solution+10% calf serum
MGC80-3 RPM11640 nutrient solution+10% calf serum
SH-SY5Y RPM11640 nutrient solution+10% calf serum
2.3 mtt assay is observed the restraining effect of 4-(4-hydroxy 3-methoxybenzene methyl) curcumine on cell proliferation
To be in the cell of logarithmic phase, be that 50000/hole of suspension cell, 8000～12000/hole of attached cell are inoculated in 96 orifice plates by density.Experimental group (attached cell is treated adherent back) adds 4-(4-hydroxy 3-methoxybenzene methyl) curcumine and the curcumine of different concns respectively, not dosing of control group, and other establishes blank control group and (only adds substratum; Acellular), establish three parallel holes for every group, cultivate 48h for 37 ℃; The MTT solution 20ul/ hole that adds 5mg/ml, after continuing to cultivate 4h, the centrifugal supernatant of abandoning; Add DMSO150ul; Vibration 10min fully after the cracking, detects absorbancy (OD570) value at 570nm place with full-automatic ELIASA (production of U.S. BIO-RAD company).Calculate inhibitory rate of cell growth according to absorbancy.
Inhibitory rate of cell growth=[control wells OD value-experimental port OD value]/[control wells OD value-blank well OD value] * 100%
To the mapping of growth of tumour cell inhibiting rate, can obtain dose response curve with the different concns of same medicine, obtain the half-inhibition concentration IC50 of this medicine according to equation of linear regression, promptly cell survival rate reduces by 50% o'clock drug level.
2.4 result
4-(4-hydroxy 3-methoxybenzene methyl) curcumine can significantly suppress the propagation of various human tumour cell; According to table 2; We can see that this compound all shows restraining effect, the especially K562 stronger than parent curcumine, this two strains cell strain of B16 to seven kinds of cell strains in this experiment; This compound is obviously better than the curcumine to their inhibited proliferation, and its half-inhibition concentration is about 1/4 and 1/7 of curcumine.Above result shows that 4-(4-hydroxy 3-methoxybenzene methyl) curcumine tumor cell in vitro inhibited proliferation is stronger than the restraining effect of its parent curcumine.
Table 2
4-(4-hydroxy 3-methoxybenzene methyl) curcumine and curcumine are to the inhibited proliferation of cultured cell in vitro
Claims (4)
- (1.4-4-hydroxy 3-methoxybenzene methyl) curcumine, its structural formula is:。
- 2. the preparation method of the described 4-of claim 1 (4-hydroxy 3-methoxybenzene methyl) curcumine; Comprise the steps: by 2; 4-diacetylmethane and Vanillin obtain 3-(4-hydroxy 3-methoxybenzene methylene radical)-2,4-diacetylmethane, catalytic hydrogenation 3-(4-hydroxy 3-methoxybenzene methylene radical)-2 earlier after the Knovenagel condensation; Obtain 3-(4-hydroxy 3-methoxybenzene methyl)-2 behind the 4-diacetylmethane; 4-diacetylmethane, 3-(4-hydroxy 3-methoxybenzene methyl)-2,4-diacetylmethane make 4-(4-hydroxy 3-methoxybenzene methyl) curcumine with Vanillin through aldol condensation again.
- 3. the described 4-of claim 1 (4-hydroxy 3-methoxybenzene methyl) curcumine is used to prepare the application of antitumor drug.
- 4. 4-as claimed in claim 3 (4-hydroxy 3-methoxybenzene methyl) curcumine is used to prepare the application of antitumor drug, it is characterized in that: described antitumor drug is the medicine of treatment white blood disease, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer.
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| CN101570496B (en) * | 2009-06-12 | 2012-08-15 | 乐山师范学院 | Curcumin-4-nitrogen-containing derivatives, and preparation method and uses thereof |
| CN104030904B (en) * | 2014-03-07 | 2017-01-18 | 福建医科大学 | Application of 4-arylmethyl curcumin analogues serving as Hsp90 inhibitor |
| US20160106687A1 (en) | 2014-10-21 | 2016-04-21 | Life Plus, LLC | Human therapeutic agents |
| US9907786B2 (en) | 2014-10-21 | 2018-03-06 | Ions Pharmaceutical S.À R.L. | Therapeutic compositions containing harmine and isovanillin components, and methods of use thereof |
| US10092550B2 (en) | 2014-10-21 | 2018-10-09 | Ions Pharmaceutical S.À R.L. | Therapeutic compositions containing curcumin, harmine, and isovanillin components, and methods of use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6664272B2 (en) * | 1999-12-03 | 2003-12-16 | Emory University | Curcumin analogs with anti-tumor and anti-angiogenic properties |
| US6790979B2 (en) * | 2002-04-17 | 2004-09-14 | University Of North Carolina At Chapel Hill | Curcumin analogues and uses thereof |
| CN101003470A (en) * | 2007-01-22 | 2007-07-25 | 温州医学院生物与天然药物开发中心有限公司 | Analog of mono carbonyl structure of curcumin, and usage |
| CN101076336A (en) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6664272B2 (en) * | 1999-12-03 | 2003-12-16 | Emory University | Curcumin analogs with anti-tumor and anti-angiogenic properties |
| US6790979B2 (en) * | 2002-04-17 | 2004-09-14 | University Of North Carolina At Chapel Hill | Curcumin analogues and uses thereof |
| CN101076336A (en) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
| CN101003470A (en) * | 2007-01-22 | 2007-07-25 | 温州医学院生物与天然药物开发中心有限公司 | Analog of mono carbonyl structure of curcumin, and usage |
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