CN101434600B - Curcumin piperidone analog and use thereof in anti-tumor medicament - Google Patents
Curcumin piperidone analog and use thereof in anti-tumor medicament Download PDFInfo
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- CN101434600B CN101434600B CN200810072457.8A CN200810072457A CN101434600B CN 101434600 B CN101434600 B CN 101434600B CN 200810072457 A CN200810072457 A CN 200810072457A CN 101434600 B CN101434600 B CN 101434600B
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- piperidone
- cancer
- methylene
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- XHNHQRYTGVGSKB-BGPOSVGRSA-N O=C(/C(/CNC1)=C/c2cccnc2)/C1=C/c1cccnc1 Chemical compound O=C(/C(/CNC1)=C/c2cccnc2)/C1=C/c1cccnc1 XHNHQRYTGVGSKB-BGPOSVGRSA-N 0.000 description 1
- 0 O=C(C(C*C1)=C[C@]2C=C3OCOC3=CC2)C1=Cc1ccc2OCOc2c1 Chemical compound O=C(C(C*C1)=C[C@]2C=C3OCOC3=CC2)C1=Cc1ccc2OCOc2c1 0.000 description 1
Abstract
The invention discloses a structural analogue of curcumin piperidone, and the application thereof in the preparation of antitumor medicaments, more particularly relates to synthesized 3, 5-bis-(3, 4-methylenedioxybenxene-benzylidene)-4-piperidone and 3, 5-bis-(3-pyridine methylene)-4-piperidone and the application thereof in the preparation of antitumor medicaments. The compound 3, 5-bis-(3, 4-methylenedioxybenxene-benzylidene)-4-piperidone and 3, 5-bis-(3-pyridine methylene)-4-piperidone can be obtained by the Claiscn-Schimidt reaction of piperonal or 3-pyridylaldehyde and 4-piperidone hydrochloride. The compound is used for preparing medicaments for curing leucocythemia, skin cancer, stomach cancer, colon cancer, liver cancer, breast cancer, prostate cancer or other malignant tumors.
Description
Technical field:
The present invention relates to synthesizing antineoplastic medicament and preparation method, be specifically related to synthetic 3, two (3-pyridine methylene)-4-piperidone of two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 5-and 3,5-and for the preparation of the application of antitumor drug.
Background technology:
Curcumine (Curcumin; write a Chinese character in simplified form Cur) be the Polyphenols natural product extracting from Zingiber curcuma turmeric (Curcuma longa L.) rhizome; there is the edible and medicinal record of more than one thousand years on India, China, Japan, Korea S and other places, there is the pharmacological actions such as antitumor, anti-oxidant, anti-inflammatory, protection.But curcumine activity is on the low side, poorly water-soluble, metabolism is fast in vivo after oral, and bioavailability is low, becomes the principal element that limits its clinical application.Synthesize curcumin derivate or the direct analogue of synthetic curcumine, enhanced activity, water-soluble significant by structure of modification.Taking 4-piperidone as the intermediate analogue of synthetic a series of curcumines directly or indirectly, there is significant effect at aspects such as antitumor, anti-inflammatory, antibacterial, treatment diabetes and complication.
Summary of the invention:
One of object of the present invention is to provide two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 3,5-and two (3-the pyridine methylene)-4-piperidone of 3,5-, and its structural formula is respectively:
And contain 3 for the treatment of significant quantity, two (3-pyridine industry the methyl)-4-piperidone of two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 5-and 3,5-and pharmaceutically acceptable salt.Described pharmacy acceptable salt is hydrochloride, acetate.Can also contain 3 for the treatment of significant quantity, two (3-the pyridine methylene)-4-piperidone compositions of two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 5-and 3,5-, the carrier described in composition is pharmaceutically acceptable carrier.
Two of the object of the invention is to provide the preparation method of two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 3,5-and two (3-the pyridine methylene)-4-piperidone of 3,5-.Compound 3 of the present invention, 5-two (3,4-methylene-dioxy α-tolylene) two (3-the pyridine methylene)-4-piperidone of-4-piperidone and 3,5-can carry out Claisen-Schimidt by piperonylaldehyde or 3-pyridylaldehyde and 4-piperidone hydrochloride and react and obtain.Signal formula is as follows:
Three of the object of the invention is to provide two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 3,5-and two (3-the pyridine methylene)-4-piperidone of 3,5-, for the preparation of the application of antitumor drug.
3,5-two (3,4-methylene-dioxy α-tolylene)-4-piperidone and two (3-the pyridine methylene)-4-piperidone of 3,5-, can be used for but be not limited to preparation treatment leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer or prostate cancer medicine.
According to other embodiments of the present invention, the present invention relates to a kind of method for the treatment of cancer, the example of treatable cancer is including, but not limited to leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer, prostate cancer.
Beneficial effect of the present invention is: 3, 5-two (3, 4-methylene-dioxy α-tolylene)-4-piperidone and 3, two (3-the pyridine methylene)-4-piperidone of 5-can significantly suppress the propagation of various human tumour cell, according to table, we can see, these two compounds all show the restraining effect stronger than parent curcumine to nine kinds of cell strains in this experiment, especially K562, PANC-1, this three strains cell strain of SW480, this compound is obviously better than curcumine to their inhibited proliferation, its half-inhibition concentration is about below 1/10 of curcumine.Above result show two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 3,5-and two (3-the pyridine methylene)-4-piperidone tumor cell in vitro inhibited proliferations of 3,5-better than the restraining effect of its parent curcumine.
Embodiment:
Below in conjunction with embodiment, the present invention is described in detail:
Synthesis material: 4-piperidone hydrochloride, piperonylaldehyde, 3-pyridylaldehyde are that Aldrich product, Glacial acetic acid, concentrated hydrochloric acid, dehydrated alcohol are Chemical Reagent Co., Ltd., Sinopharm Group's product, nuclear magnetic resonance spectrometer (Bruker Avance III, 400MHZ), mass spectrograph (Agilent 1100LC/MSD Trap ion trap LC-MS instrument); Micro-meldometer (X-4, Shanghai precision instrument factory).
Embodiment 1
1) 3, the preparation of two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 5-:
3，5-Bis(Piperonal)-piperidin-4-one
4-piperidone hydrochloride 1.536g (10mmol) is dissolved in saturated HCl gas/glacial acetic acid solution 30ml, under stirring at room temperature, after clarifying, adds piperonylaldehyde 3g (20mmol).Under room temperature, react 6h, stopped reaction, aftertreatment in 5 days.Suction filtration, ethanol water mixed solvent recrystallization, obtains 3.51 grams of yellow powders (productive rate 88%), and fusing point is 222-225 DEG C.Molecular formula C
21h
18clNO
5; ESI-MS (M+H-HCl) 364.2; 1H NMR (CDCl3) δ (ppm) 7.71 (S, 2H ,-CH=), 6.94 (2H, Ar), 6.92 (2H, Ar), 6.87 (2H, Ar), 6.00 (4H, O-CH
2-O), 4.12 (S, 4H ,-CH
2-)
Embodiment 2
2) 3, the preparation of two (3-the pyridine methylene)-4-piperidone of 5-:
3，5-Bis(3-pyridyl)-piperidin-4-one
4-piperidone hydrochloride 1.536g (10mmol) is dissolved in saturated HCl gas/glacial acetic acid solution 30ml, under stirring at room temperature, after clarifying, adds 3-pyridylaldehyde 2.14g (20mmol).Under room temperature, react 6h, stopped reaction, aftertreatment in 5 days.Suction filtration, ethanol water mixed solvent recrystallization, obtains 2.50 grams of pale yellow powders (productive rate 80%), and fusing point is 258-260 DEG C.Molecular formula C
17h
16clN
3o; ESI-MS (M+H-HCl) 278.2;
1h NMR (D
2o) δ (ppm) 8.76 (S, 2H), 8.70 (2H, Ar), 8.55 (2H, Ar), 8.10 (2H, Ar), 8.01 (S, 2H ,-CH=), 4.57 (S, 4H ,-CH
2-),
13c NMR (D
2o) δ (ppm) 182.26,146.90,142.21,141.73,134.97,133.12,131.12,127.64,43.99
Embodiment 3
The detection of the anti tumor activity in vitro of two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 3,5-and two (3-the pyridine methylene)-4-piperidone of 3,5-:
The tumor cell line using has: mankind's acute transformation of chronic myelocytic leukemia cell strain K562, mouse melanin tumor cell strain B-16, human liver tumor cell's strain HepG2, Multiple myeloma cell lines U266, human pancreas cancer cell strain PANC-1, human colon cancer cell strain SW480, human neuroblastoma cell strain SH-SY5Y, human esophagus cancer cell strain TE-L1, cell line of human osteosarcoma U2OS, above cell all derives from Chinese Academy of Sciences's Shanghai cell bank.
Cell cultures in the RPMI 1640 that adds 10% calf serum cultivates, at 37 DEG C, 5%CO
2in incubator, cultivate, take the logarithm vegetative period cell for experiment.
By certain cell in logarithmic phase, be inoculated in (attached cell is after adherent) in 96 orifice plates by certain density, experimental group adds respectively the tested medicine of different concns, not dosing of control group, separately establish blank group and (only add substratum, acellular), establish three parallel holes for every group, cultivate 48h for 37 DEG C, add the MTT solution 20ul/ hole of 5mg/ml, continue to cultivate after 4h, the centrifugal supernatant of abandoning, add DMSO150ul, vibration 10min, fully after cracking, detect absorbancy (OD570) value at 570nm place by full-automatic microplate reader (production of BIO-RAD company of the U.S.).Calculate inhibitory rate of cell growth according to absorbancy.Inhibitory rate of cell growth=[OD contrast-OD experiment]/[OD contrast-OD blank] × 100%.
Different concns with same medicine is mapped to growth of tumour cell inhibiting rate, can obtain dose response curve, and obtaining according to equation of linear regression the concentration that this medicine cell growth inhibiting rate is 50% is half-inhibition concentration IC
50.The results are shown in Table 1.3,5-two (3,4-methylene-dioxy α-tolylene)-4-piperidone and 3, two (3-the pyridine methylene)-4-piperidone of 5-can significantly suppress the propagation of various human tumour cell, as can be seen from Table 1, above-mentioned 2 compounds all show the restraining effect stronger than parent curcumine to nine kinds of cell strains in this experiment, and especially, to K562, PANC-1, this three strains cell strain of SW480, its IC50 is all lower than 1/10 of curcumine IC50.Above result shows that the extracorporeal anti-tumor function of two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 3,5-and two (3-pyridine industry the methyl)-4-piperidone of 3,5-is all better than curcumine.
The inhibited proliferation of table 1 test-compound to tumour cell
Claims (8)
1. the compound of following chemical structure:
Its chemical name is two (3,4-methylene-dioxy the α-tolylene)-4-piperidone of 3,5-.
2. antineoplastic compound of following chemical structure:
Its chemical name is two (3-the pyridine methylene)-4-piperidone of 3,5-.
3. being used for the treatment of the medical compounds of tumour, is the compound of claim 1 or claim 2 and acceptable salt pharmaceutically thereof.
4. the medical compounds for the treatment of tumour as claimed in claim 3, is characterized in that described pharmacy acceptable salt is hydrochloride, acetate.
5. the medical compounds for the treatment of tumour as claimed in claim 3, is characterized in that described medical compounds is the medical compounds for the treatment of leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer, prostate cancer or other malignant tumours.
6. be used for the treatment of the pharmaceutical composition of tumour, wherein contain and treat the claim 1 of significant quantity or the compound of claim 2 and pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
7. the pharmaceutical composition for the treatment of tumour as claimed in claim 6, is characterized in that described pharmaceutical composition is the pharmaceutical composition for the treatment of leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer, prostate cancer or other malignant tumours.
8. as claimed in claim 13,5-two (3,4-methylene-dioxy α-tolylene)-4-piperidone compound and claimed in claim 23, the compound of two (3-the pyridine methylene)-4-piperidone of 5-is in the application of preparing in antitumor drug.
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101723935B (en) * | 2009-11-27 | 2013-05-01 | 中山大学 | 1,5-diaryl-substituted 2,4-dienone derivative as well as preparation method and application thereof |
| CN102153508B (en) * | 2010-10-08 | 2013-01-09 | 福建医科大学 | 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs |
| CN102477012B (en) * | 2011-07-21 | 2014-08-13 | 暨南大学 | Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human |
| CN102477013B (en) * | 2011-07-28 | 2014-04-02 | 暨南大学 | Preparation and application of curcumin compound capable of inhibiting activity of human type 1 11beta-hydroxysteroid dehydrogenase |
| CN106083704B (en) * | 2016-06-06 | 2018-07-27 | 福建医科大学 | Application of-two aryl methylene-N- cyclopropyl piperidine -4- ketone compounds of 3,5- (E) as Hsp90 inhibitor |
| CN106800547B (en) * | 2017-01-03 | 2019-07-23 | 中国人民解放军第二军医大学 | A kind of disubstituted aryl class compound and its application |
| CN113354577B (en) * | 2021-05-27 | 2022-08-26 | 西南医科大学附属中医医院 | Monocarbonyl curcuminoid compound and preparation method and application thereof |
| CN115260212B (en) * | 2022-08-01 | 2023-05-23 | 桂林医学院 | 3, 5-bis (benzylidene) -4-piperidone derivative as well as preparation method and application thereof |
Citations (2)
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|---|---|---|---|---|
| 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 |
| CN101255119A (en) * | 2008-01-07 | 2008-09-03 | 沈阳药科大学 | Novel tetrahydro curcumin derivatives and salt |
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| WO2001040188A1 (en) * | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
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| 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 |
| CN101255119A (en) * | 2008-01-07 | 2008-09-03 | 沈阳药科大学 | Novel tetrahydro curcumin derivatives and salt |
Non-Patent Citations (2)
| Title |
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| Khairia M.Youssef et al..Synthesis of curcumin anologes as potential antioxidant, cancer chemopreventive agents.《Arch.Pharm.Pharm.Med.Chem.》.2004,第337卷第42-54页. |
| Synthesis of curcumin anologes as potential antioxidant, cancer chemopreventive agents;Khairia M.Youssef et al.;《Arch.Pharm.Pharm.Med.Chem.》;20041231;第337卷;第42-54页 * |
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