CN101434600A - Curcumin piperidone analog and use thereof in anti-tumor medicament - Google Patents
Curcumin piperidone analog and use thereof in anti-tumor medicament Download PDFInfo
- Publication number
- CN101434600A CN101434600A CNA2008100724578A CN200810072457A CN101434600A CN 101434600 A CN101434600 A CN 101434600A CN A2008100724578 A CNA2008100724578 A CN A2008100724578A CN 200810072457 A CN200810072457 A CN 200810072457A CN 101434600 A CN101434600 A CN 101434600A
- Authority
- CN
- China
- Prior art keywords
- piperidone
- cancer
- treatment
- compound
- methylene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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 Claisen-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, the application that is specifically related to synthetic 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone and is used to prepare antitumor drug.
Background technology:
Curcumine (Curcumin; write a Chinese character in simplified form Cur) be the Polyphenols natural product that from Zingiber curcuma turmeric (Curcuma longa L.) rhizome, extracts; edible and the medicinal record of more than one thousand years is arranged on India, China, Japan, Korea S and other places, have pharmacological actions such as antitumor, anti-oxidant, anti-inflammatory, protection.But the curcumine activity is on the low side, poorly water-soluble, and metabolism is fast in vivo after oral, and bioavailability is low, becomes the principal element that limits its clinical application.By the synthetic curcumin derivate of structure of modification or the direct analogue of synthetic curcumine, enhanced activity, water-soluble significant.With the 4-piperidone is the intermediate analogue of a series of curcumines of synthetic directly or indirectly, at antitumor, anti-inflammatory, antibiotic, aspects such as treatment diabetes and complication significant effect is arranged.
Summary of the invention:
One of purpose of the present invention is to provide 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone, and its structural formula is respectively:
And contain 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone for the treatment of significant quantity and at pharmacy acceptable salt.Described pharmacy acceptable salt is hydrochloride, acetate.Can also contain 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone compositions for the treatment of significant quantity, the described carrier of composition is pharmaceutically acceptable carrier.
Two of the object of the invention is to provide the preparation method of 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone.Compound 3 of the present invention, 5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone can carry out the Claisen-Schimidt reaction by piperonylaldehyde or 3-pyridylaldehyde and 4-piperidone hydrochloride and obtain.The signal formula is as follows:
Three of the object of the invention is to provide 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone, the application that is used to prepare antitumor drug.
3,5-two (3,4-methylene-dioxy Ben Yajiaji)-and 4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone, can be used for but be not limited to preparation treating 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 treatment method for 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 Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone 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 the curcumine to their inhibited proliferation, and its half-inhibition concentration is about below 1/10 of curcumine.Above result shows that 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone tumor cell in vitro inhibited proliferations are better than the restraining effect of its parent curcumine.
Embodiment:
The present invention is described in detail below in conjunction with embodiment:
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 1100 LC/MSD Trap ion trap LC-MS instrument); Micro-fusing point instrument (X-4, Shanghai precision instrument factory).
Embodiment 1
1) preparation of 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone:
3，5-Bis(Piperonal)-piperidin-4-one
4-piperidone hydrochloride 1.536g (10mmol) is dissolved in saturated HCl gas/glacial acetic acid solution 30ml, after waiting to clarify under the stirring at room, adds piperonylaldehyde 3g (20mmol).React 6h under the room temperature, stopped reaction, aftertreatment in 5 days.Suction filtration, ethanol water mixed solvent recrystallization obtains yellow powder 3.51 grams (productive rate 88%), and fusing point is 222-225 ℃.Molecular formula C
21H
18ClNO
5ESI-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) preparation of 3,5-two (3-pyridine methylene)-4-piperidone:
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, after waiting to clarify under the stirring at room, adds 3-pyridylaldehyde 2.14g (20mmol).React 6h under the room temperature, stopped reaction, aftertreatment in 5 days.Suction filtration, ethanol water mixed solvent recrystallization obtains pale yellow powder 2.50 grams (productive rate 80%), and fusing point is 258-260 ℃.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 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone:
The tumor cell line that uses has: human acute transformation of chronic myelocytic leukemia cell strain K562, mouse melanin tumor cell strain B-16, human liver tumor cell's strain HepG2, people's multiple myeloma cell line 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, human osteosarcoma cell's strain U2OS, above cell all derive from Chinese Academy of Sciences's Shanghai cell bank.
Cell cultures in the RPMI 1640 that adds 10% calf serum cultivates, at 37 ℃, 5%CO
2Cultivate in the incubator, take the logarithm vegetative period cell be used for the experiment.
The cell of logarithmic phase will necessarily be in, be inoculated in (attached cell is treated adherent back) in 96 orifice plates by certain density, what experimental group added different concns respectively is subjected to the reagent thing, not dosing of control group, other establishes blank group and (only adds substratum, acellular), establish three parallel holes for every group, cultivate 48h for 37 ℃, add the MTT solution 20ul/ hole of 5mg/ml, after continuing to cultivate 4h, the centrifugal supernatant of abandoning adds DMSO150ul, vibration 10min, fully after the cracking, detect absorbancy (OD570) value at 570nm place with full-automatic microplate reader (production of U.S. BIO-RAD company).Calculate inhibitory rate of cell growth according to absorbancy.Inhibitory rate of cell growth=[OD contrast-OD experiment]/[OD contrast-OD blank] * 100%.
To the mapping of growth of tumour cell inhibiting rate, can obtain dose response curve with the different concns of same medicine, obtaining this medicine cell growth inhibiting rate according to equation of linear regression is that 50% concentration is half-inhibition concentration IC
50The results are shown in Table 1.3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone 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 all is lower than 1/10 of curcumine IC50.Above result shows that the extracorporeal anti-tumor function of 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone and 3,5-two (3-pyridine methylene)-4-piperidone all is better than curcumine.
Table 1 test-compound is to the inhibited proliferation of tumour cell
Claims (8)
1. the compound of following chemical structure:
Its chemical name is 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone.
2. the compound of following chemical structure:
Its chemical name is 3,5-two (3-pyridine methylene)-4-piperidone.
3. be used for the treatment of the anti-tumor drug compound, wherein contain the compound of the claim 1 for the treatment of significant quantity or claim 2 and at pharmacy acceptable salt.
4. treatment anti-tumor drug compound as claimed in claim 3 is characterized in that described pharmacy acceptable salt is hydrochloride, acetate.
5. be used for the treatment of antitumor medicine composition, wherein contain the compound of the claim 1 for the treatment of significant quantity or claim 2 and at pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. the application of the compound of 3,5-two (3,4-methylene-dioxy Ben Yajiaji)-4-piperidone compounds as claimed in claim 1 and described 3,5-two (3-pyridine methylene)-4-piperidone of claim 2 in the preparation antitumor drug.
7. treatment anti-tumor drug compound as claimed in claim 3 is characterized in that the medical compounds of described medical compounds for treatment leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer, prostate cancer or other malignant tumours.
8. treatment antitumor medicine composition as claimed in claim 5 is characterized in that the pharmaceutical composition of described pharmaceutical composition for treatment leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer, prostate cancer or other malignant tumours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810072457.8A CN101434600B (en) | 2008-12-25 | 2008-12-25 | Curcumin piperidone analog and use thereof in anti-tumor medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810072457.8A CN101434600B (en) | 2008-12-25 | 2008-12-25 | Curcumin piperidone analog and use thereof in anti-tumor medicament |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101434600A true CN101434600A (en) | 2009-05-20 |
| CN101434600B CN101434600B (en) | 2014-08-06 |
Family
ID=40709251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810072457.8A Expired - Fee Related CN101434600B (en) | 2008-12-25 | 2008-12-25 | Curcumin piperidone analog and use thereof in anti-tumor medicament |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101434600B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723935A (en) * | 2009-11-27 | 2010-06-09 | 中山大学 | 1,5-diaryl-substituted 2,4-dienone derivative as well as preparation method and application thereof |
| CN102153508A (en) * | 2010-10-08 | 2011-08-17 | 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 |
| CN102477013A (en) * | 2011-07-28 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin compound capable of inhibiting activity of human type 1 11beta-hydroxysteroid dehydrogenase |
| CN102477012A (en) * | 2011-07-21 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin analogs capable of inhibiting activity of 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) of human |
| CN106083704A (en) * | 2016-06-06 | 2016-11-09 | 福建医科大学 | 3,5 (E) two aryl methylene N cyclopropyl piperidine 4 ketone compounds is as the application of Hsp90 inhibitor |
| CN106800547A (en) * | 2017-01-03 | 2017-06-06 | 中国人民解放军第二军医大学 | A kind of disubstituted aryl class compound and its application |
| CN113354577A (en) * | 2021-05-27 | 2021-09-07 | 西南医科大学附属中医医院 | Monocarbonyl curcumin analogue and preparation and application thereof |
| CN115260212A (en) * | 2022-08-01 | 2022-11-01 | 桂林医学院 | 3, 5-bis (benzylidene) -4-piperidone derivative and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001040188A1 (en) * | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
| 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 |
-
2008
- 2008-12-25 CN CN200810072457.8A patent/CN101434600B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001040188A1 (en) * | 1999-12-03 | 2001-06-07 | Emory University | Curcumin analogues for treating cancer |
| 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 (1)
| Title |
|---|
| KHAIRIA M.YOUSSEF ET AL.: "Synthesis of curcumin anologes as potential antioxidant, cancer chemopreventive agents", 《ARCH.PHARM.PHARM.MED.CHEM.》 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723935A (en) * | 2009-11-27 | 2010-06-09 | 中山大学 | 1,5-diaryl-substituted 2,4-dienone derivative as well as preparation method and application thereof |
| 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 |
| CN102153508A (en) * | 2010-10-08 | 2011-08-17 | 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 |
| 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 |
| CN102477012A (en) * | 2011-07-21 | 2012-05-30 | 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 |
| CN102477013A (en) * | 2011-07-28 | 2012-05-30 | 暨南大学 | Preparation and application of curcumin compound capable of inhibiting activity of human type 1 11beta-hydroxysteroid dehydrogenase |
| CN106083704A (en) * | 2016-06-06 | 2016-11-09 | 福建医科大学 | 3,5 (E) two aryl methylene N cyclopropyl piperidine 4 ketone compounds is as the application of Hsp90 inhibitor |
| 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 |
| CN106800547A (en) * | 2017-01-03 | 2017-06-06 | 中国人民解放军第二军医大学 | A kind of disubstituted aryl class compound and its application |
| 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 |
| CN113354577A (en) * | 2021-05-27 | 2021-09-07 | 西南医科大学附属中医医院 | Monocarbonyl curcumin analogue and preparation and application thereof |
| CN115260212A (en) * | 2022-08-01 | 2022-11-01 | 桂林医学院 | 3, 5-bis (benzylidene) -4-piperidone derivative 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101434600B (en) | 2014-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101434600B (en) | Curcumin piperidone analog and use thereof in anti-tumor medicament | |
| Rodrigo et al. | Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: synthetic and biological studies | |
| Thapa et al. | Design, synthesis, and antitumor evaluation of 2, 4, 6-triaryl pyridines containing chlorophenyl and phenolic moiety | |
| Lee et al. | Synthesis and anticancer activity of new 1-[(5 or 6-substituted 2-alkoxyquinoxalin-3-yl) aminocarbonyl]-4-(hetero) arylpiperazine derivatives | |
| CN102234259B (en) | Sphaelactone derivatives, their pharmaceutical compositions, preparation method thereof and application thereof | |
| KR101421140B1 (en) | Sphaelactone derivatives, their pharmaceutical compositions, preparation methods and uses | |
| CN102875560B (en) | 5-substituted tetrandrine compound and application thereof in preparing anticarcinogen sensitizer | |
| Liu et al. | Ervadivamines A and B, two unusual trimeric monoterpenoid indole alkaloids from Ervatamia divaricata | |
| CN106083704B (en) | Application of-two aryl methylene-N- cyclopropyl piperidine -4- ketone compounds of 3,5- (E) as Hsp90 inhibitor | |
| Lobo et al. | Synthesis and cytotoxic activity evaluation of some novel 1-(3-(aryl-4, 5-dihydroisoxazol-5-yl) methyl)-4-trihalomethyl-1H-pyrimidin-2-ones in human cancer cells | |
| CN102153508B (en) | 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 | |
| CN105418490B (en) | Purposes of the mustargen base piperlongumine class compound in medicine | |
| CN104151391A (en) | Oleanolic acid derivative having antineoplastic effect, preparation method and purpose thereof | |
| CN101434525B (en) | 4-(4-hydroxy3-methoxybenzene methyl) curcumin and use thereof in preparing anti-tumor medicament | |
| CN101332198B (en) | Pharmaceutical use of 6-aryl-3-substituted carbonyl pyridine compound | |
| CN101691353A (en) | N-Boc-3,5-(E)-diarylidene-4-piperidone and application thereof in preparation of anti-tumor drugs | |
| Liu et al. | Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property | |
| Sirignano et al. | Different 6-aryl-fulvenes exert anti-proliferative effects on cancer cells | |
| Bi et al. | Synthesis and biological evaluation of 12-Np-chlorobenzyl sophoridinol derivatives as a novel family of anticancer agents | |
| CN110882251A (en) | Synthesis method and anti-tumor application of 10-HCPT and Crizotinib coupled compound | |
| CN103130632A (en) | 1-substituted benzylidene-2-naphthalenone derivative, preparation method thereof and use thereof | |
| CN101434524B (en) | 4-(4-hydroxy-3-methoxybenzene methylene) curcumin, preparation thereof and use in preparing anti-cancer medicament | |
| CN104098457B (en) | Tetrahydrocurcumin analogue, preparation and application thereof | |
| CN101289453B (en) | Ellagic acid compounds preparation method | |
| CN104744518A (en) | Metallic ruthenium complex as well as preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140806 Termination date: 20211225 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |