CN102432447A - Cyclopentanone-containing curcumin monocarbonyl structural analogues and application thereof - Google Patents

Cyclopentanone-containing curcumin monocarbonyl structural analogues and application thereof Download PDF

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CN102432447A
CN102432447A CN2011102658248A CN201110265824A CN102432447A CN 102432447 A CN102432447 A CN 102432447A CN 2011102658248 A CN2011102658248 A CN 2011102658248A CN 201110265824 A CN201110265824 A CN 201110265824A CN 102432447 A CN102432447 A CN 102432447A
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梁广
李校堃
杨树林
赵昱
周慧萍
姜丽娟
雷培培
温红
林滨
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Wenzhou Medical University
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Biological & Natural Medicines Development Center Co Ltd Wenzhou Medical Col
Wenzhou Medical College
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Abstract

The invention relates to curcumin structural analogues and application thereof. Curcumin is an excellent lead compound and has a plurality of pharmacological activity. Compared to curcumin, the analogues provided in the invention have a more stable monocarbonyl intermediate joining chain, and the joining chain is cyclopentanone; substituents on a phenyl ring of the analogues have a specific combination. The invention also includes pharmaceutically acceptable salts of the analogues, medicinal preparations containing the analogues and application of the analogues in pharmacy. According to results of related research, the analogues can be used for treating inflammation and tumors.

Description

Contain analog of mono carbonyl structure of curcumin of ketopentamethylene and uses thereof
The present invention is dividing an application of No. the 200710066787.1st, one Chinese patent application.
One. technical field
The present invention relates to the analog of a curcuminoids, the structure of this compounds is compared with curcumine, only contains a carbonyl group; The invention still further relates to preparation, pharmaceutical prepn and they of this compounds purposes at anti-inflammatory, anti-tumor aspect.
Two. background technology
Curcumine is a kind of important activity composition that nearly all zingiberaceous plant all contains.Edible and the medicinal record of more than one thousand years is all arranged on India, Brazil, Philippines, Japan, Korea S and other places.Curcumine is a compound that pharmacologically active is strong, indication is wide.In recent years, pharmaceutical chemistry and pharmaceutical research find that curcumine has multiple pharmacological effect such as anti-inflammatory, antitumor, angiogenesis inhibitor, mutation, antibiotic, antiviral, anti-oxidant and neuroprotective, and curcumine has got into the I phase clinical experiment stage in the U.S..Its antitumor action comprises the growth in vitro of kinds of tumor cells is suppressed and apoptosis-induced and suppress tumorigenic ability in vivo; The blood vessel formation against function of curcumine comprises that the inhibition capillary vessel generates and growth in vitro inhibition vascular endothelial cell proliferation and the body; Its anti-inflammatory activity comprises release that scavenger cell is discharged multiple inflammatory factor etc.Exactly because effects such as its antitumor and anti-inflammatory, and lower molecular weight, characteristics such as nontoxic, curcumine once was considered to one of ideal chemotherapeutic agent.Yet, further discover in curcumine active on the low side, the body in vivo absorb less, tachytrophism and bioavailability be low, greatly limited its application.But; Consider its definite biological activity, simple relatively molecular structure; Curcumine still the can yet be regarded as a kind of outstanding structural modification and the lead compound of screening anti-tumor medicine; At present, with keep its drug safety, increase anti-tumor activity and water-soluble be that the curcumin analogue design of purpose, synthetic, assessment and screening study have attracted a lot of medicament research and development mechanisms and pharmaceutical companies.
Figure BSA00000571744800011
Curcumine
At present; With the curcumine is in the structure of modification and drug screening of lead compound; Investigators have drawn a lot of valuable conclusions; Especially more to the pharmacophores such as planarity that the substituting group kind on the phenyl ring in the curcumine structure and position, beta-diketon part, 4 methylene radical replace, the flexible and variation of middle connection chain and molecule are whole to the influence and the contribution research of pharmacologically active, be used to instruct the further research and development of curcumin novel drugs, significant.
In research at present to the various structure activity relationships of curcumine, generally believe that curcumine passes through its phenolic hydroxyl group and beta-diketon partly produces the proton radical, block intravital oxyradical and react, play oxidation resistant effect; At the lesions position of each indication, also be to bring into play various pharmacological actions through eliminating radical.This relates to two important molecular radicals of curcumine: phenolic hydroxyl group and beta-diketon part; Wherein the anti-oxidant activity of phenolic hydroxyl group mainly is because the hydroxyl proton donor on the aromatic ring can be blocked free chain reaction, and its resistance of oxidation depends on other substituent character on quantity and the distribution and the aromatic ring of phenolic hydroxyl group; The active main proton by the intermediate sub methyl of beta-diketon part loses easily and produces.Therefore; Still imperfectly understanding under the curcumine acceptor enzyme and proteic situation in vivo at present; Transformation for curcumine also mainly concentrates on these two reactive groups: 1, and substituent position and kind change and the change of aromatic nucleus, the variation of beta-diketon structure and the replacement on the methylene radical of 4-position on the aromatic nucleus of 7-position.
Structure of modification to curcumine mainly concentrates on following several aspect.CN1646473A; WO2003/088927; Liebigs Ann.Chem, 1557-1569 (1985); People such as Roughley, j.Chem.Soc.Perkin I, 2379-2388 (1973); People such as Ishida, Cancer Lett., 159.135-140 (2000)
1. substituent kind and position on the phenyl ring, as:
2. the replacement of 4 methylene radical, as:
Figure BSA00000571744800022
3. remove conjugated structure, as:
Figure BSA00000571744800023
4. generate the imidazoles substituent, as:
Figure BSA00000571744800031
5. the length of connection chain in the middle of shortening, as:
Figure BSA00000571744800032
Consult through a large amount of documents and patent; We find; Though generally believe that at present the reactive group in the curcumine structure is its phenolic hydroxyl group and beta-diketon group; But aspect the curcumin analogue research that does not contain these two reactive groups, find that also the single carbonyl curcumin analogue do not contain beta-diketon sometimes also shows stronger activity, this is that the active essential group of curcumine has proposed query for the beta-diketon group.And, because the existence of beta-diketon structure, the stability of curcumine a little less than, only o'clock just have stability preferably in PH＜6.5.
It is thus clear that the structure activity relationship possibility of curcumine is also so simple unlike what study at present, be that the drug screening of guide's thing should be not prerequisite to keep phenolic hydroxyl group and diketone structure fully also with the curcumine.In view of the above, we have designed stable curcumine list carbonyl analogue to remove the beta-diketon group; Consider that phenolic hydroxyl group is under the situation of nonessential group, we have selected the structure precursor of nearly multiple phenyl ring substituent as our design.
On the other hand; The two dimensional structure of connection chain is to the influence of pharmacologically active in the middle of considering; We selected acetone, ketopentamethylene and pimelinketone be middle connection chain with of the influence of studying plane spatial result to pharmacologically active, the result proves that this design plays a positive role to the raising of pharmacologically active.
Three. summary of the invention
According to embodiment of the present invention, the present invention relates to the compound of a kind of formula I:
Figure BSA00000571744800033
This compounds is with the curcumine list carbonyl analogue of acetone as middle connection chain, wherein R 1, R 2, R 3And R 4Be independently from each other hydrogen, hydroxyl, halogen, alkoxyl group, alkyl, haloalkyl, amino and alkylamino.
According to other embodiment of the present invention, the present invention relates to the compound of a kind of formula II:
This compounds is with the curcumine list carbonyl analogue of ketopentamethylene as middle connection chain, wherein R 5, R 6, R 7And R 8Be independently from each other hydrogen, hydroxyl, halogen, alkoxyl group, alkyl, haloalkyl, amino and alkylamino.
According to other embodiment of the present invention, the present invention relates to a kind of compound of formula III:
Figure BSA00000571744800042
This compounds is with the curcumine list carbonyl analogue of pimelinketone as middle connection chain, wherein R 5, R 6, R 7And R 8Be independently from each other hydrogen, hydroxyl, halogen, alkoxyl group, alkyl, haloalkyl, amino and alkylamino.
According to other embodiment of the present invention, the present invention relates to a kind of treatment method for cancer, comprise to a kind of compound of treating the following formula of significant quantity of the patient of this treatment of needs.The example of treatable cancer comprises; But be not limited to skin carcinoma, small cell lung cancer, carcinoma of testis, lymphatic cancer, white blood disease, esophagus cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, carcinoma of endometrium, ovarian cancer, cns cancer, liver cancer and prostate cancer.
According to other embodiment of the present invention, the present invention relates to a kind of method of treating inflammation, comprise to a kind of following formula compound of treating significant quantity of the patient of this treatment of needs.Treatable inflammation example includes, but are not limited to, furuncle, hepatitis, lymphadenitis, pneumonia, dysentery, ecphyaditis and trauma infection contamination.
Four. description of drawings
Here cited compound is just in order to explain compounds category of the present invention and structure formation better, and unrestricted the present invention.
Fig. 1 explanation is the structure of the curcumine list carbonyl analogue (1-13) of connection chain with acetone;
Fig. 2 explanation is the structure of the curcumine list carbonyl analogue (14-28) of connection chain with the ketopentamethylene;
Fig. 3 explanation is the structure of the curcumine list carbonyl analogue (29-40) of connection chain with the pimelinketone;
Fig. 4 explanation is through the activity of the lipopolysaccharide-induced scavenger cell expressing tumor necrosin (TNF-α) of the compound inhibition of curcumine and selection;
Fig. 5 explanation suppresses the activity that lipopolysaccharide-induced scavenger cell is expressed interleukin-(IL-6) through the compound of curcumine and selection;
Five. detailed description of the invention and embodiment
Now, with reference to accompanying drawing hereinafter, further set forth the present invention at this, with present invention is described in more detail.Yet the present invention can comprise different forms, and is not regarded as limiting of the invention in the embodiment of this elaboration.On the contrary, these embodiments are provided,, and scope of the present invention are fully conveyed to the skilled of this area so that thoroughly and completely disclose the present invention.
Only if it is different definition is arranged in addition, identical with scientific terminology with the implication of this area ordinary personnel common sense in all technology of this use.They all are incorporated herein by reference at this at these all publications of mentioning, patented claim, patent and other reference.
Term " alkyl " in this use is meant C 1-C 8Alkyl, it can be straight chain, side chain or cyclic and saturated or unsaturated.
" alkoxyl group " in this use is meant straight chain, side chain or cyclic and saturated or unsaturated oxo hydrocarbon chain, comprises for example methoxyl group, oxyethyl group, isopropoxy, allyl group oxygen base, tetrahydropyrans-2-oxygen base, phenoxy.
" haloalkyl " in this use is meant the substituted straight chain of halogen or side chain and saturated or unsaturated alkyl, comprises for example trifluoromethyl, trichloromethyl, trisbromomethyl, chloroethyl, bromotrifluoromethane.
" alkylamino " in this use is the alkylamino of single replacement or dibasic straight or branched, comprises for example dimethylamino, diethylamino, methylamino-, carboxymethylamino.
" pharmaceutically acceptable " in this use is meant: compound or compsn be suitable to give the patient obtaining said therapeutic action, and considers from the angle that needs of severity of disease and treatment, less than too deleterious spinoff.
Usually, active compound of the present invention comprises series structure:
Figure BSA00000571744800051
(I) compounds is with the curcumine list carbonyl analogue of acetone as middle connection chain, wherein R 1, R 2, R 3And R 4Be independently from each other hydrogen, hydroxyl, halogen, alkoxyl group, alkyl, haloalkyl, amino and alkylamino.
In the compound of formula (I), preferred compound has:
R wherein 1Be bromine, R 2, R 3, R 4Compound for hydrogen;
R wherein 3Be fluorine, R 1, R 2, R 4Compound for hydrogen;
R wherein 1, R 4Be hydrogen, R 2Be methoxyl group, R 3Compound for hydroxyl;
R wherein 1, R 2, R 4Be hydrogen, R 3The compound of hydroxyl.
Figure BSA00000571744800061
(II) compounds is with the curcumine list carbonyl analogue of ketopentamethylene as middle connection chain, wherein R 5, R 6, R 7And R 8Be independently from each other hydrogen, hydroxyl, halogen, alkoxyl group, alkyl, haloalkyl, amino and alkylamino.
In the compound of formula (II), preferred compound has:
R wherein 6Be bromine, R 5, R 7, R 8Compound for hydrogen;
R wherein 5Be hydrogen, R 6, R 7, R 8Compound for methyl;
R wherein 5, R 8Be hydrogen, R 6Be methoxyl group, R 7Compound for hydroxyl;
R wherein 5, R 6, R 8Be hydrogen, R 7The compound of hydroxyl.
Figure BSA00000571744800062
(III) compounds is with the curcumine list carbonyl analogue of pimelinketone as middle connection chain, wherein R 9, R 10, R 11And R 12Be independently from each other hydrogen, hydroxyl, halogen, alkoxyl group, alkyl, haloalkyl, amino and alkylamino.
In the compound of formula (III), preferred compound has:
R wherein 9, R 10, R 12Be hydrogen, R 11Compound for tetrahydropyrans-2-oxygen base;
R wherein 9, R 10, R 12Be hydrogen, R 11Compound for dimethylamino;
R wherein 9, R 12Be hydrogen, R 10Be methoxyl group, R 11Compound for tetrahydropyrans-2-oxygen base;
R wherein 9, R 12Be hydrogen, R 10Be methoxyl group, R 11Compound for hydroxyl;
R wherein 9, R 10, R 12Be hydrogen, R 11The compound of hydroxyl.
These preferred compounds and they constitute the part of complete content of the present invention at the additive salt of pharmaceutically acceptable acid.
A. concrete compound
Concrete compound is seen Figure of description and description of drawings, and cited here compound is just in order to explain compounds category of the present invention and structure formation better, and unrestricted the present invention.
B. the preparation of compound
According to the present invention, below the change carried out in the general compound method be conspicuous to this area skilled personnel, and be deemed to be within the scope of the present invention.
In the curcumin analogue that Fig. 1 representes with formula (I), the 1,2,3,4,5,6, the 8th, be raw material with acetone and corresponding phenyl ring substituent, under the catalysis of sodium methylate, stirring reaction and generating.The feed ratio of two kinds of raw materials is 1: 1.5～1: 3, and temperature of reaction is 0 ℃～80 ℃, and the reaction times is 2～10 hours.7 and 9 preparation is first by PARA HYDROXY BENZALDEHYDE or vanillin food grade,1000.000000ine mesh and dihydropyrane reaction, and product carries out condensation with acetone again and generates.10 and 11 preparation is to be raw material with 7 and 9 respectively, generates as the catalyzer hydrolysis reaction with p-methyl benzenesulfonic acid.12 and 13 preparation is first by PARA HYDROXY BENZALDEHYDE or vanillin food grade,1000.000000ine mesh and allyl bromide 98 reaction, and product carries out condensation with acetone again and generates.The above crude product that responds generation all needs under silica gel column chromatography, to carry out separation and purification and obtains pure article.
In the curcumin analogue that Fig. 2 representes with formula (II), the 14,15,16,17,18,19,21,26,27, the 28th, be raw material with ketopentamethylene and corresponding phenyl ring substituent, under the catalysis of sodium methylate, stirring reaction and generating.The feed ratio of two kinds of raw materials is 1: 1～1: 3, and temperature of reaction is 0 ℃～80 ℃, and the reaction times is 2～10 hours.20 and 22 preparation is first by PARA HYDROXY BENZALDEHYDE or vanillin food grade,1000.000000ine mesh and dihydropyrane reaction, and product carries out condensation with ketopentamethylene again and generates.23 and 24 preparation is to be raw material with 20 and 22 respectively, generates as the catalyzer hydrolysis reaction with p-methyl benzenesulfonic acid.25 preparation is first by PARA HYDROXY BENZALDEHYDE or vanillin food grade,1000.000000ine mesh and allyl bromide 98 reaction, and product carries out condensation with ketopentamethylene again and generates.The above crude product that responds generation all needs under silica gel column chromatography, to carry out separation and purification and obtains pure article.
In the curcumin analogue that Fig. 3 representes with formula (III), the 29,30,31,32,33,34, the 36th, be raw material with pimelinketone and corresponding phenyl ring substituent, under the catalysis of sodium methylate, stirring reaction and generating.The feed ratio of two kinds of raw materials is 1: 1～1: 3, and temperature of reaction is 0 ℃～80 ℃, and the reaction times is 2～10 hours.35 and 37 preparation is first by PARA HYDROXY BENZALDEHYDE or vanillin food grade,1000.000000ine mesh and dihydropyrane reaction, and product carries out condensation with pimelinketone again and generates.38 and 39 preparation is to be raw material with 35 and 37 respectively, generates as the catalyzer hydrolysis reaction with p-methyl benzenesulfonic acid.40 preparation is first by PARA HYDROXY BENZALDEHYDE or vanillin food grade,1000.000000ine mesh and allyl bromide 98 reaction, and product carries out condensation with pimelinketone again and generates.The above crude product that responds generation all needs under silica gel column chromatography, to carry out separation and purification and obtains pure article.
C. pharmacy acceptable salt be used for the pharmaceutical prepn of anti-inflammatory or anticancer usage
The compound that also comprises defined in the claim 1,2,3,4,5,6 in the content of the present invention is at pharmacy acceptable salt.Pharmacy acceptable salt is more such salt, and their keep the ideal biological activity of parent compound, and do not give undesirable toxicology effect.The example of such salt comprises the salt that forms with mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc.; With the salt of organic acid formation, like acetate, oxalic acid, tartrate, toxilic acid, Hydrocerol A, xitix etc.; And the salt that forms by the element negatively charged ion, like chlorine, bromine and iodine.
For curcumine list carbonyl analogue of the present invention, the more preferred pharmaceutical prepn that is suitable for administration that these compounds are mixed with.In order to treat various illnesss, can compound of the present invention be prepared.In the preparation of pharmaceutical prepn of the present invention, with acceptable salt on compound of the present invention and its physiology or its acid derivative usually with, especially acceptable carrier mixes.Certainly, from preparation the suitable meaning of any other component say that carrier must be acceptable, and must not can the patient be damaged.Carrier can be solid or liquid, and preferred and compound is mixed with the preparation of unitary dose, tablet for example, and it can comprise the active compound of 0.5%～95% weight.Can add one or more active compounds in the preparation of the present invention, preparation of the present invention can prepare through any technique known in the pharmacy field, mainly comprises component is mixed, optional one or more auxiliary agents that comprises.
Preparation of the present invention comprises that those (for example are suitable for oral, rectum, part, oral cavity, hypogloeeis, parenteral; Subcutaneous, muscle, intravenously) and the preparation of percutaneous dosing; Although under any given situation, optimum route will depend on the character and the seriousness of the illness of being treated and the character that depends on employed particular active compounds.
Specific embodiment
In the following non-limiting Examples, the present invention will be described in more detail.
A. materials and methods
The preparation of compound 1,2,3,4,5,6,8: under the room temperature, corresponding phenyl ring substituent 0.01mol is dissolved in the 10ml absolute ethyl alcohol, slowly drips the dry acetone of crossing of 0.005mol, stirred 10 minutes; Slowly drip 18% the methanol solution contain the 0.005mol sodium methylate again, stirring reaction 3～10 hours generates yellow mercury oxide.The reaction back adds 50ml water, filters, and successively uses 50ml water and 50ml washing with alcohol filter residue, 30 ℃ of vacuum-dryings, and the crude product that obtains is with silica gel column chromatography (methyl alcohol: purifying chloroform 1: 13).
Compound 1, yellow powder (56.1% yield), mp122-124 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.39 (6H, t, CH 3* 2), 4.10 (4H, q, O-CH 2* 2), 6.99 (4H, m, J=7.2, Ar-H), 7.14 (2H, d, J=16Hz, CH-C=O * 2), 7.68～7.74 (6H, m). ultimate analysis: theoretical value %C 78.23H6.88O 14.89, measured value %C 78.41H 7.10O 14.69; ESI-MS m/z:322.2.
Compound 2, yellow powder (78.0% yield), mp151-152 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 7.00 (2H, d, J=16Hz, CH-C=O * 2); 7.13 (4H, m), 7.60 (4H, m), 7.70 (2H; D, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 75.55H 4.48O 5.92, measured value %C75.60H 4.43O 5.82; ESI-MS m/z:270.1.
Compound 3, yellow powder (45.9% yield), mp136 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.89 (18H, s, O-CH 3* 6), 6.84 (4H, s, Ar-H), and 6.98 (2H, q, J=16Hz, CH-C=O * 2), 7.65 (2H, q, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 66.65H 6.32O 27.02, measured value %C 66.48H 6.37O 27.11; ESI-MS m/z:414.2
Compound 4, yellow powder (90.1% yield), mp185 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.04 (12H, s, N-CH 3* 4), 6.69 (4H, m, J=8.4Hz, Ar-H); (6.90 2H, d, J=15.6Hz, C=CH-CO * 2), 7.52 (4H; M, J=8.4Hz, Ar-H), 7.68 (2H; D, J=15.6Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 78.71H 7.55O 4.99, measured value %C 78.80H 7.41O 4.04; ESI-MS m/z:320.2.
Compound 5, yellow powder (88.1% yield), mp121-123 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.90 (18H, s, CH 3* 6), 6.85 (4H, m, Ar-H), and 6.98 (2H, d, J=16Hz, CH-C=O * 2), 7.66 (2H, d, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 86.75H 8.23O 5.02, measured value %C 86.70H 8.17O 5.10; ESI-MS m/z:318.2
Compound 6, yellow powder (72.2% yield), mp97 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 7.03 (2H, d, J=16Hz, C=CH-CO * 2); 7.22～7.63 (8H, m, Ar-H), 8.09 (2H; D, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 52.08H 3.08O 4.08, measured value %C 52.00H3.13O 4.10; ESI-MS m/z:391.9.
Compound 8, yellow powder (56.3% yield), mp117 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 7.05 (2H, d, J=16Hz, C=CH-CO * 2); 7.22～7.52 (8H, m, Ar-H), 7.65 (2H; D, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 52.08H 3.08O 4.08, measured value %C 52.11H3.09O 4.01; ESI-MS m/z:391.9.
The preparation of compound 7: under the room temperature; Be dissolved in the 40ml methylene dichloride the 0.1mol PARA HYDROXY BENZALDEHYDE is outstanding; The tosic acid pyridinium salt that adds catalytic amount stirs and slowly splashes into 3 of 0.2mol, the mixed solution of 4-dihydropyrane and 10ml methylene dichloride after 5 minutes again as catalyzer; Behind the stirring reaction 3 hours, reaction solution is used frozen water, NaHCO successively 3Saturated solution, brine wash, the pressure reducing and steaming methylene dichloride gets yellow oil product 4-(tetrahydropyrans-2-yl) phenyl aldehyde.Above-mentioned 4-(tetrahydropyrans-2-yl) phenyl aldehyde 0.01mol is dissolved in the 10ml absolute ethyl alcohol, slowly drips the dry acetone of crossing of 0.05mol, stirred 10 minutes; Slowly drip 18% the methanol solution contain the 0.05mol sodium methylate again, stirring reaction 3～10 hours generates yellow mercury oxide.The reaction back adds 50ml water, filters, and successively uses 50ml water and 50ml washing with alcohol filter residue, 30 ℃ of vacuum-dryings, and the crude product that obtains is with silica gel column chromatography (methyl alcohol: purifying chloroform 1: 13).Yellow powder (73.2% yield), mp146～150 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.61～1.69 (4H, m, 4CH 2* 2), 1.72～1.78 (4H, m, 5CH 2* 2), 1.88～1.99 (4H, m, 3CH 2* 2), 3.61 (2H, m, O-CH 2 e* 2), 3.88 (2H, m, O-CH 2 a* 2), 5.49 (2H, t, O-CH-O * 2), 6.95 (2H, d, J=16Hz, C=CH-CO * 2), 7.08 (4H, m, Ar-H 2,6* 2), 7.56 (4H, m, Ar-H 3,5* 2), 7.70 (2H, d, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 74.63H 6.96O 18.41, measured value %C 74.49H 6.97O 18.47; ESI-MS m/z:434.2.
The preparation of compound 9 is according to the preparation method of compound 7, and difference is that replacing PARA HYDROXY BENZALDEHYDE with 4-hydroxy 3-methoxybenzene formaldehyde (vanillin food grade,1000.000000ine mesh) is raw material.Yellow powder (55.7% yield), mp67 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.61～2.05 (12H, m, CH 2CH 2CH 2* 2), 3.63 (2H, m, O-CH 2* 2), 3.92 (6H, s, O-CH 3* 2), 5.49 (2H, s, O-CH-O * 2); (6.90 2H, d, J=13.2Hz, C=CH-CO * 2); 6.91～7.26 (6H, m, Ar-H), 7.68 (2H; D, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 70.43H 6.93O 22.64, measured value %C 70.44H 6.80O 22.58; ESI-MS m/z:494.2.
The preparation of compound 10: under the room temperature, 7 choosings of the compound of 0.01mol are dissolved in the 20ml absolute ethyl alcohol, add a small amount of tosic acid as catalyzer; Stir adding 100ml frozen water termination reaction after 10 hours, separate out solid, filter; Washing, filter residue get pure article with ethanol/water (9: 1) recrystallization.Yellow powder (39.2% yield), mp246～248 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 5.21 (2H, s, OH * 2), 6.94 (2H; D, J=16Hz, CH-C=O * 2), 6.99～7.21 (4H, m; Ar-H),, 7.53～7.64 (6H, m, Ar-H); (7.83 2H, d, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 76.68H 5.30O 18.02, measured value %C 76.59H 5.37O 17.99; ESI-MS m/z:266.1.
The preparation of compound 11 is according to the preparation method of compound 10, and difference is to use compound 9 to replace compound 7 to be raw material.Yellow powder (44.8% yield), mp90～92 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 4.11 (6H, s, O-CH 3* 6), 4.67 (2H, s, OH * 2), 7.06 (2H; D, J=16Hz, CH-C=O * 2), 7.21～7.35 (4H, m; Ar-H),, 7.61～7.79 (6H, m, Ar-H); (8.08 2H, d, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 69.93H 5.56O 24.51, measured value %C69.78H 5.70O 24.56; ESI-MS m/z:326.1.
The preparation of compound 12 is according to the preparation method of compound 7, and difference is to replace 3 with allyl bromide 98, and the 4-dihydropyrane is a raw material.Yellow powder (57.9% yield), mp123～124 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 4.61 (4H, d, J=9.4Hz, O-CH 2* 2), 5.23～5.25 (4H, m, C=CH 2* 2), 5.89 (2H, m, CH=CH 2* 2), 6.76 (4H, d, J=10Hz, Ar-H 3,5* 2), 7.03 (2H, d, J=15.6Hz, CH-C=O * 2), 7.17 (4H, d, J=10Hz, Ar-H 2,6* 2), 7.66 (2H, d, J=15.6Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 79.94H 6.40O 13.86, measured value %C 79.99H 6.51O 14.00; ESI-MS m/z:346.2.
The preparation of compound 13 is according to the preparation method of compound 9, and difference is to replace 3 with allyl bromide 98, and the 4-dihydropyrane is a raw material.Red oily liquids (88.7% yield); 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.89 (6H, s, O-CH 3* 2), 4.59 (4H, d, J=9.8Hz, O-CH 2* 2), 5.19～5.22 (4H, m, C=CH 2* 2), 5.91 (2H, m, CH=CH 2* 2), 7.05 (2H, d, J=15.6Hz, CH-C=O * 2); 7.10～7.25 (8H, m, Ar-H), 7.89 (2H; D, J=15.6Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 73.87H 6.45O 19.68, measured value %C 73.80H 6.56O 19.71; ESI-MS m/z:406.2.
The preparation of compound 14,15,16,17,18,19,21,26,27,28 is according to the preparation method of compound 1, and difference is to use ketopentamethylene to replace acetone to be raw material.
Compound 14, yellow powder (78.9% yield), mp191-192 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.44 (6H, t, CH 3* 2), 3.08 (4H, t, CH 2-CH 2), 4.09 (4H, q, O-CH 2* 2), 6.93～6.96 (4H, m), 7.54～7.57 (6H, m). ultimate analysis: theoretical value %C 79.28H 6.94O13.78, measured value %C 79.33H 6.70O 13.91; ESI-MS m/z:348.2
Compound 15, yellow powder (89.7% yield), mp237 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.10 (4H, t, CH 2-CH 2* 2), 7.11～7.15 (4H, m, Ar-H), 7.56～7.60 (6H, m). ultimate analysis: theoretical value %C 77.01H 4.76O 5.40, measured value %C 76.90H 4.83O 5.45; ESI-MS m/z:296.1.
Compound 16, yellow powder (86.2% yield), mp202-204 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.15 (4H, m, CH 2-CH 2), 3.91 (18H, s, O-CH 3* 6), 6.80～6.85 (4H, m, Ar-H), and 7.53 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 68.17H 6.41O 25.43, measured value %C 68.21H 6.47O 25.47; ESI-MS m/z:440.2.
Compound 17, yellow powder (79.4% yield), mp251 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.07 (12H, s, N-CH 3* 4), 3.18 (4H, m, CH 2-CH 2) 6.74 (4H, m, J=9.6Hz, Ar-H), 6.99 (2H, d; J=16Hz, C=CH-CO * 2), 7.71 (4H, m, J=9.6Hz, Ar-H); (7.91 2H, d, J=16Hz, Ar-CH=C * 2). ultimate analysis: theoretical value %C 79.73H 7.56O 4.62, measured value %C79.80H 7.62O 4.51; ESI-MS m/z:346.2.
Compound 18, yellow powder (43.7% yield), mp202-203 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.15 (4H, m, CH 2-CH 2), 3.89 (18H, s, CH 3* 6), 6.80～6.84 (4H, m, Ar-H), and 7.52 (2H, d, Ar-CH=C * 2). ultimate analysis: theoretical value %C 87.16H 8.19O 4.64, measured value %C87.17H 8.10O 4.70; ESI-MS m/z:344.2.
Compound 19, yellow powder (54.7% yield), mp163 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.93 (4H, s, CH 2-CH 2), 7.23 (2H, m, Ar-H 6* 2), 7.37 (2H, m, Ar-H 4* 2), 7.52 (2H, m, Ar-H 5* 2), 7.66 (2H, m, Ar-H 3* 2), 7.86 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 54.58H 3.37O 3.83, measured value %C 54.41H 3.30O 3.94; ESI-MS m/z:418.
Compound 21, yellow powder (66.6% yield), mp186 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.12 (4H, m, CH 2-CH 2), 7.30 (2H, m, Ar-H 5* 2), 7.50～7.52 (6H, m, Ar-H), and 7.72 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 54.58H 3.37O 3.83, measured value %C54.68H 3.29O 3.87; ESI-MS m/z:417.9.
Compound 26, yellow powder (65.4% yield), mp198 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.05 (4H, s, CH 2-CH 2), 7.19～7.32 (2H, m, Ar-H), 7.61～7.65 (2H, m, Ar-CH=C * 2), 7.75～7.79 (4H, m, Ar-H). ultimate analysis: theoretical value %C 58.34H 2.80O3.70, measured value %C 58.61H 2.89O 3.61; ESI-MS m/z:432.1.
Compound 27, yellow powder (63.9% yield), mp223 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.03 (4H, s, CH 2-CH 2), 7.26～7.34 (2H, m, Ar-H), 7.62～7.66 (2H, m, Ar-CH=C * 2), 7.73～7.78 (4H, m). ultimate analysis: theoretical value %C 58.34H 2.80O3.70, measured value %C 58.87H 2.90O 3.75; ESI-MS m/z:432.7.
Compound 28, yellow powder (70.6% yield), mp154 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.98 (4H, m, CH 2* 2), 2.26 (12H, s, N-CH 3* 4), 2.46 (4H, t, CH 2-N * 2), 3.08 (4H, m, CH 2-CH 2* 2), 6.95～6.97 (4H, m), 7.54～7.56 (6H, m). ultimate analysis: theoretical value %C74.28H 8.31O 10.99, measured value %C 74.39H 8.33O 11.17; ESI-MS m/z:462.3.
The preparation of compound 20 is according to the preparation method of compound 7, and difference is to use ketopentamethylene to replace acetone to be raw material.Yellow powder (49.0% yield), mp209 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.59～1.72 (8H, m, 4CH 2 5CH 2* 2), 1.87～1.97 (4H, m, 3CH 2* 2), 3.09 (4H, s, CH 2-CH 2), 3.61 (2H, m, J=5.2Hz, O-CH 2 e* 2), 3.90 (2H, m, J=10.7Hz, O-CH 2 a* 2), 5.50 (2H, t, O-CH-O * 2), 7.10～7.13 (4H, m, Ar-H), 7.55～7.57 (6H, m). ultimate analysis: theoretical value %C75.63H 7.00O 17.37, measured value %C 75.70H 7.11O 17.29; ESI-MS m/z:460.2.
The preparation of compound 22 is according to the preparation method of compound 9, and difference is to use ketopentamethylene to replace acetone to be raw material.Yellow powder (57.9% yield), mp138 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.64～2.01 (12H, m, CH 2-CH 2-CH 2* 2), 3.11 (4H, m, CH 2-CH 2* 2), 3.91 (6H, s, O-CH 3* 2), 3.95～4.01 (4H, m, O-CH 2* 2), 5.50 (2H, s, O-CH-O * 2), 7.09～7.23 (6H, m, Ar-H), and 7.54 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 71.51H 6.97O 21.51, measured value %C 71.44H 6.80O 21.58; ESI-MS m/z:520.2.
The preparation of compound 23 is according to the preparation method of compound 10, and difference is to use compound 20 to replace compound 7 to be raw material.Yellow powder (60.8% yield), mp288 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 2.99 (4H, m, CH 2CH 2), 4.77 (2H, s, OH * 2), 6.64～6.89 (10H, m, Ar-H), and 7.38 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 78.06H 5.52O 16.42, measured value %C78.11H 5.47O 16.32; ESI-MS m/z:292.1.
The preparation of compound 24 is according to the preparation method of compound 10, and difference is to use compound 22 to replace compound 7 to be raw material.Yellow powder (59.8% yield), mp194 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.13 (4H, m, CH 2CH 2), 3.91 (6H, s, O-CH 3* 6), 5.01 (2H, s, OH * 2), 6.69～6.85 (10H, m, Ar-H), and 7.49 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 71.58H 5.72O 22.70, measured value %C 71.70H 5.68O 22.81; ESI-MS m/z:352.1.
The preparation of compound 25 is according to the preparation method of compound 20, and difference is to use ketopentamethylene to replace acetone to be raw material.Yellow powder (59.7% yield), mp192 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 3.04 (4H, m, CH 2CH 2), 4.55 (4H, m, O-CH 2* 2), 5.22～5.26 (4H, m, C=CH 2* 2), 5.73 (2H, m, CH=CH 2* 2), 6.76～7.08 (8H, m, Ar-H), and 7.41 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 80.62H 6.49O 12.89, measured value %C 80.60H 6.40O 13.00; ESI-MS m/z:372.2.
The preparation of compound 29,30,31,32,33,34,36,41,42,43 is according to the preparation method of compound 1, and difference is to use ketopentamethylene to replace acetone to be raw material.
Compound 29, yellow powder (58.9% yield), mp147-149 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.56 (6H, t, CH 3* 2), 1.81 (2H, m, CH 2), 3.08 (4H, t, CH 2-CH 2), 3.89 (4H, q, O-CH 2* 2), 6.79～7.21 (8H, m, Ar-H), and 7.73 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 79.53H 7.23O 13.24, measured value %C 79.50H 7.40O 13.29; ESI-MS m/z:362.2.
Compound 30, yellow powder (79.1% yield), mp156 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.81 (2H, m, CH 2), 2.90 (4H, t, J=5.4 ,=C-CH 2* 2), 7.12 (4H, m, Ar-H 2,6* 2), 7.45 (4H, m, Ar-H 3,5* 2), 7.76 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 77.29H5.19O 5.22, measured value %C 77.40H 5.20O 5.16; ESI-MS m/z:310.1.
Compound 31, yellow powder (72.6% yield), mp196 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.83 (2H, m, CH 2), 2.97 (4H, t ,=C-CH 2* 2), 3.90 (18H, s, O-CH 3* 6), 6.71 (4H, s, Ar-H), and 7.73 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 68.71H 6.65O24.64, measured value %C 68.79H 6.74O 24.69; ESI-MS m/z:454.2.
Compound 32, yellow powder (80.9% yield), mp160 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.82 (2H, m, CH 2), 2.93 (4H, t ,=C-CH 2* 2), 3.01 (12H, s, N-CH 3* 4), 6.72 (4H, m, Ar-H), 7.45 (4H, m, Ar-H), and 7.76 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 79.96H 7.83O 4.44, measured value %C 80.12H 7.91O 4.29; ESI-MS m/z:360.2.
Compound 33, yellow powder (88.9% yield), mp206-208 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.84 (2H, m, CH 2), 2.96 (4H, t ,=C-CH 2* 2), 3.89 (18H, s, CH 3* 6), 6.99 (4H, s, Ar-H), and 7.73 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 87.10H 8.43O 4.46, measured value %C 87.01H 8.49O 4.52; ESI-MS m/z:358.2.
Compound 34, yellow powder (76.9% yield), mp120 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.75 (2H, m, CH 2), 2.75 (4H, m, J=6.1Hz ,=C-CH 2), 7.18～7.35 (6H, m, Ar-H), 7.64 (2H, m, Ar-H 6* 2), 7.86 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 55.59H3.73O 3.70, measured value %C 55.67H 3.60O 3.77; ESI-MS m/z:431.9.
Compound 36, yellow powder (58.0% yield), mp112 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.03 (2H, m, CH 2), 2.90 (4H, m, J=6.1Hz ,=C-CH 2* 2), 7.27 (2H, m, Ar-H 5* 2), 7.30 (2H, m, Ar-H 6* 2), 7.37 (2H, m, Ar-H 4* 2), 7.47 (2H, s, Ar-H 2* 2), 7.70 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 55.59H 3.73O 3.70, measured value %C55.71H 3.70O 3.81; ESI-MS m/z:431.9.
The preparation of compound 35 is according to the preparation method of compound 7, and difference is to use pimelinketone to replace acetone to be raw material.Yellow powder (59.7% yield), mp160 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.61～2.02 (12H, m, 3CH 2 4CH 2 5CH 2* 2), 2.04 (2H, m, CH 2), 2.92 (4H, m ,=C-CH 2* 2), 3.62 (2H, m, J=11.6Hz, O-CH 2 e* 2), 3.90 (2H, m, J=9.2Hz, O-CH 2 a* 2), 5.48 (2H, t, O-CH-O * 2), 7.03 (4H, m, Ar-H 2,6* 2), 7.43 (4H, m, Ar-H 3,5* 2), 7.82 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 75.92H 7.22O 16.86, measured value %C 75.80H7.27O 16.91; ESI-MS m/z:474.2.
The preparation of compound 37 is according to the preparation method of compound 9, and difference is to use pimelinketone to replace acetone to be raw material.Yellow powder (60.0% yield), mp138 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.65～2.04 (12H, m, CH 2-CH 2-CH 2* 2), 1.83 (2H, m, CH 2), 2.94 (4H, t ,=C-CH 2* 2), 3.62 (2H, d, J=11.2Hz, O-CH 2 e* 2), 3.89 (6H, s, O-CH 3* 2), 3.97 (2H, m, J=9.0Hz, O-CH 2 a* 2), 5.47 (2H, s, O-CH-O * 2), 6.98～7.17 (6H, m, Ar-H), and 7.74 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 70.43H 6.93O 22.64, measured value %C 70.49H6.99O 22.37; ESI-MS m/z:534.3.
The preparation of compound 38 is according to the preparation method of compound 10, and difference is to use compound 35 to replace compound 7 to be raw material.Yellow powder (48.9% yield), mp269～271 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.52 (2H, m, CH 2), 3.07 (4H, m ,=C-CH 2* 2), 4.99 (2H, s, OH * 2), 6.67～6.85 (10H, m, Ar-H), and 7.45 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 78.41H 5.92O 15.67, measured value %C 78.40H 5.04O 15.88; ESI-MS m/z:306.1.
The preparation of compound 39 is according to the preparation method of compound 10, and difference is to use compound 37 to replace compound 7 to be raw material.Yellow powder (51.4% yield), mp172～173 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.51 (2H, m, CH 2), 3.01 (4H, m ,=C-CH 2* 2), 3.99 (6H, s, O-CH 3* 6), 5.10 (2H, s, OH * 2), 6.64～6.71 (10H, m, Ar-H), and 7.29 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 69.93H 5.56O 24.51, measured value %C 69.78H 5.58O 24.61; ESI-MS m/z:366.2.
The preparation of compound 40 is according to the preparation method of compound 35, and difference is to use ketopentamethylene to replace acetone to be raw material.Yellow powder (71.3% yield), mp120～122 ℃; 1HNMR (CDCl 3, 400MHz) δ (ppm) 1.49 (2H, m, CH 2), 2.98 (4H, m, CH 2CH 2), 4.32 (4H, q, J=9.7Hz, O-CH 2* 2), 5.19～5.21 (4H, m, C=CH 2* 2), 5.62 (2H, m, CH=CH 2* 2), 6.65～6.70 (8H, m, Ar-H), and 7.28 (2H, s, Ar-CH=C * 2). ultimate analysis: theoretical value %C 80.80H 6.78O 12.42, measured value %C 80.89H 6.69O 12.45; ESI-MS m/z:386.1.
B. the active test of extracorporeal anti-inflammatory
Derive from monocytic scavenger cell and in the their early stage of inflammatory reaction and the course of disease, bring into play important role.The key distinction of monocyte and scavenger cell is to raise some scavenger receptor to combine the ability of LDL of modification type different.Modification type lipoprotein by the scavenger cell picked-up can form foam proteins at vessel wall, and (like TNF-α and IL-6, generation Fig.2) adds the reunion inflammatory response through stimulating inflammatory mediator.Therefore, scavenger cell is regarded as the treatment target spot of antiphlogiston.The content of the inflammatory factor of its release also is regarded as the table important means of being tried the thing anti-inflammatory activity seized with terror.
Testing method: be the compound treatment 2 hours among the present invention of 10 μ mol/L with mouse J774A.1 scavenger cell with biological level other DMSO 99.8MIN. (DMSO) and concentration.Use LPS (LPS subsequently; 0.5 μ g/ml) induce processing 24 hours; The burst size of two kinds of inflammatory factor-tumor necrosis factor-alphas of scavenger cell excretory (TNF-α) and interleukin-6 (IL-6) is used the enzymoimmunoassay analysis, and the inflammatory factor content that the J774A.1 scavenger cell during with administration not discharges is compared.
Result and discussion: the active result of extracorporeal anti-inflammatory sees Fig. 4 and Fig. 5.First data among two figure only have LPS inductive blank for not adding any compound; Last compound is the test result of guide's thing curcumine.Can find that from two figure this type analog of mono carbonyl structure major part has the anti-inflammatory activity stronger than curcumine, especially suppress in release to IL-6.Indicate the activity in vivo that they are possible, and might be developed to the medicine of corresponding treatment inflammation.
C. the test of anti tumor activity in vitro
In order to explain that the compound among the present invention has antineoplastic pharmacologically active; We test their growth-inhibiting abilities to tumor cell in vitro with MTT (tetramethyl-azo azoles salt colourimetry) method, represent the power of their anti tumor activity in vitro with IC50 (half-inhibition concentration) value.
Testing method:
(a) material four Cuo salt (MTT), with the phosphate buffered saline buffer dissolving MTT of 0.01mol/L, final concentration is 5mg/mL, filtration sterilization, 4 ℃ of preservations after the packing; MTT lysate, the sodium laurylsulfonate of 80g are dissolved in the N of 200ml, and heating for dissolving adds 200ml zero(ppm) water, regulate pH value to 4.7 with the hydrochloric acid mixed solution (1: 1) of 80% acetate and 1N; The selection of cell strain: human hepatoma cell strain Bel-7402 and Human Prostate Cancer Cells strain PC-3.
(b) the method single cell suspension is inoculated in 96 orifice plates, and 37 ℃, 5%CO 2, cultivated 24 hours 4 every group parallel appearance under the saturated humidity; Remove substratum, the substratum of getting new configuration prepares the solution of test-compound by series concentration, and every hole 200uL cultivated 48 hours; Every hole adds the MTT 20uL of 2mg/mL, hatches 4 hours; As far as possible nutrient solution in the sucking-off hole fully adds DMSO liquid (150uL/ hole), and vibrating fully dissolves crystallisate; The OD value in each hole of ELIASA detection (λ=570nm); Draw the cell viability graphic representation, obtain the IC50 value.
Result and discussion: experimental result is as shown in table 1; Presentation of results; Majority of compounds among the present invention has stronger cytotoxicity; Activity than guide's thing curcumine (Cur) is strong a lot, and this has not only confirmed the reasonableness of the analog of mono carbonyl structure of our designs, explains that also this compounds among the present invention might be developed to anti-tumor drug.
Table 1: the part of compounds among the present invention is to the IC50 value (μ g/ml) of Bel-7402 and PC-3 cell
Figure BSA00000571744800161

Claims (3)

1. the compound of formula II or its pharmacy acceptable salt:
Figure FSA00000571744700011
Wherein, R 5Be H, R 6Be H, R 7Be OCH 2CH 3, and R 8Be H;
Perhaps, R 5Be H, R 6Be H, R 7Be F, and R 8Be H;
Perhaps, R 5Be H, R 6Be OCH 3, R 7Be OCH 3, and R 8Be OCH 3
Perhaps, R 5Be H, R 6Be H, R 7Be N (CH 3) 2, and R 8Be H;
Perhaps, R 5Be H, R 6Be CH 3, R 7Be CH 3, and R 8Be CH 3
Perhaps, R 5Be Br, R 6Be H, R 7Be H, and R 8Be H;
Perhaps, R 5Be H, R 6Be H, R 7Be
Figure FSA00000571744700012
And R 8Be H;
Perhaps, R 5Be H, R 6Be Br, R 7Be H, and R 8Be H;
Perhaps, R 5Be H, R 6Be OCH 3, R 7Be
Figure FSA00000571744700013
And R 8Be H;
Perhaps, R 5Be H, R 6Be H, R 7Be OCH 2CH=CH 2, and R 8Be H;
Perhaps, R 5Be CF 3, R 6Be F, R 7Be H, and R 8Be H;
Perhaps, R 5Be F, R 6Be CF 3, R 7Be H, and R 8Be H;
Perhaps, R 5Be H, R 6Be H, R 7Be
Figure FSA00000571744700014
And R 8Be H.
2. be used to treat the pharmaceutical prepn of inflammation or cancer, it contains compound or its pharmacy acceptable salt that claim 1 limits in a kind of pharmaceutically acceptable carrier.
3. the compound that claim 1 limited or its pharmacy acceptable salt are used for treating the application of the medicine of inflammation or tumour in preparation.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103222970A (en) * 2013-04-10 2013-07-31 温州医学院 Application of asymmetric single-carbonyl curcumin analogues in preparing antitumor medicines
CN103467320A (en) * 2013-08-15 2013-12-25 沈阳药科大学 2,5-disubstituted cyclopentanone derivatives and applications thereof
CN103601672A (en) * 2013-11-04 2014-02-26 广东中烟工业有限责任公司 Curcuminoid and preparation method and application thereof
CN105837425A (en) * 2016-05-18 2016-08-10 苏州大学 Novel application of (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and derivative thereof

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WO2001046110A2 (en) * 1999-12-23 2001-06-28 The University Of Georgia Research Foundation, Inc. Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states
US6790979B2 (en) * 2002-04-17 2004-09-14 University Of North Carolina At Chapel Hill Curcumin analogues and uses thereof

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CN103222970A (en) * 2013-04-10 2013-07-31 温州医学院 Application of asymmetric single-carbonyl curcumin analogues in preparing antitumor medicines
CN103222970B (en) * 2013-04-10 2019-03-26 温州医科大学 Asymmetric list carbonyl curcumin analog application in preparation of anti-tumor drugs
CN103467320A (en) * 2013-08-15 2013-12-25 沈阳药科大学 2,5-disubstituted cyclopentanone derivatives and applications thereof
CN103467320B (en) * 2013-08-15 2015-12-23 沈阳药科大学 The two substituted cyclopentanone analog derivative of 2,5-and application thereof
CN103601672A (en) * 2013-11-04 2014-02-26 广东中烟工业有限责任公司 Curcuminoid and preparation method and application thereof
CN103601672B (en) * 2013-11-04 2016-08-17 广东中烟工业有限责任公司 A kind of Curcuminoids and its preparation method and application
CN105837425A (en) * 2016-05-18 2016-08-10 苏州大学 Novel application of (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and derivative thereof
CN105837425B (en) * 2016-05-18 2018-08-07 苏州大学 The new opplication of (2E, 6E) -2- (3,5- dimethoxy benzenes methylene) -6- (4- chlorobenzenes methylene) cyclohexanone and its derivative

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