CN103848747A - Curcumin analogs, medicinal salts thereof, and preparation and application of the curcumin analogs - Google Patents
Curcumin analogs, medicinal salts thereof, and preparation and application of the curcumin analogs Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and relates to a preparation method and applications of a series of curcumin analogs having structure characteristics shown as the formula I, the formula II, the formula III and the formula IV. Pharmaceutically acceptable salts and solvates of the curcumin analogs, and medicines containing the curcumin analogs or the pharmaceutically acceptable salts thereof as active components can be used for treating cancer and inflammation type diseases. The curcumin analogs and the pharmaceutically acceptable salts thereof have good anticancer activity. The preparation method is simple and feasible, and is easy to operate.
Description
Technical field
The present invention relates to a series of new curcumin analogues, the salt of this compound and the medicine taking this compound or its salt class as activeconstituents, can be used for treating cancer and inflammation class disease.The present invention relates to the preparation method of a series of curcumin analogues and synthetic described intermediate.
Background technology
Curcumine (Curcumin) be from Zingiber curcuma turmeric (
curcumalonga L.) the phenols natural product that extracts in rhizome, have antitumor, anti-oxidant, antibacterial, anti-inflammatory etc. widely biological activity (Anand P, Thomas SG, Kunnumakkara AB,
et al. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature[J]. Biochem Pharmacol, 2008,76:1590 – 1611.).In recent years research shows, this compound has no side effect, antitumor spectra extensively and simultaneously has cancer prevention and cancer therapy effect (Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as " Curcumin ": from kitchen to clinic[J]. Biochem Pharmacol, 2008, 75 (4): 787 – 809.), national cancer institute (national cancer institute, NCI) classified as third generation chemoprevention of cancer medicine (Chauhan DP. Chemotherapeutic potential of curcumin for colorectal cancer[J]. Curr Pharm Des, 2002, 8 (19): 1695-1706.), clinicalⅰstage and the test of clinical II phase are now entered.Curcumine poor selectivity, water insoluble, and owing to thering is α, β-unsaturated beta-diketone structure and the long conjugated structure forming with end phenyl ring thereof, unstable in vivo and in vitro, metabolism is rapid, thereby anti-tumor activity is lower.Research is found endogenous small molecules amino acid, acetic acid, phenolic hydroxyl group on glucose and nucleic acid and curcumine structure end phenyl ring carries out amalgamation and can improve bioavailability (Mishra S, Narain U, Mishra R, Misra K. Design, development and synthesis of mixedbioconjugates of piperic acid-glycine, curcumin-glycine/alanine and curcumin-glycine-piperic acid and their antibacterial and antifungal properties[J]. Bioorganic & Medicinal Chemistry, 2005, 13 (5): 1477-1486., Kumar S, Narain U, Tripathi S, Misra K. Syntheses of curcumin bioconjugates and study of their antibacterial activities against β-lactamase-producing microorganisms[J]. Bioconjugate Chemistry, 2001,12 (4): 464-469., Ferrari E, Lazzari S, Marverti, G,
et al. Synthesis, cytotoxic and combined cDDP activity of new stable curcumin derivatives[J]. Bioorganic & Medicinal Chemistry, 2009,17 (8): 3043-3052.).Wichitnithad etc. introduce succsinic acid on the phenolic hydroxyl group of curcumine, form ester structure, improved curcumine anti-tumor activity (Wichitnithad W, Nimmannit U, Wacharasindhu S,
et al. Synthesis, Characterization and Biological Evaluation of Succinate Prodrugs of Curcuminoids for Colon Cancer Treatment[J]. Molecules, 2011,16 (2): 1888-1900.).Tamvakopoulos etc. methylate to the phenolic hydroxyl group of curcumine, improved metabolic stability in vivo of curcumine and anti-tumor activity (Tamvakopoulos C, Dimas K, So anos ZD,
et al. Metabolism and Anticancer Activity of the Curcumin Analogue, Dimethoxycurcumin[J] .Clinical Cancer Research, 2007,13 (4): 1269-1277.).Ohtsu etc. have introduced two propyl group and the phenolic hydroxyl group of curcumine is carried out to the compound that propylated obtains on the carbon atom of the active methylene group of curcumine has identical androgen antagonist activity (Ohtsu H with the treatment prostate cancer medicine Sch 16423 using clinically, Itokawa H, Xiao ZY
et al. Antitumor Agents 222. Synthesis and Anti-androgen Activity of New Diarylheptanoids[J]. Bioorganic & Medicinal Chemistry, 2003,11 (23): 5083 – 5090.).Han etc. are in order to eliminate unsettled β-diketone structure, on active methylene group carbon atom, introduce two methyl improved curcumine anti-tumor activity (Han YM, Shin DS, Lee YJ,
et al. 2-Hydroxycurcuminoid induces apoptosis of human tumor cells through the reactive oxygen species – mitochondria pathway[J]. Bioorganic & Medicinal Chemistry Letters, 2011,21 (2): 747 – 751.).Li Pui-Kai laboratory is to having introduced cyclohexyl and two hydroxyls having been methylated on the active methylene group carbon atom of curcumine, synthetic compound is named as FLLL32, it is a JAK2/STAT3 inhibitor, in experiment, all show powerful antitumor activity (Lin L in vitro and in vivo, Hutzen B, Zuo M
et al. Novel STAT3 phosphorylation inhibitors exhibit potent growthsuppressive activity in pancreatic and breast cancer cells[J]. Cancer Research, 2010,70 (6): 2445 – 2454, Lin L, Deangelis S, Foust E,
et al. A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells[J]. Molecular Cancer, 2010,9 (1): 217-227, Bill MA, Fuchs JR, Li C,
et al. RTehseaerc hsmall molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity[J]. Molecular Cancer, 2010,9 (1): 165-177, Fossey SL, Bear MD, Lin J,
et al. The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines[J]. BMC Cancer, 2011,11 (112), 1-15, Onimoe GI, Liu A, Lin L,
et al. Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice[J]. Investigational New Drugs, 2012,30 (3): 916-926, Wei CC, Ball S, Lin L,
et al. Two small molecule compounds, LLL12 and FLLL32, exhibit potent inhibitory activity on STAT3 in human rhabdomyosarcoma cells[J]. International Journal of oncology, 2011, 38 (1): 279-85.), and to its synthetic method and purposes application patent (Li PK, Li CL, Lin JY, Fuchs JR. Curcumin Analoges as Dual JAK2/STAT3 Inhibitors and Methods of Making and Using the Same[P] .WO2010/121007 A1.).This laboratory shows in the early-stage Study aspect anti-tumor activity curcumine and analogue thereof, improve compound stability and water-soluble be conducive to improve anti-tumor activity (Yin Xuezhi. the synthetic and activity research of curcumine Mannich base derivative. [academic dissertation]. Shenyang Pharmaceutical University, 2007,05.; Chen Na. the synthetic and activity research of curcumin derivative. [academic dissertation]. Shenyang Pharmaceutical University, 2009,05; Zhang Tongbo. the synthetic and activity research of curcumin derivate. [academic dissertation]. Shenyang Pharmaceutical University, 2010,05).Therefore, the present invention clearly proposes to transform two positions of substituting group on active methylene group and the phenyl ring of curcumine first simultaneously, on the carbon atom of curcumine active methylene group, insert together with two alkyl, to block its long conjugated structure, and eliminated this reaction site of active methylene group, thereby improve stability; On this basis,, raising anti-tumor activity water-soluble for increasing, on the phenolic hydroxyl group of curcumine or on phenyl ring, introduce again hydrophilic amine substituted alkyl side chain, synthesized curcumin analogue of the present invention, and studied its anti-tumor activity and mechanism through pharmacological testing.
Summary of the invention
The present invention, taking curcumine and analogue thereof as lead compound, for improving the stability of curcumine, inserts together with two hydrocarbyl groups on the one hand on active methylene group carbon atom, thereby blocks the long conjugated structure of its parent nucleus, and eliminates this reactive behavior site of methylene radical; On the other hand, for improve compound polarity or wetting ability, strengthen its antitumour activity, the phenyl ring at curcumine structure two ends or (with) introduce hydrophilic amine alkyls group on the phenolic hydroxyl group of phenyl ring, synthesize curcumin analogue of the present invention, and proving to suppress kinds of tumor cells increment through pharmacological testing, their Main Function is antitumor.Mechanism to curcumin analogue Ica induction human melanoma A375-S2 cell apoptosis is studied, and Ica can concentration, the inhibition A375-S2 cell proliferation of time-dependent manner, and the protein expression of Hsp90 is lowered on time-dependent manner ground, promotes cytochrome
cbe discharged into cytoplasm from plastosome, reduce the protein expression of procaspase-9, induction caspase-3 precursor procaspase-3 cuts into the caspase-3 of activity form, and reduces the level of its substrate ICAD, by activating mitochondria pathway induction A375-S2 apoptosis.
The object of the present invention is to provide a kind of curcumin analogue and its esters or their solvate of novel structure.
Another object of the present invention is to provide the preparation method of this analogue.
The 3rd object of the present invention is to provide the pharmaceutical composition that contains this analogue.
The 4th object of the present invention is to provide the purposes of this analogue, and curcumin analogue of the present invention or composition can be for the preparation of various anti-tumor drugs.
Specifically, curcumin analogue provided by the invention has following structure:
Or its pharmacy acceptable salt or solvate.
Wherein:
1) n is 0～4, R
1for methyl, benzyl.R
2for hydrogen, C1-C3 acyl group or R
3.R
3for with substituent amino, described substituting group is selected from: C1-C6 alkyl; Or with substituent piperazine, described substituting group is selected from: methyl, ethyl, sec.-propyl, isobutyl-, phenyl, benzyl, phenyl allyl group, hydroxyethyl; Or be morpholinyl, Pyrrolidine base, piperidyl, 4-piperidinyl piperidine base.R
4for hydrogen or CH
2r
3.R
5for hydrogen or CH
2r
3.
2) n is 0 o'clock, R
2for hydrogen, C1-C3 acyl group; N is 1～4 o'clock, R
2for R
3.
Preferably described curcumin analogue, R
1for methyl, benzyl.N is 0 o'clock, R
2for hydrogen, ethanoyl; N is 1～4 o'clock, R
2for R
3.R
3for with substituent amino, described substituting group is selected from: C1-C2 alkyl; Or with substituent piperazine, described substituting group is selected from: methyl, ethyl, sec.-propyl, isobutyl-, phenyl, benzyl, phenyl allyl group, hydroxyethyl; Or be morpholinyl, Pyrrolidine base, piperidyl, 4-piperidinyl piperidine base.R
4for hydrogen or CH
2r
3.R
5for hydrogen or CH
2r
3.
The present invention also provide with curcumin analogue and pharmaceutically can received salt, the composition of the ingredients of solvate and vehicle.
In embodiment provided by the present invention, compound of the present invention contains basic group, can with sour salify, adopt method well-known to those skilled in the art can prepare the pharmaceutical salts of curcumin analogue.
The invention provides containing above-mentioned curcumin analogue and medicinal salts thereof, it is characterized in that, described pharmaceutical salts is the salt becoming with suitable non-toxicity organic acid or mineral acid.
The present invention also provides the preparation method of above-mentioned curcumin analogue, it is characterized in that: pass through intermediate
1or
4, carry out Mannich reaction with fatty amines, substituted-piperazinyl, morpholinyl, Pyrrolidine base, piperidyl, substituted piperidine base; Or by using obtained Mannich base as intermediate
3, carry out etherification reaction with right haloalkane or haloalkyl secondary amine; Or by halogen ether curcuminoids intermediate
2, carry out composite reaction with fatty amines, substituted-piperazinyl, morpholinyl, Pyrrolidine base, piperidyl, substituted piperidine base.
Synthetic route for the synthesis of curcumin analogue is provided in the present invention.
Intermediate
1synthetic route as follows:
Intermediate
4synthetic route as follows:
Formula
iand intermediate
2synthetic route as follows:
Formula
iIand intermediate
3synthetic route as follows:
Formula
iIIsynthetic route as follows:
Formula
iVsynthetic route as follows:
In the preparation process of the above-mentioned curcumin analogue of the present invention and medicinal salts thereof, solvent for use is conventional reaction solvent, without particular requirement.
Curcumin analogue of the present invention has water-soluble preferably, by mtt assay to human cervical carcinoma cell HeLa, human liver cancer cell HepG2, human fibrosarcoma cell HT-1080, human colon cancer cell HCT116, human melanoma cell A375-S2, human breast cancer cell MCF-7, human lung cancer cell A549, the lymphoma cell U-937 of human tissue cell, the former leukemia cell K562 of the chronic marrow of people, the external activity test of the ten class cells such as people's promyelocytic leukemia cell HL60, compared with curcumine, activity and selectivity all improves a lot, therefore, likely therefrom find the newtype drug for the treatment of tumour.
Brief description of the drawings
Fig. 1 is A375-S2 cell is processed the cell proliferation inhibition rate of different time variation through different concns Ica;
（Inhibition raio of Ica on A375-S2 cell；
A375-S2 cells were cultured in different concentrations of Ⅰca in the MEM for different time）。
Fig. 2 is that the MTT Faxian survival rate that peripheral blood lymphocytes (hPBMC) processes after 12,24,48 hours through different concns Ica and curcumin of leting others have a look at changes (Control is blank) (n=3, mean ± SD);
（Effect of Ica on hPBMC viability；
hPBMC were cultured in different concentrations of Ica in RPMI-1640 medium with human AB serum for different time．Cell viability were measured by MTT assay. n=3, mean±SD）。
Fig. 3 is that A375-S2 cell is through Ica(3 μ mol/L) and curcumin(20 μ mol/L) process morphological change after 24 hours (magnification is 200, scale be 30 μ m);
（Morphologic changes of Ica treated A375-S2 cells；
The cells were incubated in the medium alone for 24 h the the medium containing 3 μM Ica or 20 μM curcumin for 24 h (magnification = 200, scale bar = 30 μm)）。
Fig. 4 is that AO/EB Fluorescent Staining Observation A375-S2 cell is through Ica(3 μ mol/L) and curcumin(20 μ mol/L) process morphological change after 24 hours (magnification is 200, scale be 30 μ m);
（Cellular morphology of A375-S2 cells treated with Ica or curcumin；
A375-S2 cells were incubated in the medium alone for 24 h or the medium containing 3 μM Ica or 20 μM curcumin for 24 h (magnification = 200, scale bar = 30 μm), AO/EB staining）。
Fig. 5 is that PI flow cytometry A375-S2 cell is through Ica(3 μ mol/L) process different time DNA content change;
（Apoptosis was induced by Ica in A375-S2 cells；
The DNA content was analyzed by flowcytometry after PI staining）。
Fig. 6 Western blot immunization shows that A375-S2 cell is through Ica(3 μ mol/L) expression of processing the caused cytochrome c of different time, Hsp90 albumen, Pro-caspase 9 albumen, ICAD albumen and Cleaved-Caspase 3 albumen changes (β-actin is protein content contrast);
（Changes of cellular protein in A375-S2 cells；
A375-S2 cells were with 3 μM Ica for indicated time periods, and the expression of cytochrome
c , Hsp90, Pro-caspase 9, ICAD and Cleaved-Caspase 3 was examined by Western blot analysis.）。
embodiment
Below by embodiment, exploitativeness of the present invention is described, it will be understood by those of skill in the art that the instruction according to prior art, corresponding technical characterictic is modified or replaced, still belong to the scope of protection of present invention.
1 pair of alkyl of embodiment replaces curcumine intermediate
1universal synthesis method
1) curcumine 10.0 g (27.06mmol) are dissolved in the methylene dichloride of 200 mL, add 7.6 mL (81.48mmol) diacetyl oxide and 6.6 mL (81.48mmol) pyridine, under stirring, be warming up to backflow, react after 1 h, be cooled to, wash with water, saturated sodium bicarbonate water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains yellow solid
5.With ethyl acetate and sherwood oil recrystallization, obtain yellow crystalline solid 9.8g, productive rate 95%, mp:168 ~ 6170 DEG C.
2) by the intermediate of 35.40mmol
5be dissolved in the acetone of 50 mL and be placed in 250 mL eggplant-shape bottles, add Anhydrous potassium carbonate 106.20mmol, under stirring, be warming up to backflow, drip halohydrocarbon 106.20mmol, finish and continue reaction.After question response completes, be cooled to, remove by filter salt of wormwood.Filtrate decompression is concentrated, obtain solid
6.With acetone and ethyl alcohol recrystallization, obtain crystalline solid.
3) by the intermediate of 0.1 mol
6be dissolved in appropriate anhydrous methanol and be placed in 250 mL eggplant-shape bottles, add sodium hydroxide 0.25mol, under stirring, be warming up to 35 DEG C.After question response completes, decompression steams methyl alcohol.Resistates is dissolved in appropriate methylene dichloride, solution is adjusted to neutrality with acetic acid, use massive laundering.By organic layer saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains two alkyl and replaces curcumine intermediate
1.With ethyl acetate and sherwood oil recrystallization, obtain crystalline solid.
Embodiment 2 halogen ether curcuminoids intermediates
2universal synthesis method
Two 12.0mmol alkyl are replaced to curcumine intermediate
1be dissolved in appropriate acetonitrile and be placed in 250 mL eggplant-shape bottles with 36.0mmol Anhydrous potassium carbonate, be warming up to backflow, after reaction 0.5h, drip the dihalo thing (by 5 mL dilution in acetonitrile) of 36.0mmol, in 15 min, dropwise, continue reaction.After question response completes, remove by filter salt of wormwood, concentrating under reduced pressure filtrate is to oily.Oily matter is dissolved in appropriate DMF, is slowly added drop-wise in a large amount of frozen water mixing, and vigorous stirring.In dropping process, have solid and separate out, finish, continue to stir and spend the night.Filter, obtain solid halogen ether curcuminoids intermediate
2, with ethyl acetate and sherwood oil recrystallization, obtain crystalline solid.
Two product in embodiment 1 alkyl are replaced to curcumine intermediate
11.0 mmol are dissolved in appropriate anhydrous methanol, and ice bath is cooling, add 1.0 mmol secondary amine, formaldehyde (37% aqueous solution) 1.0 mmol, and reaction 30min, removes ice bath, reacts 24 h under room temperature.After question response finishes, be cooled to room temperature, washing, with dichloromethane extraction, merges organic layer, anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is methylene chloride-methanol), obtains intermediate
3.
4 asymmetric pairs of alkyl of embodiment replace curcumin analogue intermediate
4universal synthesis method
1) by methyl ethyl diketone 16mL(160 mmol) and boron trioxide 7.80 g(112mmol) be dissolved in 100ml ethyl acetate, under stirring, be warming up to 80 DEG C, react after 0.5 h, add 3-methoxy-4-hydroxybenzaldehyde 12.0 g(80 mmol) and tri-n-butyl borate 2.16mL(80mmol).Continue, after reaction 0.5 h, to drip 8 mL(80 mmol) n-Butyl Amine 99 (with 10 mL ethyl acetate dilutions), in 30 min, dropwise, keep reaction 12 h, be cooled to 50 DEG C.Adding concentration is the rare HCl of 50 mL of 0.4 N, and stirring reaction 1 h, is cooled to room temperature, and washing, is extracted with ethyl acetate (3 × 30 mL), merges organic layer, saturated sodium-chloride water solution washing, anhydrous Na
2sO
4dry, filter, concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is petroleum ether-ethyl acetate), obtains yellow crystalline solid
7, productive rate 25%, mp:139 ~ 141 DEG C.
2) by 9.0g(37.50mmol) intermediate
7with boron trioxide 1.8 g(26.25mmol) be dissolved in 100ml ethyl acetate, under stirring, be warming up to 80 DEG C, after reaction 0.5 h, add 4-hydroxy benzaldehyde 45.0 g(375.0 mmol) and tri-n-butyl borate 10mL(37.50mmol).Continue reaction 0.5 h, drip 3.6 mL(37.50mmol) piperidines (with 5 mL ethyl acetate dilutions), in 30 min, dropwise, keep, after reaction 12 h, being cooled to 50 DEG C.Adding concentration is the rare HCl of 40 mL of 0.4 N, and stirring reaction 1 h, is cooled to room temperature, and washing, is extracted with ethyl acetate (3 × 30 mL), merges organic layer, saturated sodium-chloride water solution washing, anhydrous Na
2sO
4dry, filter, concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is petroleum ether-ethyl acetate), obtains red-brown solid
8, productive rate 18%, mp:171 ~ 173 DEG C.
3) to intermediate
8phenolic hydroxyl group first carry out acetylize protection, obtain intermediate
9; Then its active methylene group carbon atom is carried out to two hydrocarbylations, obtain intermediate
10; Finally slough blocking group, obtain intermediate
4.Synthetic method is as embodiment 1.
Embodiment 5 formulas
icompound (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-replaces secondary amine alkoxyl phenyl)-4,4-dialkyl heptan-1,6-diene-3, the universal synthesis method of 5-diketone
By the product halogen ether curcuminoids intermediate in embodiment 2
21.43 mmol, salt of wormwood 7.15mmol,
n-substituted-piperazinyl or replacement secondary amine 7.15 mmol are dissolved in 10mL acetonitrile, reflux 5 h.Remove by filter salt of wormwood, pressure reducing and steaming acetonitrile, residuum is dissolved in 30 mL methylene dichloride, with 3N hydrochloric acid soln washing (30 mL × 3), merge acid solution, anhydrous sodium carbonate is neutralized to pH9.0 ~ 10.0, dichloromethane extraction (30 mL × 5), merge organic layer, use saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is methylene chloride-methanol), obtains formula
icompound.
Embodiment 6 formulas
iIcompound (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-replaces secondary amine aminomethyl phenyl)-4,4-dialkyl heptan-1,6-diene-3, the universal synthesis method of 5-diketone
Two product in embodiment 1 alkyl are replaced to curcumine intermediate
11.0 mmol are dissolved in 3 mL anhydrous methanols, under room temperature, add secondary amine 2.5 mmol, and formaldehyde (37% aqueous solution) 2.5mmol reacts 10 h at 40 DEG C.After question response finishes, be cooled to room temperature, washing, with dichloromethane extraction, merges organic layer, anhydrous sodium sulfate drying, and concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is methylene chloride-methanol), obtains formula
iIcompound.
Embodiment 7 formulas
iIIcompound (1
e, 6
e)-1-(3-methoxyl group-4-substituted alkoxy-5-replaces secondary amine aminomethyl phenyl)-7-(3-methoxyl group-4-substituted alkoxy phenyl)-4,4-dialkyl group heptan-1,6-diene-3, the universal synthesis method of 5-diketone
By the product Mannich base intermediate in embodiment 3
30.5 mmol, Anhydrous potassium carbonate 1.5 mmol are dissolved in 10mL acetone, and back flow reaction 30 min add haloalkane or haloalkyl ammonia 1.5 mmol, continue reaction 5 h.After question response completes, remove by filter salt of wormwood, remove acetone under reduced pressure, add 30mL water, with dichloromethane extraction (30 mL × 3), merge organic layer, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is petroleum ether-ethyl acetate), obtains formula
iIIcompound.
Asymmetric product in embodiment 4 pair of alkyl replaced to curcumin analogue intermediate
41.74mmol is dissolved in 10 mL DMF, under room temperature, adds secondary amine 8.70mmol, and formaldehyde (37% aqueous solution) 8.70mmol reacts 10 h at 80 DEG C.After question response finishes, be cooled to room temperature, add 50mL water, with dichloromethane extraction (30 mL × 3), merge organic layer, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is methylene chloride-methanol), obtains formula
iVcompound.
Embodiment 9 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-dimethylin propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iaa) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with dimethylamine hydrochloride, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.04(quint., 4H), 2.30(s, 12H), 2.54(t, 4H), 3.38(s, 4H), 3.84(s, 6H), 4.07(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.82(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.8 Hz), 7.04(dd, 2H,
J = 1.8, 8.4 Hz), 7.10(m, 4H), 7.18(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 10 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-dimethylamino ethoxy) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iab) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with dimethylamine hydrochloride, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.36(m, 12H), 2.83(t, 4H), 3.38(s, 4H), 3.83(s, 6H), 4.14(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.82(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.2 Hz), 7.04(dd, 2H,
J = 1.2, 8.1 Hz), 7.10(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 11 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-dimethylin propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iac) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with dimethylamine hydrochloride, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 2.01(quint., 4H), 2.24(s, 12H), 2.45(t, 4H), 3.87(s, 6H), 4.09(t, 4H), 6.64(d, 2H,
J = 15.6 Hz), 6.86(d, 2H,
J = 8.4 Hz), 7.00(s, 2H), 7.10(d, 2H,
J = 7.2 Hz), 7.68(d, 2H,
J = 15.6 Hz)。
Embodiment 12 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-dimethylamino ethoxy) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iad) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with dimethylamine hydrochloride, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 2.40(s, 12H), 2.86(t, 4H), 3.86(s, 6H), 4.17(t, 4H), 6.64(d, 2H,
J = 15.6 Hz), 6.85(d, 2H,
J = 8.4 Hz), 6.99(s, 2H), 7.10(d, 2H,
J = 8.1 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 13 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-diethylin propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iba) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with diethylamine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.41(t, 12H), 2.36(quint., 4H), 3.15(m, 8H), 3.24(m, 4H), 3.38(s, 4H), 3.81(s, 6H), 4.13(t, 4H), 6.51(d, 2H,
J = 15.6 Hz), 6.81(d, 2H,
J = 8.4 Hz), 6.84(d, 2H,
J = 1.8 Hz), 7.03(dd, 2H,
J = 1.5, 8.4 Hz), 7.11(m, 4H), 7.19(m, 6H), 7.67(d, 2H,
J = 15.3 Hz)。
Embodiment 14 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-diethylin oxyethyl group) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
ibb) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with diethylamine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.06(t, 12H), 2.65(q, 8H), 2.93(t, 4H), 3.38(s, 4H), 3.83(s, 6H), 4.11(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.83(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.5 Hz), 7.05(dd, 2H,
J = 1.5, 8.4 Hz), 7.10(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 15 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-diethylin propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
ibc) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with diethylamine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.01(t, 12H), 1.47(s, 6H), 1.97(quint., 4H), 2.54(m, 12H), 3.87(s, 6H), 4.08(t, 4H), 6.64(d, 2H,
J = 15.6 Hz), 6.85(d, 2H,
J = 8.4 Hz), 7.00(d, 2H,
J = 1.5 Hz), 7.10(dd, 2H,
J = 1.5, 8.4 Hz), 7.68(d, 2H,
J = 15.6 Hz)。
Embodiment 16 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-diethylin oxyethyl group) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
ibd) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with diethylamine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.05(t, 12H), 1.47(s, 6H), 2.62(q, 8H), 2.91(t, 4H), 3.87(s, 6H), 4.10(t, 4H), 6.64(d, 2H,
J = 15.3 Hz), 6.85(d, 2H,
J = 8.4 Hz), 6.99(d, 2H,
J = 1.5 Hz), 7.10(dd, 2H,
J = 1.5, 8.4 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 17 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(pyrroles-1-yl) propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
ica) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with Pyrrolidine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.80(s, 8H), 2.07(quint., 4H), 2.59(s, 8H), 2.67(t, 4H), 3.38(s, 4H), 3.83(s, 6H), 4.09(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.83(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.5 Hz), 7.04(dd, 2H,
J = 1.5, 8.1 Hz), 7.10(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.6 Hz)。
Embodiment 18 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(pyrroles-1-yl) oxyethyl group) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
icb) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with Pyrrolidine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.81(m, 8H), 2.64(s, 8H), 2.96(t, 4H), 3.38(s, 4H), 3.83(s, 6H), 4.17(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.83(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.8 Hz), 7.04(dd, 2H,
J = 1.8, 8.4 Hz), 7.11(m, 4H), 7.18(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 19 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(pyrroles-1-yl) propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
icc) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with Pyrrolidine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 1.80(m, 8H), 2.08(quint., 4H), 2.56(m, 8H), 2.65(t, 4H), 3.87(s, 6H), 4.11(t, 4H), 6.64(d, 2H,
J = 15.3 Hz), 6.86(d, 2H,
J = 8.4 Hz), 7.00(d, 2H,
J = 1.8 Hz), 7.10(dd, 2H,
J = 1.8, 8.4 Hz), 7.67(d, 2H,
J = 15.3 Hz)。
Embodiment 20 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(pyrroles-1-yl) oxyethyl group) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
icd) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with Pyrrolidine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 1.80(m, 8H), 2.63(m, 8H), 2.95(t, 4H), 3.87(s, 6H), 4.17(t, 4H), 6.64(d, 2H,
J = 15.3 Hz), 6.85(d, 2H,
J = 8.4 Hz), 7.00(d, 2H,
J = 1.2 Hz), 7.10(dd, 2H,
J = 1.5, 8.4 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 21 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(piperidin-1-yl) propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
ida) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with six hydrogen piperidines, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.54(m, 4H), 1.78(m, 8H), 2.19(quint., 4H), 2.88(m, 12H), 3.38(s, 4H), 3.82(s, 6H), 4.07(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.80(d, 2H,
J = 8.1 Hz), 6.85(d, 2H,
J = 1.5 Hz), 7.04(dd, 2H,
J = 1.5, 8.4 Hz), 7.10(m, 4H), 7.18(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 22 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(piperidin-1-yl) oxyethyl group) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
idb) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with six hydrogen piperidines, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.44(m, 4H), 1.59(m, 8H), 2.50(m, 8H), 2.80(t, 4H), 3.38(s, 4H), 3.83(s, 6H), 4.15(t, 4H), 6.53(d, 2H,
J = 15.6 Hz), 6.82(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.5 Hz), 7.04(dd, 2H,
J = 1.5, 8.4 Hz), 7.11(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.6 Hz)。
Embodiment 23 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(piperidin-1-yl) propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
idc) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with six hydrogen piperidines, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.43(m, 4H), 1.47(s, 6H), 1.56(m, 8H), 2.01(quint., 4H), 2.38(s, 8H), 2.45(t, 4H), 3.87(s, 6H), 4.09(t, 4H), 6.64(d, 2H,
J = 15.6 Hz), 6.86(d, 2H,
J = 8.4 Hz), 7.00(d, 2H,
J = 1.5 Hz), 7.10(dd, 2H,
J = 1.5, 8.4 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 24 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(piperidin-1-yl) oxyethyl group) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
idd) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with six hydrogen piperidines, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(m, 10H), 1.60(m, 8H), 2.50(m, 8H), 2.80(t, 4H), 3.87(s, 6H), 4.16(t, 4H), 6.64(d, 2H,
J = 15.6 Hz), 6.85(d, 2H,
J = 8.1 Hz), 6.99(d, 2H,
J = 1.5 Hz), 7.10(dd, 2H,
J = 1.8, 8.4 Hz), 7.67(d, 2H,
J = 15.3 Hz)。
Embodiment 25 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(morpholinyl propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iea) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with morpholine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.08(quint., 4H), 2.64(m, 12H), 3.38(s, 4H), 3.76(t, 8H), 3.83(s, 6H), 4.08(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.81(d, 2H,
J = 8.4 Hz), 6.87(d, 2H,
J = 1.8 Hz), 7.04(dd, 2H,
J = 1.8, 8.4 Hz), 7.11(m, 4H), 7.18(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 26 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-morpholinyl oxyethyl group) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
ieb) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with morpholine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.57(t, 8H), 2.83(t, 4H), 3.38(s, 4H), 3.71(t, 8H), 3.83(s, 6H), 4.15(t, 4H), 6.53(d, 2H,
J = 15.3 Hz), 6.82(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.5 Hz), 7.04(dd, 2H,
J = 1.5, 8.4 Hz), 7.10(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 27 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(morpholinyl propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iec) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with morpholine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 2.02(m, 4H), 2.50(m, 12H), 3.71(m, 8H), 3.87(s, 6H), 4.10(t, 4H), 6.64(d, 2H,
J = 15.3 Hz), 6.86(d, 2H,
J = 8.4 Hz), 7.00(s, 2H), 7.10(d, 2H,
J = 7.8 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 28 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-morpholinyl oxyethyl group) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
ied) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with morpholine, obtain yellow oil product.
1H-NMR(CDCl
3, 600MHZ)，δ(ppm)：1.47(s, 6H), 2.57(m, 8H), 2.83(t, 4H), 3.71(t, 8H), 3.87(s, 6H), 4.17(t, 4H), 6.64(d, 2H,
J = 15.0 Hz), 6.85(d, 2H,
J = 8.4 Hz), 7.00(d, 2H,
J = 1.8 Hz), 7.10(dd, 2H,
J = 1.8, 8.4 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 29 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(4-methylpiperazine-1-yl) propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
ifa) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-methylpiperazine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.01(quint., 4H), 2.32(s, 6H), 2.53(m, 20H), 3.38(s, 4H), 3.83(s, 6H), 4.08(t, 4H), 6.54(d, 2H,
J = 15.6 Hz), 6.83(d, 2H,
J = 8.4 Hz), 6.87(d, 2H,
J = 1.8 Hz), 7.04(dd, 2H,
J = 1.8, 8.4 Hz), 7.11(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 30 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
ifb) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-methylpiperazine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.29(s, 6H), 2.56(d, 16H), 2.84(t, 4H), 3.38(s, 4H), 3.83(s, 6H), 4.15(t, 4H), 6.53(d, 2H,
J = 15.6 Hz), 6.82(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.5 Hz), 7.04(dd, 2H,
J = 1.5, 8.4 Hz), 7.11(m, 4H), 7.18(m, 6H), 7.68(d, 2H,
J = 15.6 Hz)。
Embodiment 31 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(4-methylpiperazine-1-yl) propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
ifc) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-methylpiperazine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 2.01(quint., 4H), 2.28(s, 6H), 2.51(m, 20H), 3.87(s, 6H), 4.10(t, 4H), 6.64(d, 2H,
J = 15.6 Hz), 6.86(d, 2H,
J = 8.4 Hz), 7.00(d, 2H,
J = 1.8 Hz), 7.10(dd, 2H,
J = 1.8, 8.4 Hz), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 32 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
ifd) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-methylpiperazine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 2.28(s, 6H), 2.45(s, 12H), 2.61(s, 8H), 3.87(s, 6H), 4.15(t, 4H), 6.64(d, 2H,
J = 15.6 Hz), 6.84(d, 2H,
J = 8.7 Hz), 7.00(s, 2H), 7.10(d, 2H,
J = 8.1 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 33 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(4-benzyl diethylenediamine-1-yl) propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iga) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-benzyl diethylenediamine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.00(quint., 4H), 2.49(m, 20H), 3.38(s, 4H), 3.50(s, 4H), 3.82(s, 6H), 4.07(t, 4H), 6.54(d, 2H,
J = 15.3 Hz), 6.82(d, 2H,
J = 8.4 Hz), 6.86(d, 2H,
J = 1.5 Hz), 7.03(dd, 2H,
J = 1.5, 8.4 Hz), 7.10(m, 4H), 7.23(m, 10H), 7.30(m, 6H), 7.69(d, 2H,
J = 15.3 Hz)。
Embodiment 34 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(4-benzyl diethylenediamine-1-yl) oxyethyl group) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
igb) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-benzyl diethylenediamine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.54(d, 20H), 3.37(s, 4H), 3.50(s, 4H), 3.82(s, 6H), 4.14(t, 4H), 6.52(d, 2H,
J = 15.3 Hz), 6.81(d, 2H,
J = 8.4 Hz), 6.85(d, 2H,
J = 1.8 Hz), 7.04(d, 4H,
J = 8.1 Hz), 7.09(m, 4H), 7.18(m, 6H), 7.29(m, 8H), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 35 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(4-benzyl diethylenediamine-1-yl) propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
igc) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-benzyl diethylenediamine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 2.00(quint., 4H), 2.51(m, 20H), 3.50(s, 4H), 3.86(s, 6H), 4.08(t, 4H), 6.63(d, 2H,
J = 15.3 Hz), 6.85(d, 2H,
J = 8.4 Hz), 6.99(d, 2H,
J = 1.8 Hz), 7.09(dd, 2H,
J = 1.8, 8.4 Hz), 7.25(m, 2H), 7.31(m, 8H), 7.67(d, 2H,
J = 15.3 Hz)。
Embodiment 36 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(4-hydroxyethyl piperazine-1-yl) propoxy-) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iha) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-hydroxyethyl piperazine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.00(s, 4H), 2.65(m, 24H), 3.38(s, 4H), 3.69(s, 4H), 3.83(s, 6H), 4.07(t, 4H), 6.54(d, 2H,
J = 15.3 Hz), 6.81(d, 2H,
J = 8.4 Hz), 6.86(s, 2H), 7.04(d, 2H,
J = 8.1 Hz), 7.10(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 37 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(2-(4-hydroxyethyl piperazine-1-yl) oxyethyl group) phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
ihb) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-hydroxyethyl piperazine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：2.60(s, 24H), 3.38(s, 4H), 3.64(m, 4H), 3.83(s, 6H), 4.15(t, 4H), 5.45(s,2H), 6.53(d, 2H,
J = 15.6 Hz), 6.83(m, 4H), 7.04(d, 2H,
J = 7.8 Hz), 7.10(m, 4H), 7.19(m, 6H), 7.68(d, 2H,
J = 15.3 Hz)。
Embodiment 38 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-(3-(4-hydroxyethyl piperazine-1-yl) propoxy-) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
ihc) synthetic
According to the product halogen ether curcuminoids intermediate of embodiment 5 methods in embodiment 2
2synthesize with 4-hydroxyethyl piperazine, obtain yellow oil product.
1H-NMR(CDCl
3, 300MHZ)，δ(ppm)：1.47(s, 6H), 2.01(quint., 4H), 2.53(m, 24H), 3.60(m, 4H), 3.87(s, 6H), 4.10(t, 4H), 6.64(d, 2H,
J = 15.3 Hz), 6.86(d, 2H,
J = 8.4 Hz), 7.00(s, 2H), 7.10(d, 2H,
J = 8.1 Hz), 7.67(d, 2H,
J = 15.6 Hz)。
Embodiment 39 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-dimethylamino methyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI aa) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with dimethylamine and formaldehyde, obtain yellow solid, mp:68-71 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(s, 6H), 2.34(s, 12H), 3.65(s, 4H), 3.88(s, 6H), 6.59(d, 2H,
J=15.6Hz), 6.82(d, 2H,
J=1.5Hz), 6.94(d, 2H,
J=1.5Hz), 7.63(d, 2H,
J=15.6Hz)。
Embodiment 40 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-diethylin aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI ab) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with diethylamine and formaldehyde, obtain yellow solid, mp:66-69 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.12(t, 12H,
J=7.1Hz), 1.46(s, 6H), 2.64(q, 8H,
J=7.1Hz), 6.59(d, 2H,
J=15.5), 6.83(brs, 2H), 6.93(brs, 2H), 7.63(d, 2H,
J=15.5Hz)。
Embodiment 41 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(piperidin-1-yl) aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI ac) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with piperidines and formaldehyde, obtain yellow solid, mp:83-86 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(brs, 10H), 1.64(m, 8H), 2.64(brs, 8H), 3.70(s, 4H), 3.89(s, 6H), 6.58(d, 2H,
J=15.5Hz), 6.84(brs, 2H), 6.92(brs,2H), 7.63(d, 2H,
J=15.5Hz)。
Embodiment 42 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-morpholinyl methyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI ad) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with morpholine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.47(s, 6H), 2.61(brs, 8H), 3.89(brs, 12H), 6.60(d, 2H,
J=15.5Hz), 6.87(brs, 2H), 6.95(brs, 2H), 7.63(d, 2H,
J=15.5Hz)。
Embodiment 43 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-methylpiperazine-1-yl) aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI ae) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with 4-methylpiperazine and formaldehyde, obtain yellow solid, mp:92-95 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(s, 6H), 2.30(s, 6H), 2.64(m, 16H), 6.59(d, 2H,
J=15.5Hz), 6.85(brs, 2H), 7.63(d, 2H,
J=15.5Hz), 9.93(brs, 2H)。
Embodiment 44 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-sec.-propyl piperazine-1-yl) aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI af) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with 4-sec.-propyl piperazine and formaldehyde, obtain yellow solid, mp:68-71 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.04(d, 12H,
J=6.3Hz),1.46(s, 6H), 2.62(m, 18H), 3.72(s, 4H), 3.88(s, 6H), 6.59(d, 2H,
J=15.5Hz), 6.84(brs,2H), 6.92(brs, 2H), 7.63(d, 2H,
J=15.5Hz)。
Embodiment 45 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-isobutyl piperazine-1-yl) aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI ag) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with 4-isobutyl piperazine and formaldehyde, obtain yellow solid, mp:68-71 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 0.89(d, 12H,
J=7.2Hz),1.46(s, 6H), 1.74(m, 2H), 2.10(d, 4H,
J=7.2Hz), 2.55(m, 16H), 6.59(d, 2H,
J=15.5Hz),6.83(brs, 2H), 6.92(brs, 2H), 7.63(d, 2H,
J=15.5Hz)。
Embodiment 46 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-benzyl diethylenediamine-1-yl) aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI ah) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with 4-benzyl diethylenediamine and formaldehyde, obtain yellow solid, mp:92-95 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(s, 6H), 2.56(m, 16H),3.51(s, 4H), 3.71(s, 4h), 3.87(s, 6H), 6.58(d, 2H,
J=15.5Hz), 6.82(brs, 2H), 6.92(brs,2H), 7.27(m, 10H), 7.62(d, 2H,
J=15.5Hz)。
Embodiment 47 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-(piperidin-1-yl) piperidin-1-yl) aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iI ai) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1with 4-(piperidin-1-yl) piperidines and formaldehyde carries out Mannich reaction, obtain yellow solid, mp:121-123 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(s, 6H), 1.50(brs, 4H), 1.72(m, 12H), 1.99(d, 4H,
J=11.6Hz), 2.17(t, 4H,
J=12.3Hz), 2.67(brs, 10H), 3.08(d, 4H,
J=11.4Hz), 3.70(s, 4H), 3.89(s, 6H), 6.59(d, 2H,
J=15.5Hz), 6.82(s, 2H), 6.93(s, 2H), 7.62(d, 2H,
J=15.5Hz)。
Embodiment 48 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-ethyl piperazidine-1-yl) aminomethyl phenyl)-4,4-dimethyl-g-1,6-diene-3,5-dione hydrochloride (
iI aj) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 6 methods
1carry out Mannich reaction with 4-ethyl piperazidine and formaldehyde, obtain yellow solid, this target compound is dissolved in to a small amount of ethyl acetate, under ice bath is cooling, drip saturated hydrochloric acid diethyl ether solution, under ice bath, be stirred to adularescent solid and separate out, dry, mp:193-195 DEG C.
1H-NMR(DMSO-
d 6)，δ(ppm): 1.24(t, 6H,
J=6.9Hz), 1.44(s, 6H), 3.15(m, 4H), 3.57(m, 16H), 3.89(s, 6H), 4.29(s, 4H), 7.04(d, 2H,
J=15.3Hz), 7.46(brs, 2H), 7.52(d, 2H,
J=15.3Hz),7.61(brs, 2H)。
Embodiment 49 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-dimethylamino methyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iI ba) synthetic
Replace curcumine intermediate according to embodiment 6 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with dimethylamine and formaldehyde, obtain yellow solid, mp:84-86 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.33(s, 12H), 3.37(s, 4H), 3.64(s, 4H), 3.86(s, 6H), 6.57(d, 2H,
J = 15.3 Hz), 6.81(d, 2H,
J = 21.6 Hz), 7.09(m, 4H), 7.18(m, 6H), 7.67(d, 2H,
J= 15.3 Hz)。
Embodiment 50 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-diethylin aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iI bb) synthetic
Replace curcumine intermediate according to embodiment 6 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with diethylamine and formaldehyde, obtain yellow solid, mp:80-83 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.11(t, 12H,
J = 7.2 Hz), 2.63(q, 8H,
J = 7.2 Hz), 3.37(s, 4H), 3.76(s, 4H), 3.82(s, 6H), 6.57(d, 2H,
J = 15.3 Hz), 6.80(d, 4H,
J = 16.2 Hz), 7.09(d, 4H), 7.18(m, 6H), 7.67(d, 2H,
J= 15.3 Hz)。
Embodiment 51 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(pyrroles-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iI bc) synthetic
Replace curcumine intermediate according to embodiment 6 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with pyrroles and formaldehyde, obtain yellow solid, mp:103-105 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.86(brs, 8H), 2.69(brs, 8H), 3.37(s, 4H), 3.84(s, 4H), 3.87(s, 6H), 6.57(d, 2H,
J = 15.3 Hz), 6.84(d, 4H), 7.08(d, 4H), 7.18(m, 6H), 7.58(d, 2H,
J= 15.3 Hz)。
Embodiment 52 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(piperidin-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iI bd) synthetic
Replace curcumine intermediate according to embodiment 6 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with piperidines and formaldehyde, obtain yellow solid, mp:112-114 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.50(brs, 4H), 1.63(m, 8H), 2.52(brs, 8H), 3.37(s, 4H), 3.67(s, 4H), 3.86(s, 6H), 6.55(d, 2H,
J = 15.3 Hz), 6.83(d, 4H), 7.09(m, 4H), 7.20(m, 6H), 7.66(d, 2H,
J= 15.3 Hz)。
Embodiment 53 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-methylpiperazine-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iI be) synthetic
Replace curcumine intermediate according to embodiment 6 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with 4-methylpiperazine and formaldehyde, obtain yellow solid, mp:112-114 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.30(s, 7H), 2.62(brs, 15H), 3.37(s, 4H), 3.71(s, 4H), 3.86(s, 6H), 6.55(d, 2H,
J = 15.3 Hz), 6.81(d, 4H), 7.08(m, 4H), 7.20(m, 6H), 7.64(d, 2H,
J= 15.3 Hz)。
Embodiment 54 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(4-hydroxyethyl piperazine-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iI bf) synthetic
Replace curcumine intermediate according to embodiment 6 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with 4-hydroxyethyl piperazine and formaldehyde, obtain yellow solid, mp:112-114 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.57(t, 20H,
J= 5.27 Hz), 3.37(s, 4H), 3.62(t, 4H,
J= 5.27 Hz), 3.72(s, 4H), 3.87(s, 6H), 6.55(d, 2H,
J = 15.4Hz), 6.81(d, 4H), 7.09(m, 4H), 7.23(m, 6H), 7.65(d, 2H,
J= 15.4 Hz)。
Embodiment 55 (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxyl-5-(U-4527-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iI bg) synthetic
Replace curcumine intermediate according to embodiment 6 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with U-4527 and formaldehyde, obtain yellow solid, mp:106-108 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.69(d, 16H), 2.80(brs, 8H), 3.37(s, 4H), 3.87(brs, 10H), 6.55(d, 2H,
J = 15.3Hz), 6.84(s, 4H), 7.08(m, 4H), 7.18(m, 6H), 7.67(d, 2H,
J= 15.3 Hz)。
Embodiment 56 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-dimethylamino methyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII aa) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with dimethylamine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.47(s, 6H), 2.49(s, 6H), 3.86(s,2H), 3.91(s, 3H), 3.93(s, 3H), 6.62(d, 1H,
J=15.3Hz), 6.63(d, 1H,
J=15.6Hz), 6.89(d, 1H,
J=8.4Hz), 6.98(d, 1H,
J=1.5Hz), 7.01(d, 1H,
J=2.1Hz), 7.02(brs, 1H), 7.09(d, 1H,
J 1=8.4Hz,
J 2=1.5Hz), 7.65(d, 1H,
J=15.3Hz), 7.67(d, 1H,
J=15.6Hz)。
Embodiment 57 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-diethylin aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ab) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with diethylamine and formaldehyde, obtain yellow solid, mp:73-76 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.14(t, 6H,
J=7.5Hz), 1.47(s, 6H), 2.66(q, 4H,
J=7, 5Hz), 3.81(s, 2H), 3.89(s, 3H).3.92(s.3H), 6.59(d, 1H,
J=15.6Hz),6.62(d, 1H,
J=15.6Hz)6.88(brs, 1H), 6.89(d.1H,
J=8.1Hz), 6.93(d, 1H,
J=2.1Hz)7.00(d, 1H,
J=1.8Hz), 7.09(d, 1H,
J 1=8.1Hz,
J 2=2.1Hz), 7.65(d, 1H,
J=15.6Hz), 7.67(d, 1H,
J=15.6Hz)。
Embodiment 58 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(pyrroles-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ac) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with pyrroles and formaldehyde, obtain yellow solid, mp:87-90 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.47(s, 6H), 1.86(brs, 4H), 2.68(brs, 4H), 3.86(s, 2H), 3.88(s, 3H), 3.92(s, 3H), 6.59(d, 1H,
J=15.5Hz), 6.62(d, 1H,
J=15.5Hz), 6.87(brs, 1H), 6.89(d, 1H,
J=8.3Hz), 6.93(brs, 1H), 6.99(brs, 1H), 7.08(d, 1H,
J=8.3Hz), 7.64(d, 1H,
J=15.5Hz), 7.67(d, 1H,
J=15.5Hz)。
Embodiment 59 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(piperidin-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ad) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with piperidines and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(brs, 8H), 1.63(m, 4H), 2.52(brs, 4H), 3.68(s, 2H), 3.88(s, 3H), 3.91(s, 3H), 6.58(d, 1H,
J=15.4Hz), 6.61(d, 1H,
J=15.5Hz), 6.82(brs, 1H), 6.89(d, 1H,
J=8.2Hz), 6.91(brs, 1H), 6.99(d, 1H,
J=1.68Hz), 7.09(dd, 1H,
J 1=8.2Hz,
J 2=1.68Hz), 7.63(d, 1H,
J=15.4Hz), 7.66(d, 1H,
J=15.5Hz)。
Embodiment 60 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-morpholinyl methyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ae) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with morpholine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.47(s, 6H), 2.60(brs, 4H), 3.74(m, 6H),3.89(s, 3H), 3.92(s, 3H), 6.60(d, 2H,
J=15.6Hz), 6.62(d, 2H,
J=15.6Hz), 6.86(brs, 1H), 6.89(d, 1H,
J=8.1Hz), 6.94 (brs, 1H), 6.99(brs, 1H), 7.19(d, 1H,
J=8.1Hz), 7.63(d, 1H,
J=15.6Hz), 7.67(d, 1H,
J=15.6Hz)。
Embodiment 61 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-methylpiperazine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII af) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with 4-methylpiperazine and formaldehyde, obtain yellow solid, mp:86-89 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.47(s, 6H), 2.31(s, 3H),2.64(brs, 8H), 3.73(s, 2H), 3.89(s, 3H), 3.91(s, 3H), 6.59(d, 1H,
J=15.5Hz), 6.62(d, 1H,
J=15.5Hz), 6.85(brs, 1H), 6.88(d, 1H,
J=8.1Hz), 6.93(brs, 1H), 6.99(brs, 1H), 7.09(d, 1H,
J=8.1Hz), 7.63(d, 1H,
J=15.5Hz), 7.67(d, 1H,
J=15.5Hz)。
Embodiment 62 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-ethyl piperazidine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ag) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with 4-ethyl piperazidine and formaldehyde, obtain yellow solid, mp:93-96 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.09(t, 3H,
J=7.8Hz), 1.47(s, 6H), 2.46(q, 2H,
J=7.8Hz), 2.65(m, 8H), 3.72(s, 2H), 3.88(s.3H), 3.91(s, 3H), 6.60(d, 1H,
J=15.5Hz), 6.62(d, 1H,
J=15.5Hz), 6.84(brs, 1H), 6.88(d, 1H,
J=8.2Hz), 6.93(brs, 1H), 6.99(brs, 1H), 7.08(d, 1H,
J=8.2Hz), 7.66(d, 1H,
J=15.5Hz), 7.63(d, 1H,
J=15.5Hz)。
Embodiment 63 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-sec.-propyl piperazine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ah) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with 4-sec.-propyl piperazine and formaldehyde, obtain yellow solid, mp:83-86 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.04(d, 6H,
J=6.6Hz), 1.47(s, 6H), 2.61(brs, 8H), 2.71(m, 1H), 3.71(s, 2H), 3.88(s, 3H), 3.90(s, 3H), 6.60(d, 1H,
J=15.6Hz), 6.62(d, 1H,
J=15.5Hz), 6.84(brs, 1H), 6.88(d, 1H,
J=8.2Hz), 6.92(brs, 1H), 6.99(d, 1H,
J=1.6), 7.08(dd, 1H,
J 1=8.2,
J 2=1.56Hz), 7.63(d, 1H,
J=15.6Hz), 7.66(d, 1H,
J=15.5Hz)。
Embodiment 64 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-isobutyl piperazine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ai) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with 4-isobutyl piperazine and formaldehyde, obtain yellow solid, mp:68-71 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 0.89(d, 6H,
J=6.5Hz), 1.46(s, 6H), 1.78(m, 1H), 2.09(brs, 2H)，2.55(m, 8H), 3.81(s, 2H), 3.88(s, 3H), 3.91(s, 3H), 6.59(d, 1H,
J=15.5Hz), 6.62(d, 1H,
J=15.5Hz), 6.83(brs, 1H), 6.88(d, 1H,
J=8.2Hz), 6.92(brs, 1H), 6.98(brs, 1H), 7.08(d, 1H,
J=8.2Hz), 7.63(d, 1H,
J=15.5Hz), 7.66(d, 1H,
J=15.5Hz)。
Embodiment 65 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-phenylpiperazine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII aj) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with 4-phenylpiperazine and formaldehyde, obtain yellow solid, mp:81-84 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.47(s, 6H), 2.80(brs, 4H),3.27(brs, 4H), 3.83(s, 2H), 3.89(s, 3H), 3.92(s, 3H), 6.63(d, 2H,
J=15.5Hz), 6.90(m,5H), 6.96(brs, 1H), 7.00(brs, 1H), 7.09(d, 1H,
J=8.2Hz), 7.26(t, 2H,
J=7.8Hz), 7.64(d, 1H,
J=15.5Hz), 7.67(d, 1H,
J=15.5Hz)。
Embodiment 66 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-benzyl diethylenediamine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ak) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with 4-benzyl diethylenediamine and formaldehyde, obtain yellow solid, mp:93-96 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(s, 6H), 2.63(m, 8H),3.53(s, 2H), 3.72(s, 2H), 3.88(s, 3H), 3.91(s, 3H), 6.59(d, 1H,
J=15.6Hz), 6.62(d, 1H,
J=15.6Hz), 6.83(brs, 1H), 6.88(d, 1H,
J=8.2Hz), 6.92(brs, 1H), 6.98(brs, 1H), 7.08(d, 1H,
J=8.2Hz), 7.30(m, 5H), 7.62(d, 1H,
J=15.6Hz), 7.66(d, 1H,
J=15.6Hz)。
Embodiment 67 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-cinnamyl group piperazine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII al) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1carry out Mannich reaction with 4-cinnamyl group piperazine and formaldehyde, obtain yellow solid, mp:92-95 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(s, 6H), 2.65(brs, 8H), 3.20(d, 2H,
J=6.3), 3.74(s, 2H), 3.89(s, 3H), 3.91(s, 3H), 6.25(m, 1H), 6.53(d,1H,
J=17.4Hz), 6.59(d, 1H,
J=15.9Hz), 6.61(d, 1H,
J=15.6Hz), 6.85(brs, 1H), 6.89(d, 1H,
J=8.1Hz), 6.93(d, 1H,
J=1.8Hz), 6.99(d, 1H,
J=1.8Hz), 7.09(dd, 1H,
J 1=7.8Hz,
J 2=1.8Hz), 7.34(m, 5H), 7.63(d, 1H,
J=15.9Hz), 7.67(d, 1H,
J=15.6Hz)。
Embodiment 68 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-(piperidin-1-yl) piperidin-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII am) synthetic
According to the two methyl substituted curcumine intermediates of the product in embodiment 1 for embodiment 3 methods
1with 4-(piperidin-1-yl) piperidines and formaldehyde carries out Mannich reaction, obtain yellow solid, mp:99-101 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.46(s, 8H), 1.73(brs, 6H), 1.95(d, 2H,
J=11.5Hz), 2.15(t, 2H,
J=11.5Hz), 2.66(brs, 5H), 3.06(d, 2H,
J=11.5Hz), 3.69(s, 2H), 3.88(s, 3H), 3.90(s, 3H), 6.59(d, 1H,
J=15.5Hz), 6.61(d, 1H,
J=15.5Hz), 6.81(brs, 1H), 6.88(d, 1H,
J=8.2Hz), 6.92(brs, 1H), 6.98(brs, 1H), 7.08(d, 1H,
J=8.2Hz), 7.63(d, 1H,
J=15.5Hz), 7.66(d, 1H,
J=15.5Hz)。
Embodiment 69 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-dimethylamino methyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iII ba) synthetic
Replace curcumine intermediate according to embodiment 3 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with dimethylamine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.30(s, 6H), 3.37(s, 4H), 3.61(s, 2H), 3.83(s, 6H), 6.55(d, 2H,
J = 15.3 Hz), 6.80(t, 4H), 7.00(d, 2H,
J = 8.4 Hz), 7.10(d, 5H,
J = 7.5 Hz), 7.21(m, 7H), 7.64(d, 1H,
J = 5.7 Hz), 7.69(d, 1H,
J 1 = 5.7 Hz,
J 2 = 15.3 Hz)。
Embodiment 70 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-diethylin aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iII bb) synthetic
Replace curcumine intermediate according to embodiment 3 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with diethylamine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.10(t, 6H,
J = 6.9 Hz), 2.62(q, 4H,
J = 6.9 Hz), 3.37(s, 4H), 3.75(s, 2H), 3.85(d, 6H,
J = 7.2 Hz), 6.55(d, 2H,
J = 14.1 Hz), 6.82(t, 4H,
J 1 = 14.4 Hz,
J 2 = 15.3 Hz), 7.07(m, 5H), 7.19(m, 6H), 6.67(dd, 2H,
J 1 = 4.8 Hz,
J 2 = 15.0 Hz)。
Embodiment 71 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(pyrroles-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iII bc) synthetic
Replace curcumine intermediate according to embodiment 3 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with pyrroles and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.86(brs, 4H), 2.68(brs, 4H), 3.37(s, 4H), 3.85(s, 2H), 3.87(d, 6H), 6.55(d, 2H,
J 1 = 3.00 Hz,
J 2 = 15.39 Hz), 6.82(brs, 2H), 6.88(d, 2H), 7.06(m, 5H), 7.16(m, 6H), 7.67(dd, 2H,
J 1 = 2.86 Hz,
J 2 = 15.3 Hz)。
Embodiment 72 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(piperidin-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iII bd) synthetic
Replace curcumine intermediate according to embodiment 3 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with piperidines and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.49(brs, 2H), 1.63(m, 4H), 2.51(brs, 4H), 3.37(s, 4H), 3.67(s, 2H), 3.87(d, 6H), 6.52(d, 1H,
J= 5.37 Hz), 6.57(d, 1H,
J= 5.37 Hz), 6.81(s, 1H), 6.86(s, 1H), 6.88(s, 2H), 7.07(s, 1H), 7.09(m, 5H), 7.18(m, 6H), 7.64(d, 1H,
J= 5.73 Hz), 7.70(d, 1H,
J= 5.70 Hz)。
Embodiment 73 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-morpholine methyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iII be) synthetic
Replace curcumine intermediate according to embodiment 3 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with morpholine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.65(brs, 4H), 3.38(s, 4H), 3.78(brs, 6H), 3.89(t, 6H), 6.52(d, 1H,
J 1 = 4.08 Hz,
J 2 = 15.33 Hz), 6.57(d, 1H,
J 2 = 15.33 Hz), 6.88(m, 4H), 7.09(m, 5H), 7.20(m, 6H), 7.66(d, 1H,
J 2 = 15.36 Hz), 7.71(d, 1H,
J 1 = 8.19 Hz,
J 2 = 15.36 Hz)。
Embodiment 74 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-methylpiperazine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iII bf) synthetic
Replace curcumine intermediate according to embodiment 3 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with 4-methylpiperazine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.29(d, 3H), 2.55(brs, 8H), 3.37(s, 4H), 3.70(s, 2H), 3.87(d, 6H), 6.53(dd, 2H,
J 1 = 3.6 Hz,
J 2 = 15.3 Hz), 6.82(q, 4H), 7.06(m, 5H), 7.18(m, 6H), 7.67(dd, 2H,
J 1 = 8.7 Hz,
J 2 = 15.3 Hz)。
Embodiment 75 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-hydroxyethyl piperazine-1-yl) aminomethyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iII bg) synthetic
Replace curcumine intermediate according to embodiment 3 methods with the two benzyls of the product in embodiment 1
1carry out Mannich reaction with 4-hydroxyethyl piperazine and formaldehyde, obtain yellow solid, mp:84-87 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.55(brs, 11H), 3.37(s, 4H), 3.67(m, 2H), 3.69(m, 2H), 3.88(d, 6H), 6.54(dd, 2H,
J 1 = 8.7 Hz,
J 2 = 15.3 Hz), 6.83(m, 4H), 7.08(m, 5H), 7.24(m, 6H), 7.67(dd, 2H,
J 1 = 8.7 Hz,
J 2 = 15.3 Hz)。
Embodiment 76 (1
e, 6
e)-1-(3-methoxyl group-4-oxyethyl group-5-morpholinyl methyl phenyl)-7-(3-methoxyl group-4-ethoxyl phenenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ca) synthetic
According to the two methyl substituted curcumine morpholine Mannich base intermediates of the product in embodiment 3 for embodiment 7 methods
3carry out etherification reaction with monobromethane, obtain yellow solid, mp:51-55 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.31 (t, 3H), 1.40 (t, 3 H) , (s, 6H), 2.40 (brs, 4H), 3.45 (s, 2H), 3.62 (t, 4H), 3.80 (s, 3H), 3.83 (s, 3H), 4.02 (m, 4H), 6.60 (d,
J=12 Hz, 1H), 6.65(d,
J=12 Hz, 1H), 6.77 (d,
J=8.1 Hz, 1H), 6.93 (dd,
J 1 =1.2 Hz,
J 2 =15.6Hz,2H),7.05(d,
J=8.4Hz,1H),7.13(brs,1H),7.64(d,
J=15.6Hz,2H)。
Embodiment 77 (1
e, 6
e)-1-(3-methoxyl group-4-butoxy-5-morpholinyl methyl phenyl)-7-(3-methoxyl group-4-butoxy phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII cb) synthetic
According to the two methyl substituted curcumine morpholine Mannich base intermediates of the product in embodiment 3 for embodiment 7 methods
3carry out etherification reaction with n-butyl bromide, obtain yellow solid, mp:51-53 DEG C.
1H-NMR(CDCl
3，400MHZ)，δ(ppm): 0.96 (m, 6H), 1.50 (m, 5H), 1.75 (t, 2H), 1.83 (t, 2H), 2.45 (brs, 4H), 3.50 (s, 2H), 3.68 (t, 4H), 3.86 (s, 3H), 3.88 (s,3H), 3.97 (t, 2H), 4.04 (t, 2H), 6.65 (dd,
J 1 =14.0Hz,
J 2 =15.2 Hz, 2H), 6.83 (d,
J=8.4, 1H), 6.94 (d,
J=2 Hz, 1H), 7.01 (d,
J=2 Hz, 1H), 7.11 (dd,
J 1 =1.6 Hz,
J 2 =15.2 Hz, 1H), 7.17(d,
J=2 Hz, 1H), 7.69 (dd,
J 1 =4.4 Hz,
J 2 =4.0 Hz, 2H)。
Embodiment 78 (1
e, 6
e)-1-(3-methoxyl group-4-(3-diethylin propoxy-)-5-morpholinyl methyl phenyl)-7-(3-methoxyl group-4-(3-diethylin propyl group) phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII cc) synthetic
According to the two methyl substituted curcumine morpholine Mannich base intermediates of the product in embodiment 3 for embodiment 7 methods
3with
n,
n-diethyl-3-chlorine propylamine carries out etherification reaction, obtains yellow solid, mp:82-85 DEG C.
1H-NMR(CDCl
3，400MHZ)，δ(ppm): 1.04 (m, 12H), 1.48 (d, 6H), 2.44 (brs, 4H), 2.55 (brs, 12H), 3.49 (s, 2H), 3.67 (m, 4H), 3.85 (s, 3H), 3.87 (s, 3H), 4.00 (t, 2H), 4.09 (t, 2H), 6.65 (dd,
J 1 =10.2 Hz,
J 2 =15.5 Hz, 2H), 6.87 (d, 1H), 6.93 (dd,
J 1 =1.9 Hz,
J 2 =1.9 Hz, 2H), 7.10 (d, 1H), 7.16 (d,
J=1.8 Hz, 1H), 7.65 (d,
J=3.7 Hz, 1H), 7.69 (d,
J=3.7 Hz, 1H)。
Embodiment 79 (1
e, 6
e)-1-(3-methoxyl group-4-(3-(4-methylpiperazine-1-yl) propoxy-)-5-morpholinyl methyl phenyl)-7-(3-methoxyl group-4-(3-(4-methylpiperazine-1-yl) propoxy-phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII cd) synthetic
According to the two methyl substituted curcumine morpholine Mannich base intermediates of the product in embodiment 3 for embodiment 7 methods
3with
n-methyl-4-(3-chloropropyl) piperazine carries out etherification reaction, obtains yellow solid, mp:100-104 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.48 (m, 10H), 2.30 (d, 6H), 2.44 (brs, 4H), 2.55 (m, 20H), 3.48 (s, 2H), 3.66 (m, 4H), 3.85 (s, 3H), 3.87 (s, 3H), 3.99 (t, 2H), 4.08 (t, 2H), 6.65 (dd,
J 1 =10.1 Hz,
J= 8.4 Hz, 1H), 6.97 (d,
J=19.7 Hz, 2H), 7.08 (d, 1H), 7.16 (d, 1H), 7.70 (
J 1 =3.5 Hz,
J 2 =15.5 Hz, 2H)。
Embodiment 80 (1
e, 6
e)-1-(3-methoxyl group-4-(3-(piperidin-1-yl) propoxy-)-5-morpholinyl methyl phenyl)-7-(3-methoxyl group-4-(3-(piperidin-1-yl) propoxy-phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII ce) synthetic
According to the two methyl substituted curcumine morpholine Mannich base intermediates of the product in embodiment 3 for embodiment 7 methods
3with 4-(3-chloropropyl) piperidines carries out etherification reaction, obtain yellow solid, mp:80-83 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.43 (m, 4H), 1.48 (d, 6H), 1.58 (m, 12H), 2.48 (m, 16H), 3.49 (s, 2H), 3.67 (t, 4H), 3.85 (s, 3H), 3.87 (s, 3H), 3.99 (t, 2H), 4.08 (t, 2H), 6.68 (dd,
J 1 =10.6 Hz,
J 2 =15.3 Hz, 2H), 6.85 (d,
J=8.4 Hz, 1H), 6.96 (dd,
J 1 =1.5 Hz,
J 2 =19.4 Hz, 2H), 7.10 (dd,
J 1 =1.5 Hz,
J 2 =8.4 Hz, 1H), 7.16 (d,
J=1.5 Hz, 1H), 7.70 (dd,
J 1 =3.6 Hz,
J 2 =15.5 Hz, 2H)。
Embodiment 81 (1
e, 6
e)-1-(3-methoxyl group-4-acetoxyl group-5-morpholinyl methyl phenyl)-7-(3-methoxyl group-4-acetoxyl group phenyl)-4,4-dimethyl-g-1,6-diene-3,5-diketone (
iII cf) synthetic
By two the product in embodiment 3 methyl substituted curcumine morpholine Mannich base intermediates
30.25 g (0.5 mmol), is dissolved in 10 mL methylene dichloride, adds 0.30 mL (4.00 mmol) pyridine and 0.35 mL (4.00 mmol) acetic anhydride, mixture back flow reaction 1 h.Stopped reaction, cooling, saturated aqueous solution of sodium bicarbonate is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained oily matter, through silica gel column chromatogram separating purification (eluent is petroleum ether-ethyl acetate), obtains yellow solid, mp:63-66 DEG C.
1H-NMR(CDCl
3，300MHZ)，δ(ppm):1.49 (d, 6H), 2.31 (d, 6H), 2.39 (brs, 4H), 3.40 (s, 2 H), 3.64 (m, 4H), 3.84 (s, 3H), 3.85 (s, 3H), 6.70 (dd,
J=15.6 Hz, 2H), 7.03 (m, 3H), 7.10 (d, 2H), 7.68 (dd,
J=15.6Hz, 2H)。
Embodiment 82 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-dimethylamino methyl phenyl)-7-(4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV a) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with dimethylamine and formaldehyde, obtain yellow oil.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.32(s, 6H), 3.37(s, 4H), 3.63(s, 2H), 3.84(s, 3H), 6.55(d, 1H,
J = 15.3 Hz), 6.63(d, 1H,
J = 15.6 Hz), 6.76(d, 2H), 6.81(d, 2H), 7.08(m, 4H,), 7.18(m, 6H), 7.35(d, 2H,
J = 8.4 Hz), 7.66(d, 1H,
J = 15.3 Hz), 7.70(d, 1H,
J = 15.6 Hz)。
Embodiment 83 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-diethylin aminomethyl phenyl)-7-(3-diethylin methyl-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV b) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with diethylamine and formaldehyde, obtain yellow oil.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.10(m, 12H), 2.62(m, 8H), 3.37(s, 4H), 3.76(d, 4H), 3.86(s, 3H), 6.57(d, 1H,
J = 15.9 Hz), 6.62(d, 1H,
J = 15.6 Hz), 6.76(m, 2H), 6.83(s, 2H,), 7.09(m, 5H), 7.18(m, 6H), 7.30(dd, 1H,
J = 1.8, 8.4 Hz), 7.67(d, 1H,
J = 15.3 Hz), 7.69(d, 1H,
J = 15.6 Hz)。
Embodiment 84 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(pyrroles-1-yl) aminomethyl phenyl)-7-(3-(pyrroles-1-yl) methyl-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV c) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with pyrroles and formaldehyde, obtain yellow oil.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 1.84(s, 8H), 2.64(s, 8H), 3.37(s, 4H), 3.81(s, 4H), 3.86(s, 3H), 6.57(d, 1H,
J = 15.6 Hz), 6.63(d, 1H,
J = 15.6 Hz), 6.79(m, 3H), 7.18(m, 7H), 7.31(dd, 1H,
J = 2.1, 8.4 Hz), 7.68(d, 1H,
J = 15.3 Hz), 7.69(d, 1H,
J = 15.3 Hz)。
Embodiment 85 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(piperidin-1-yl) aminomethyl phenyl)-7-(3-(piperidin-1-yl) methyl-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV d) and (1
e, 6
e)-1-(3,5-bis-((piperidin-1-yl) methyl)-4-hydroxy phenyl)-7-(3-methoxyl group-4-hydroxyl-5-(piperidin-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV e) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with piperidines and formaldehyde, obtain yellow oil
iV d:
1h-NMR (CDCl
3, 300MHZ), δ (ppm): 1.49 (s, 4H), 1.62 (m, 8H), 2.52 (br., 8H), 3.36 (s, 4H), 3.65 (d, 4H), 3.86 (s, 3H), 6.55 (d, 1H
j=15.9 Hz), 6.61 (d, 1H,
j=15.9 Hz), 6.75 (d, 2H,
j=8.4 Hz), 6.82 (s, 1H), 7.09 (m, 5H), 7.18 (m, 6H), 7.29 (dd, 1H,
j=1.8,8.4 Hz), 7.66 (d, 1H,
j=15.3 Hz), 7.68 (d, 1H,
j=15.3 Hz) and yellow oil
iV e:
1h-NMR (CDCl
3, 300MHZ), δ (ppm): 1.47 (s, 6H), 1.60 (m, 12H), 2.45 (s, 12H), 3.37 (s, 4H), 3.55 (s, 4H), 3.66 (s, 2H), 3.86 (s, 3H), 6.56 (d, 1H
j=15.3 Hz), 6.63 (d, 1H,
j=15.6 Hz), 6.77 (s, 1H), 6.83 (s, 1H), 7.07 (m, 4H), 7.18 (m, 8H), 7.66 (d, 1H,
j=15.0 Hz), 7.71 (d, 1H,
j=14.7 Hz).
Embodiment 86 (1
e, 6
e)-1-(3,5-bis-(morpholine methyl)-4-hydroxy phenyl)-7-(3-methoxyl group-4-hydroxyl-5-morpholine methyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV f) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with morpholine and formaldehyde, obtain yellow oil.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): δ 2.52(m, 8H), 2.58(s, 4H), 3.38(s, 4H), 3.59(s, 4H), 3.71(m, 14H), 3.87(s, 3H), 6.57(d, 1H,
J = 15.3 Hz), 6.63(d, 1H,
J = 15.6 Hz), 6.80(s, 1H), 6.85(d, 1H,
J = 1.8 Hz), 7.09(m, 4H), 7.19(m, 8H), 7.67(d, 1H,
J = 15.3 Hz), 7.70(d, 1H,
J = 15.3 Hz)。
Embodiment 87 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-methylpiperazine-1-yl) aminomethyl phenyl)-7-(3-(4-methylpiperazine-1-yl) methyl-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV g) and (1
e, 6
e)-1-(3,5-bis-((4-methylpiperazine-1-yl) methyl)-4-hydroxy phenyl)-7-(3-methoxyl group-4-hydroxyl-5-(4-methylpiperazine-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV h) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with 4-methylpiperazine and formaldehyde, obtain yellow oil
iV g:
1h-NMR (CDCl
3, 300MHZ), δ (ppm): 2.29 (d, 6H), 2.58 (br., 16H), 3.36 (s, 4H), 3.71 (d, 4H), 3.86 (s, 3H), 6.56 (d, 1H
j=15.6 Hz), 6.61 (d, 1H,
j=15.6 Hz), 6.79 (m, 3H), 7.08 (m, 4H), 7.16 (m, 7H), 7.31 (dd, 1H,
j=1.8,8.4 Hz), 7.66 (d, 1H,
j=15.3 Hz), 7.68 (d, 1H,
j=15.6 Hz) and yellow oil
iV h:
1h-NMR (CDCl
3, 300MHZ), δ (ppm): 2.29 (d, 9H), 2.53 (d, 24H), 3.37 (s, 4H), 3.61 (s, 4H), 3.72 (s, 2H), 3.87 (s, 3H), 6.57 (d, 1H
j=15.6 Hz), 6.62 (d, 1H,
j=15.6 Hz), 6.82 (m, 2H), 7.08 (m, 4H), 7.19 (m, 8H), 7.66 (d, 1H,
j=15.3 Hz), 7.69 (d, 1H,
j=15.3 Hz).
Embodiment 88 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-benzyl diethylenediamine-1-yl) aminomethyl phenyl)-7-(3-(4-benzyl diethylenediamine-1-yl) methyl-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV i) and (1
e, 6
e)-1-(3,5-bis-((4-benzyl diethylenediamine-1-yl) methyl)-4-hydroxy phenyl)-7-(3-methoxyl group-4-hydroxyl-5-(4-benzyl diethylenediamine-1-yl) aminomethyl phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV j) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with 4-benzyl diethylenediamine and formaldehyde, obtain yellow oil
iV i:
1h-NMR (CDCl
3, 300MHZ), δ (ppm): 2.59 (br., 16H), 3.36 (s, 4H), 3.50 (d, 4H), 3.69 (d, 4H), 3.85 (s, 3H), 6.55 (d, 1H
j=15.6 Hz), 6.60 (d, 1H,
j=15.6 Hz), 6.75 (d, 2H,
j=8.7 Hz), 6.82 (d, 1H,
j=1.5 Hz), 7.08 (m, 4H), 7.18 (m, 6H), 7.30 (m, 12H), 7.65 (d, 1H,
j=15.3 Hz), 7.67 (d, 1H,
j=15.3 Hz) and yellow oil
iV j:
1h-NMR (CDCl
3, 300MHZ), δ (ppm): 2.53 (br., 24H), 3.37 (s, 4H), 3.51 (s, 6H), 3.59 (s, 4H), 3.69 (s, 2H), 3.85 (s, 3H), 6.55 (d, 1H
j=15.9 Hz), 6.61 (d, 1H,
j=15.6 Hz), 6.77 (s, 1H), 6.82 (s, 1H), 7.07 (m, 4H), 7.17 (m, 7H), 7.26 (m, 2H), 7.30 (m, 14H), 7.65 (d, 1H
j=15.3 Hz), 7.69 (d, 1H,
j=15.3 Hz).
Embodiment 89 (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-(4-hydroxyethyl piperazine-1-yl) aminomethyl phenyl)-7-(3-(4-hydroxyethyl piperazine-1-yl) methyl-4-hydroxy phenyl)-4,4-dibenzyl heptan-1,6-diene-3,5-diketone (
iV k) synthetic
Replace curcumine intermediate according to embodiment 8 methods with asymmetric pair of benzyl of the product in embodiment 4
4carry out Mannich reaction with 4-hydroxyethyl piperazine and formaldehyde, obtain yellow oil.
1H-NMR(CDCl
3，300MHZ)，δ(ppm): 2.56(m, 20H), 3.37(s, 4H), 3.61(m, 4H), 3.71(d, 4H), 3.86(s, 3H), 6.55(d, 1H,
J = 15.3 Hz), 6.61(d, 1H,
J = 15.3 Hz), 6.77(d, 2H,
J = 8.4 Hz), 6.83(d, 1H,
J = 1.8 Hz), 7.09(m, 4H), 7.12(d, 1H,
J = 1.8 Hz), 7.18(m, 6H), 7.31(dd, 1H,
J = 2.1, 8.4 Hz), 7.66(d, 1H,
J = 15.3 Hz), 7.68(d, 1H,
J = 15.3 Hz)。
Measure target compound to human cervical carcinoma cell HeLa with mtt assay, human liver cancer cell HepG2, human fibrosarcoma cell HT-1080, human colon cancer cell HCT116, human melanoma cell A375-S2, human breast cancer cell MCF-7, human lung cancer cell A549, the lymphoma cell U-937 of human tissue cell, the former leukemia cell K562 of the chronic marrow of people, the inhibited proliferation of the ten class tumour cells such as people's promyelocytic leukemia cell HL60.
1) attached cell is selected the adherent tumour cell of logarithmic phase, with after trysinization, uses containing the RPMI l640 substratum of 10% calf serum and is made into 5 × 10
4the cell suspension of/ml, is seeded in 96 well culture plates, every hole 1000 μ l, 37 DEG C, 5%CO
2cultivate 24 h.The nutrient solution containing different concns sample (10 ~ 100 μ molL-1) that experimental group more renews, control group is changed the nutrient solution containing equal-volume solvent, establishes 3 parallel holes, 37 DEG C, 5%CO for every group
2cultivate 48 h.Abandoning supernatant, carefully washes 2 times with PBS, and every hole adds the freshly prepared substratum that contains 0.5 mg/ml MTT of 100 μ l, and 37 DEG C are continued to cultivate 4 h.Careful supernatant discarded, and add 150 μ l DMSO, mixes after 10 min with microoscillator, with microplate reader 492 nm places mensuration optical density value (
oD).
2) suspension cell is selected the cell of logarithmic phase, uses containing the RPMI l640 substratum of 10% calf serum and is made into 1 × 10
4the cell suspension of/ml, is seeded in 96 well culture plates, every hole 50 μ l, 37 DEG C, 5%CO
2cultivate 24 h.Experimental group adds the nutrient solution 50 μ l containing different concns sample (10 ~ 100 μ molL-1), and control group adds the nutrient solution containing equal-volume solvent, establishes 3 parallel holes, 37 DEG C, 5%CO for every group
2cultivate 48 h, every hole adds the freshly prepared substratum that contains 5 mg/ml MTT of 100 μ l, and 37 DEG C are continued to cultivate 4 h.With three liquid (isopropylcarbinol 5 mL, with distilled water diluting to 100 mL for SDS 10 g, 10 M HCl 0.1 mL), 100 μ l are dissolving crystallized, hatch 12 h for 37 DEG C.With microplate reader 492 nm places measure optical density value (
oD).
Calculate as follows the inhibiting rate (Inhibition Rate, IR%) of medicine to Proliferation of Tumor Cells In Vitro:
IR%=（1-OD
sample/OD
control）′ 100%
With the half-inhibition concentration (IC of ICP1.0.0 computed in software medicine
50).
The results are shown in following table, show and curcumine comparison, the IC of these target compound inhibition tumor cell strains
50value increases, and therefore this compounds is expected to exploitation becomes treatment anti-tumor drug.
Formula
icompound
Table
1formula
ithe chemical structure of compound
Table
2formula
icompound and the curcumine IC to tumour cell
50value
Formula
iIcompound
iI aclass
Table
3formula
iIcompound
iI athe chemical structure of class and with curcumine to K
562the IC of cell
50value
Formula
iIcompound
iI bclass
Table
4formula
iIcompound
iI bthe chemical structure of class and with curcumine to K
562the IC of cell
50value
Formula
iIIcompound
iII aclass
Table
5formula
iIIcompound
iII athe chemical structure of class and with curcumine to K
562the IC of cell
50value
Formula
iIIcompound
iII bclass
Table
6formula
iIIcompound
iII bthe chemical structure of class and with curcumine to K
562the IC of cell
50value
Formula
iIIcompound
iII cclass
Table
7formula
iIIcompound
iII cthe chemical structure of class and with curcumine to K
562the IC of cell
50value
Formula
iVcompound
Table
8formula
iVthe chemical structure of compound
Table
9formula
iVcompound and curcumine thereof the IC to tumour cell
50value
Embodiment 91
The research of curcumin analogue Ica induction human melanoma A375-S2 cell Death Mechanism.Hsp90 is molecular chaperone protein, and its client's albumen exceedes 100, comprises Bcr/Abl, EGFR, Src, Erb2B, VEGF and Telomerase etc.Hsp90 level raises in kinds of tumor cells.Hsp90 is combined with the carinogenicity sudden change that helps maintain some client protein, makes cell detachment adjusting and controlling growth and develops into tumour.The chemical inhibitor that studies show that Hsp90 in the past contributes to block cell fission, promotes cell suicide and the tumour diffusion of slowing down, become the important target spot of antitumor drug.
Ica (1-16 μ M) can concentration, the inhibition A375-S2 cell proliferation of time-dependent manner, the IC of 24 h
50be 3.1 μ M, and its lead compound curcumine is at the IC of 24 h
50be 22.0 μ M.I ca (2-64 μ M) is to significantly restraining effect of human peripheral blood mononuclear cell (hPBMC) nothing.Inverted phase contrast microscope, fluorescent dye and Flow cytometry show, 3 μ M Ica act on A375-S2 cell 24 h and mainly cause cell generation apoptosis.Immunoblotting result shows, the protein expression of time-dependent manner ground downward Hsp90 after Ica effect A375-S2 cell, and the action target spot that shows Ica may be Hsp90 albumen.Ica promotes cytochrome
cbe discharged into cytoplasm from plastosome, reduce the protein expression of procaspase-9, induction caspase-3 precursor procaspase-3 cuts into the caspase-3 of activity form, and reducing the level of its substrate ICAD, the above results shows that Ica can be by activating mitochondria pathway induction A375-S2 apoptosis.
Experimental technique
(1) Ica is on the cytostatic impact of A375-S2
Get the cell in the A375-S2 of logarithmic phase, be inoculated in 96 orifice plates (5 × 10
3/ hole), cultivate after 24 h, add the Ica of different concns, each concentration is established 3 of parallel holes, in 37 DEG C, 5% CO
2condition under cultivate after 24 h, every hole adds MTT 100 μ L, continues to cultivate after 3 hours, every hole adds 150 μ L DMSO to dissolve, and detects in 492 nm places, measures light absorption value (OD value), and presses formula calculating mortality ratio, curve plotting.
(2) impact of Ica on human peripheral lymphocyte hPBMC
Get three healthy adult blood donors' fresh blood 70 mL, the hPBMC cell obtaining after separation and purification is resuspended with the RPMI-1640 nutrient solution containing 2% people AB type serum, and counting, with 5 × 10
4/ hole is inoculated in 96 orifice plates, cultivates to incubator.Abandoning supernatant after 3 h, remaining attached cell major part is monocyte (as shown in the figure), add Ica and Curcumin by concentration gradient, cultivate 12,24 and 48 h, every hole adds MTT 100 μ L, continues to cultivate after 3 hours, every hole adds 150 μ l DMSO to dissolve, detect in 492 nm places, measure light absorption value (OD value), and press formula and calculate survival rate.
(3) morphocytology changes observation
A375-S2 cell is inoculated in 96 orifice plates with 5 × 103/ holes, in 37 DEG C, under the condition of 5% CO2, cultivates after 24 h, adds the Ica of 3 μ M to process 24 h, observation of cell form under inverted microscope.
(4) fluorescent dye
Get the cell in the A375-S2 of logarithmic phase, be inoculated in (3 × 104/ hole) in 24 orifice plates, cultivate after 24 h, add the Ica of 3 μ M, after 24 h, wash once AO/EB(10 μ g/mL with phosphate buffered saline buffer (PBS)) dyeing 30 min, fluorescence microscopy Microscopic observation.
(5) flow cytometry method
Get the cell in the A375-S2 of logarithmic phase, be inoculated in (2 × 105/ hole) in 6 orifice plates, cultivate after 24 h, add Ica effect 24 h.Collecting cell, wash once with PBS, with 70%(v/v) 4 ° of C of ethanol under hold over night, object is by fixing cytolemma punching, add PI staining fluid (0.1% RNase) the 500 μ L of 100 mg/L, put 4 DEG C of lucifuges and dye and detect the variation of observation of cell mortality ratio after 30 min with flow cytometer.
(6) Western blot immunoblotting
Get in the A375-S2 of logarithmic phase cell and be inoculated in culturing bottle with 2 × 105/ bottles, after 24 h, add 3 μ M Ica, respectively at 12,18,24 h collecting cells after dosing, with centrifugal 10 min of 1000 × g, wash 2 times with PBS, with 100 μ L cell pyrolysis liquid ice bath cracking 1 h, centrifugal 5 min of 15000 × g, collect supernatant.After Bio-Rad method is carried out protein quantification with 12% SDS-PAGE gel electrophoresis isolated protein.After electrophoresis, albumen is transferred on nitrocellulose filter, after 5% skim-milk sealing, primary antibodie sealing is spent the night, then seals 2 h with two anti-confining liquids of horseradish peroxidase mark, with the colour developing of ECL test kit, sweep record.
Experimental result
Ica (1-16 μ M) can concentration, the inhibition A375-S2 cell proliferation (Fig. 1) of time-dependent manner, and the IC50 of 24 h is 3.1 μ M, and its lead compound curcumine is 22.0 μ M at the IC50 of 24 h.
The effect of Ica to human peripheral blood mononuclear cell (hPBMC): compared with negative control group (Fig. 2), the survival rate that Ica acts on hPBMC after cell 12,24 and 48 h does not obviously reduce, and its parent compound curcumine acts on after cell, the survival rate of hPBMC does not also obviously reduce, show that Ica is to significantly restraining effect of hPBMC survival nothing, selectivity and the security of this compound are higher.
Morphological observation: medicine Ica and Curcumin act on respectively after A375-S2 cell 24 h observation of cell form (Fig.3) under inverted phase contrast microscope, find that smaller volume appears in cell, and cell sprouts, and forms the phenomenons such as apoptotic body.Ica, compared with curcumine, can cause under low concentration that cell produces obvious apoptosis phenomenon, this shows that Ica activity inducing apoptosis is higher than curcumine.
AO/EB fluorescent dye: 3 μ M Ica and 20 μ M curcumines act on after A375-S2 cell 24 h through AO/EB fluorescent dye (Fig.4), observe that cell sends bright green fluorescence, tenuigenin shrinkage, formation apoptotic body sprouts, a few cell is safran, illustrates that 3 μ M Ica effect 24 h mainly cause A375-S2 cell generation apoptosis.
PI flow cytometry: for the further generation of checking phenomena of apoptosis, and detect the ratio of apoptotic cell, we the have adopted Flow cytometry cell of PI dyeing.As shown in Fig.5,3 μ M Ica process after cell, hypodiploid peak (SubG1, M1) obviously raise, and the prolongation of time thereupon, SubG1 phase cells ratio is and increases progressively trend, occurs that the cell count of DNA break increases, combining form is learned observations, further shows that Ica can be time-dependent manner induction A375-S2 cell generation apoptosis.
Western blot method detects the variation of Ica to cell death related protein expression amount: Cytochrome c participates in the transmission of mitochondrial respiratory chain electronics, and formation that can apoptosis involvement complex body in the time inserting to cytoplasm also starts endogenous apoptosis pathway.Experiment shows that Ica is time-dependent manner and promotes cytochrome c to be discharged into cytoplasm from plastosome.Caspase-9 is the short antiapoptotic factors of a class, and in tenuigenin, cytochrome c is combined with Apaf-1, jointly forms apoptotic proteins combined enzyme agent, causes caspase-9 to activate, and then activates the apoptosis-induced generation of downstream effect caspase.Result demonstration, Ica can be the protein expression of time-dependent manner reduction procaspase-9.Heat shock protein(HSP) Hsp90 has negative regulation effect to apoptotic proteins combined enzyme agent, research report, and Hsp90 can suppress by the oligomerization of the Apaf-1 of inhibition cytochrome c mediation the activation of caspase-9.
After Ica effect A375-S2 cell, the protein expression of Hsp90 is lowered on time-dependent manner ground.Caspase-3 is one of member of Interleukin-1β-converting enzyme family, and it brings into play important execution effect in the apoptosis process of various external stimulus inductions.The precursor procaspase-3 of Caspase-3 becomes activated form after cleaved.Activated caspase-3 can its death substrate of cracking, as ICAD and PARP.Result shows that the time dependent induction of Ica energy caspase-3 precursor procaspase-3 cuts into the caspase-3 of activity form, and the level (Fig. 6) of its effect substrate of cracking ICAD.The above results shows that Ica can be by activating mitochondria pathway induction A375-S2 apoptosis.
Claims (7)
1. curcumin analogue and a pharmaceutical salts thereof, has following constitutional features:
N is 0～4 integer, R
1for methyl, benzyl, R
2for hydrogen, C1-C3 acyl group or R
3;
R
3for with substituent amino, described substituting group is selected from: C1-C6 alkyl; Or with substituent piperazine, described substituting group is selected from: methyl, ethyl, sec.-propyl, isobutyl-, phenyl, benzyl, phenyl allyl group, hydroxyethyl; Or be morpholinyl, Pyrrolidine base, piperidyl, 4-piperidinyl piperidine base;
R
4for hydrogen or CH
2r
3; R
5for hydrogen or CH
2r
3.
2. curcumin analogue claimed in claim 1 and pharmaceutical salts thereof, wherein n is 0 o'clock, R
2for hydrogen, C1-C3 acyl group; N is 1～4 o'clock, R
2for R
3.
3. curcumin analogue and pharmaceutical salts thereof according to claim 1, wherein:
R
1for methyl, benzyl;
N is 0 o'clock, R
2for hydrogen, ethanoyl; N is 1～4 o'clock, R
2for R
3;
R
3for with substituent amino, described substituting group is selected from: C1-C2 alkyl; Or with substituent piperazine, described substituting group is selected from: methyl, ethyl, sec.-propyl, isobutyl-, phenyl, benzyl, phenyl allyl group, hydroxyethyl; Or be morpholinyl, Pyrrolidine base, piperidyl, 4-piperidinyl piperidine base;
R
4for hydrogen or CH
2r
3, R
5for hydrogen or CH
2r
3.
4. according to curcumin analogue described in claim 1 and pharmaceutical salts thereof, it is characterized in that, described pharmaceutical salts is the salt becoming with suitable non-toxicity organic acid or mineral acid.
5. a pharmaceutical composition, comprises claim 1-4 curcumin analogue or its pharmaceutical salts and vehicle described in any one.
6. a preparation method for curcumin analogue as claimed in claim 1, is characterized in that: replace curcumine intermediates (1 by two alkyl
e, 6
e)-1,7-bis-(3-methoxyl group-4-hydroxy phenyl)-4,4-dialkyl heptan-1,6-diene-3,5-diketone (
1) or (1
e, 6
e)-1-(3-methoxyl group-4-hydroxy phenyl)-7-(4-hydroxy phenyl)-4,4-dialkyl heptan-1,6-diene-3,5-diketone (
4), carrying out Mannich reaction with substitutional amine-group, substituted-piperazinyl, morpholinyl, Pyrrolidine base, piperidyl, substituted piperidine base, substituting group is as defined in claim 1; Or by by obtained Mannich base (1
e, 6
e)-1-(3-methoxyl group-4-hydroxyl-5-substituted amine methyl phenyl)-7-(3-methoxyl group-4-hydroxy phenyl)-4,4-dialkyl heptan-1,6-diene-3,5-diketone (
3) as intermediate, carrying out etherification reaction with haloalkane or haloalkyl amine, substituting group is as defined in claim 1; Or by halogen ether curcuminoids intermediate (1
e, 6
e)-1,7-bis-(3-methoxyl group-4-halogenated alkoxy phenyl)-4,4-dialkyl heptan-1,6-diene-3,5-diketone (
2), carrying out Mannich reaction with substitutional amine-group, substituted-piperazinyl, morpholinyl, Pyrrolidine base, piperidyl, substituted piperidine base, substituting group is as defined in claim 1
Claim 1-4 described in any one curcumin analogue and pharmaceutical salts thereof or composition claimed in claim 5 in the application of preparing in cancer therapy drug.
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