CN109879808A - One kind chalcones derivative of base containing five-membered azole heterocycle and preparation method and medical usage - Google Patents
One kind chalcones derivative of base containing five-membered azole heterocycle and preparation method and medical usage Download PDFInfo
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- CN109879808A CN109879808A CN201910162458.XA CN201910162458A CN109879808A CN 109879808 A CN109879808 A CN 109879808A CN 201910162458 A CN201910162458 A CN 201910162458A CN 109879808 A CN109879808 A CN 109879808A
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- membered azole
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- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 235000005513 chalcones Nutrition 0.000 title claims abstract description 25
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 150000001789 chalcones Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 9
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- -1 1- ethyl Chemical group 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 210000004027 cell Anatomy 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 210000005265 lung cell Anatomy 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 238000004809 thin layer chromatography Methods 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 230000020477 pH reduction Effects 0.000 claims description 3
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000071 diazene Inorganic materials 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 230000035755 proliferation Effects 0.000 abstract description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 2
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 201000005202 lung cancer Diseases 0.000 abstract 1
- 208000020816 lung neoplasm Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 229940125904 compound 1 Drugs 0.000 description 8
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 8
- 229920002554 vinyl polymer Polymers 0.000 description 8
- 230000001093 anti-cancer Effects 0.000 description 7
- GOUHYARYYWKXHS-UHFFFAOYSA-N para-formylbenzoic acid Natural products OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- YVXRZCXBCWUVGY-UHFFFAOYSA-N 3-(2-methoxycarbonylphenyl)prop-2-enoic acid Chemical compound COC(=O)C1=CC=CC=C1C=CC(O)=O YVXRZCXBCWUVGY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229940095102 methyl benzoate Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000005457 optimization Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 150000001788 chalcone derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of chalcones derivative of base containing five-membered azole heterocycle and preparation method and medical usage, the chalcones derivative of base containing five-membered azole heterocycle as described in leading to formula (I),R1ForOr
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of chalcones of base containing five-membered azole heterocycle are derivative
Object, preparation method and the application as field of antineoplastic medicaments.
Background technique
Protein kinase becomes a kind of popular anticancer target spot because of cell cycle regulation physiology course, and inhibitor is also anticancer
The important sources of lead compound.But only have nearly 30 kinds of kinases inhibitors at present successfully to list as anticancer drug, it is big absolutely
Majority is forced to stop later period research due to selectivity is low, toxic side effect is big etc. low druggability defect, becomes and restricts anticancer drug and grind
One of main bottleneck of hair.
Protein kinase C K2 is serine/threonine protein kitase generally existing in a kind of eukaryocyte, the hair with tumour
Disease is closely related, has important clinical value and application prospect as the cancer drug development of target spot using it.Currently, being based on CK2
The anticancer lead compound of target spot has complicated multiring structure so that by structure optimization with improve its druggability be faced with it is huge
Big technological challenge.Therefore, novel linear backbone kind anti-cancer drugs object is found to have potential application value.
Chalcone compound is widely distributed in some medicinal plants and the bioactive molecule of synthesis, is shown extensive
Bioactivity becomes the important sources of anticancer lead compound.The present invention is in investigation domestic and foreign literature, patent and seminar early period
On the basis of research work, for the 2- propenone skeleton for looking into youngster's ketone, the group of anticancer drug effect segment five-membered azole heterocycle base is carried out
Optimization is closed, and then obtains new type anticancer chalcone compound
Summary of the invention
The present invention relates to a kind of chalcones derivative of base containing five-membered azole heterocycle, preparation method and in field of medicaments
Application.
Inventor is by going deep into comparative analysis natural products chalcone and anticancer activating compound the CX-4945 mould in conjunction with CK2
The core skeleton region of the otherness of formula, the 2- propenone skeleton and CX4945 that find its chalcone is completely coincident, this shows needle
The Combinatorial Optimization of anticancer drug effect segment is carried out to the 2- propenone skeleton of chalcone, and there is stronger reasonability and feasibility.It is logical
Cross the anticancer pharmacophoric group of optimization different structure and property, the final R proposed in 2 propenone skeletons1Position introduces five yuan of azoles
Class heterocyclic group, to obtain the compound of novel antitumor cell proliferation activity.
In order to achieve the object of the present invention, a kind of base chalcones derivative of base containing five-membered azole heterocycle tool provided by the invention
Just like logical formula (I) structure compound represented:
Wherein, R1ForIn any one.
Work as R1ForWhen, the compound is 4- ((E) -2- ((1H- imidazoles -2- base) carbamoyl) ethylene
Base) benzoic acid (compound 1)
Work as R1ForWhen, the compound is 4- ((E) -2- (1H- pyrazoles -4- base-carbamoyl) ethylene
Base) benzoic acid (compound 2).
The present invention also provides the preparation method of two above base containing the five-membered azole heterocycle base chalcones derivative, institutes
State the reaction mechanism mechanism of reaction of method are as follows:
R1ForIn any one.
The specific synthesis step of compound provided by the present invention is as follows:
(1) by compound c, EDCI (1- ethyl -3- (3- dimethylaminopropyl) phosphinylidyne diimine) and DMAP (4- bis-
Methylamino pyridine) it is dissolved in THF, after being stirred to react 1-3 hours, compound R 1-NH2, the stirring of gained system are added into solution
Overnight, add water filtering precipitate, be concentrated in vacuo, obtain compound d；
(2) compound d obtained by step (1) is dissolved in methanol, adds LiOH aqueous solution, is stirred to react；Thin-layer chromatography prison
Reaction process is surveyed, is concentrated in vacuo after reaction, dilute hydrochloric acid acidification adjustment solution ph is acidity, adds water to filter, through anhydrous sulphur
Sour magnesium is dry, obtains crude product, then isolate and purify through silica gel column chromatography, obtains compound e, is i.e. base containing five-membered azole heterocycle is looked into
That ketones derivant.
In the above method:
In the step (1):
Compound c, EDCI, DMAP and the R1—NH2Molar ratio be 2:2-4:1-3:2-5；
The reaction temperature of compound c, EDCI and DMAP are controlled at 25-30 DEG C；
Compound R is added into the reaction solution of compound c, EDCI and DMAP1-NH2Reaction temperature control in 25-30
℃。
In the step (2):
The molar ratio of the compound d and LiOH is 1:1-3；
Reaction time controls in 2h-5h；
Reaction temperature is controlled at 25-30 DEG C；
Hydrochloric acid acidification concentration of hydrochloric acid solution used is 10%-30%, and control pH value of solution is 4-6；
Eluant, eluent used in silica gel column chromatography is methanol and methylene chloride, using gradient elution, methanol and methylene chloride
Volume ratio is 1:8-1:15.
The purposes of the base chalcones of base containing five-membered azole heterocycle derivative of the present invention in the preparation of antitumor drugs
It belongs to the scope of protection of the present invention.
Further, the base of base containing five-membered azole heterocycle chalcones derivative of the present invention has certain antitumor cell
The activity of proliferation.Tumour cell includes one or both of lung cell A549 and breast cancer cell MCF-7.
Specific embodiment
Below with reference to embodiment the present invention will be further described book, but the present invention is not limited to following embodiments.
Compound 1, the structural formula of compound 2 involved in following embodiment are as follows:
The reaction step of synthesis is following (including from compound a to the synthesis step of compound c):
R1ForIn any one.
1 4- of embodiment ((E) -2- ((1H- imidazoles -2- base) carbamoyl) vinyl) benzoic acid (compound 1)
Synthesis
(1) synthesis of p formylbenzoic acid ester
Weigh Compound a (1g, 6.66mmol) is dissolved in anhydrous CH3CN (20mL), addition DBU (1.105mL,
7.325mmol),CH3I (0.54mL, 8.66mmol) is stirred 2 hours at room temperature, TLC monitoring reaction (petroleum ether: ethyl acetate
=1:1).Vacuum concentration, obtains yellow oily liquid, residue is dissolved in ethyl acetate, use H2O, HCl are saturated NaHCO3,
Salt water washing organic phase, uses MgSO4It is dry, solvent is removed in vacuum, it is solid to be dried to obtain compound b (1.5g, 9.14mmol) white
Body, yield 69%.
(2) synthesis of 3- (2- (methoxycarbonyl) phenyl) acrylic acid
Weigh p formylbenzoic acid ester b (1.23g, 7.5mmol), malonic acid (1.56g, 15mmol), pyridine
(1.25mL), the mixture system of piperidines (0.75mL) are heated to reflux 5 hours.The mixture of heat is poured into ice water, use is dilute
Hydrochloric acid (10%) is acidified to pH < 2, and filtering precipitate is washed with water, and with 95% ethyl alcohol recrystallization, vacuum drying obtains structural formula 3
Shown (0.52g) faint yellow solid, yield 34%.
(3) synthesis of 4- ((E) -2- ((1H- imidazoles -2- base) carbamoyl) vinyl) methyl benzoate
Weigh 3- (2- (methoxycarbonyl) phenyl) acrylic acid (1.03g, 5mmol), EDCI (0.95g, 5mmol), DMAP
(0.3g, 2.45mmol) is dissolved in THF (15mL), is stirred at room temperature, later be added compound 1H- imidazoles -2- amine (0.5g,
5mmol).System is stirred at room temperature overnight.Add water filtering precipitate, vacuum concentration obtains shown in crude product structural formula 4
(0.695g, 5.12mmol) white solid, yield 48%.
(4) synthesis of 4- ((E) -2- ((1H- imidazoles -2- base) carbamoyl) vinyl) benzoic acid
Weigh (4- ((E) -2- ((1H- imidazoles -2- base) carbamoyl) vinyl) methyl benzoate (0.865g,
It 3mmol) is dissolved in methanol (15mL), the aqueous solution (15mL) of LiOH (0.252g, 6mmol) is added, is stirred at room temperature.Vacuum concentration,
It is 5-6 that dilute hydrochloric acid, which is acidified to PH, adds water to filter, is dried to obtain target product compound 1 (1.07g, 3.14mmol) white solid,
Yield is 65%.1HNMR (400MHz, DMSO-d6) δ 10.77 (d, J=7.9Hz, 1H), 6.74 (d, J=3.4Hz, 1H),
7.26 (d, J=3.3Hz, 1H), 12.77 (s, 1H), 7.41 (d, J=15.7Hz, 1H), 7.00 (d, J=16.0Hz, 1H),
7.95 (d, J=8.4Hz, 2H), 7.75 (d, J=8.4Hz, 2H), 12.82 (s, 1H) .HRMS (ESI) calcd for [M+H]+
C13H12N3O3 +: 257.0821,found:257.0800.
The conjunction of 2 4- of embodiment ((E) -2- (1H- pyrazoles -4- base-carbamoyl) vinyl) benzoic acid (compound 2)
At
(1) synthesis of p formylbenzoic acid ester
It weighs p formylbenzoic acid a (1.2g, 8.1mmol) and is dissolved in anhydrous CH3CN (24mL), addition DBU (1.38mL,
8.79mmol),CH3I (0.65mL, 10.4mmol) is stirred 2 hours at room temperature, TLC monitoring reaction (petroleum ether: ethyl acetate=
1:1).Vacuum concentration, obtains yellow oily liquid, residue is dissolved in ethyl acetate, use H2O, HCl are saturated NaHCO3, salt
Water washing organic phase, uses MgSO4It is dry, solvent is removed in vacuum, be dried to obtain p formylbenzoic acid ester (1.8g,
10.36mmol) white solid, yield 71%.
(2) synthesis of 3- (2- (methoxycarbonyl) phenyl) acrylic acid
Weigh p formylbenzoic acid ester b (1.28g, 7.8mmol), malonic acid (1.64g, 15.76mmol), pyridine
(1.5mL), the mixture system of piperidines (0.86mL) are heated to reflux 5 hours.The mixture of heat is poured into ice water, with dilute salt
Sour (10%) is acidified to pH < 2, and filtering precipitate is washed with water, and with 95% ethyl alcohol recrystallization, vacuum drying obtains 3 institute of structural formula
Show (0.58g, 2.82mmol) faint yellow solid, yield 36%.
(3) synthesis of 4- ((E) -2- (1H- pyrazoles -4- base-carbamoyl) vinyl) methyl benzoate
Weigh 3- (2- (methoxycarbonyl) phenyl) acrylic acid (1.23g, 5.97mmol), EDCI (1g, 5.24mmol),
DMAP (0.35g, 2.87mmol) is dissolved in THF (18mL), is stirred at room temperature, and compound 1H- pyrazoles -4- amine is added later
(0.56g,5.6mmol).System is stirred at room temperature overnight.Add water filtering precipitate, vacuum concentration obtains crude product structural formula 4
Shown (0.72g, 2.66mmol) white solid, yield 49%.
(4) synthesis of 4- ((E) -2- (1H- pyrazoles -4- base-carbamoyl) vinyl) benzoic acid
Weigh 4- ((E) -2- (1H- pyrazoles -4- base-carbamoyl) vinyl) methyl benzoate (0.88g,
It 0.325mmol) is dissolved in methanol (16mL), the aqueous solution (16mL) of LiOH (0.28g, 6.67mmol) is added, is stirred at room temperature.Vacuum
Concentration, it is 5-6 that dilute hydrochloric acid, which is acidified to pH, adds water to filter, is dried to obtain (1.17g, 3.44mmol) shown in target product compound 2
White solid, yield 66%.1HNMR (400MHz, DMSO-d6) δ 10.07 (d, J=7.9Hz, 1H), 8.60-8.59 (m,
2H), 12.51 (s, 1H), 7.84 (d, J=8.4Hz, 2H), 7.56 (d, J=8.4Hz, 2H), 7.05 (d, J=15.4Hz,
1H), 7.65 (d, J=14.9Hz, 1H), 13.88 (s, 1H) .HRMS (ESI) calcd for [M+H]+C13H12N3O3 +:
257.0875, found:257.0800.
Embodiment 3 is measured to compound 1 and compound 2 using CCK-8 method to lung cell A549 and breast cancer cell
The inhibiting effect of MCF-7 proliferation
The lung cell A549 for being in cell log growth period and breast cancer cell MCF-7 are made into certain density cell
Suspension is separately added into 96 orifice plates, in 37 DEG C of constant temperature CO according to 7500, every hole cell2Incubator culture is for 24 hours.By compound 1
Preparing respectively with 2 becomes 6-1000 μM of medical fluid, is separately added into corresponding 96 orifice plate, and negative control and blank pair is arranged
According to culture 48h.CCK-8 reagent is added in every hole, continues to cultivate 4h, terminates culture.With microplate reader in 490-570nm wave-length coverage
Interior its absorbance value of measurement simultaneously draws curve, indirect reaction cell survival quantity.As shown in Table 1, compound 1 inhibits lung carcinoma cell
The value-added C of A54950Value is 100 μM, IC value-added to breast cancer cell MCF-750Value is 35.63 μM.As shown in Table 2, chemical combination
The IC value-added to lung cell A549 of object 250Value is 158 μM, IC value-added to breast cancer cell MCF-750Value is 79.34 μM.
2 object anti-tumour cell proliferative activity (μM) of 1 compound 1 of table and compound
Claims (9)
1. a kind of chalcones derivative of base containing five-membered azole heterocycle, it is characterized in that such as the compound of logical formula (I) expression:
Wherein, R1ForIn any one.
2. the preparation method of the chalcones of base containing five-membered azole heterocycle derivative described in claim 1, which is characterized in that under warp
The reaction synthesis of 2 step of column:
R1ForIn any one；
Including following reaction step:
(1) by compound c, EDCI (1- ethyl -3- (3- dimethylaminopropyl) phosphinylidyne diimine) and DMAP (4- dimethylamino
Pyridine) it is dissolved in THF, after being stirred to react 1-3 hours, 1-NH2 of compound R is added into solution, gained system is stirred overnight,
Add water filtering precipitate, is concentrated in vacuo, obtains compound d；
(2) compound d obtained by step (1) is dissolved in methanol, adds LiOH aqueous solution, is stirred to react；Thin-layer chromatography monitoring is anti-
Process to be answered, is concentrated in vacuo after reaction, dilute hydrochloric acid acidification adjustment solution ph adds water to filter, and it is dry through anhydrous magnesium sulfate, it obtains
It is isolated and purified to crude product, then through silica gel column chromatography, obtains compound e, is i.e. the chalcones of base containing five-membered azole heterocycle are derivative
Object.
3. the preparation method of the chalcones of base containing five-membered azole heterocycle derivative according to claim 2, which is characterized in that
In the step (1), compound c, EDCI, DMAP and the R1—NH2Molar ratio be 2:2-4:1-3:2-5；Two stirrings are anti-
The temperature answered is controlled at 25-30 DEG C.
4. the preparation method of the chalcones of base containing five-membered azole heterocycle derivative according to claim 2, which is characterized in that
The molar ratio of compound d and LiOH are 1:1-3 in the step (2).
5. the preparation method of the chalcones of base containing five-membered azole heterocycle derivative according to claim 2, which is characterized in that
The step (2) is stirred to react temperature control at 25-30 DEG C, reaction time 2h-5h.
6. the preparation method of the chalcones of base containing five-membered azole heterocycle derivative according to claim 2, which is characterized in that
The mass percent concentration of step (2) hydrochloric acid solution is 10%-30%；Control pH value of solution is 4-6.
7. the preparation method of the chalcones of base containing five-membered azole heterocycle derivative according to claim 2, which is characterized in that
Step (2) silica gel column chromatography, eluant, eluent used is methanol and methylene chloride, using gradient elution, methanol and dichloro
Methane volumetric ratios are 1:8-1:15.
8. the chalcones derivative of base containing five-membered azole heterocycle described in claim 1 is as the application for preparing anti-tumor drug.
9. the chalcones derivative of base containing five-membered azole heterocycle is as the application for preparing anti-tumor drug as claimed in claim 8,
It is characterized in that, wherein tumour cell includes one or both of lung cell A549 and breast cancer cell MCF-7.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113603657A (en) * | 2021-07-02 | 2021-11-05 | 北京工业大学 | Thiazolyl-containing propenone derivative and application thereof in preparation of kinase inhibitor |
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| JPH0987282A (en) * | 1995-09-21 | 1997-03-31 | Kyowa Hakko Kogyo Co Ltd | Thiazole derivative |
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