CN105061409B - A kind of diphenyl pyrone class compound of 1,2,3- triazoles substitution and its preparation method and application - Google Patents
A kind of diphenyl pyrone class compound of 1,2,3- triazoles substitution and its preparation method and application Download PDFInfo
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- diphenyl pyrone
- triazoles
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- -1 diphenyl pyrone class compound Chemical class 0.000 title claims abstract description 19
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000000177 1,2,3-triazoles Chemical group 0.000 title claims description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 125000001424 substituent group Chemical group 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 7
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- JHNLZOVBAQWGQU-UHFFFAOYSA-N 380814_sial Chemical compound CS(O)(=O)=O.O=P(=O)OP(=O)=O JHNLZOVBAQWGQU-UHFFFAOYSA-N 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001553 phloroglucinol Drugs 0.000 claims description 3
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 3
- 229960005055 sodium ascorbate Drugs 0.000 claims description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- YJTHQNSUSFCKDA-UHFFFAOYSA-N 3,4-diphenylpyran-2-one Chemical class O=c1occc(-c2ccccc2)c1-c1ccccc1 YJTHQNSUSFCKDA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 229910052794 bromium Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- ZFXMPYNGDGXWSU-UHFFFAOYSA-N CBrCC1=CC=CC=C1 Chemical compound CBrCC1=CC=CC=C1 ZFXMPYNGDGXWSU-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008425 anthrones Chemical class 0.000 description 1
- UDLLFLQFQMACJB-UHFFFAOYSA-N azidomethylbenzene Chemical compound [N-]=[N+]=NCC1=CC=CC=C1 UDLLFLQFQMACJB-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical group 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of diphenyl pyrone class compound of 1,2,3 triazoles substitution, its general structure are as follows：Wherein substituent R is halogen, alkyl or electron-withdrawing substituent, can be located at ortho position, the meta or para position of phenyl ring.Preparation the invention further relates to the diphenyl pyrone class compound of above-mentioned 1,2,3 triazole substitution and its application in antitumor.The compound on tumor cell of the present invention has stronger inhibitory activity, such compound can be used for the treatment of tumour.
Description
Technical field
The present invention relates to pharmaceutical technology field, is a kind of diphenyl pyrone class of 1,2,3-triazoles substitution specifically
Compound and its preparation method and application.
Background technology
Tumour is one of disease for seriously endangering human health, is shown according to Chinese Medical Association's data in 2007, pernicious swollen
Knurl has become the first killer in the various diseases for endangering China's resident's life, and China has 2,000,000 people to die of tumour every year.Change
It is one of three big means for the treatment of of cancer to learn treatment, and through making great efforts for many years, a part of cancer can be cured by chemotherapy.Mesh
There are serious toxic side effect for preceding antitumor drug used：(1) it is not strong to the selectivity of tumour cell, in killing tumor cell
While, also there is damage to normal nucleus tissue；(2) tumour cell produces drug resistance to antitumor drug.This is tumour medicine
Thing treats problem urgently to be resolved hurrily.
Diphenyl pyrone skeleton is simple tricyclic structure, and tricyclic is in same plane, formation π-pi-conjugated, with anthrone class
The chemical constitution of antitumor drug is similar, has significant antitumor activity.Second Military Medical University, PLA, 2012
Year May master thesis《Design, synthesis and its bioactivity research of diphenyl pyrone derivative》, disclosing one kind has three
The diphenyl pyrone compound of azoles ring, but its structure is different from the present invention, and involved compound is for non-small cell lung cancer
Without obvious inhibiting effect.
The present invention is obtained in the 3- different azacyclo-s of introducing using diphenyl pyrone as basic parent nucleus：1-hydroxyl-3-
(1H-1,2,3- triazole-4-yls) diphenyl pyrone class compound has good antitumor activity, its structure and activity are gone back so far
Have no and have been reported that.
The content of the invention
The purpose of the present invention is for deficiency of the prior art, there is provided a kind of diphenyl pyrone of 1,2,3-triazoles substitution
Class compound.
Another purpose of the present invention is to provide the preparation method of diphenyl pyrone class compound as described above.
Another purpose of the present invention is to provide the purposes of diphenyl pyrone class compound as described above.
To achieve the above object, the present invention adopts the technical scheme that：
A kind of diphenyl pyrone class compound of 1,2,3-triazoles substitution, it is characterised in that the 1,2,3-triazoles substitution
Diphenyl pyrone class compound structure general formula it is as follows：
Wherein substituent R is halogen, alkyl or electron-withdrawing substituent, positioned at the ortho position of phenyl ring, meta or para position.
Preferably, the substituent R is halogen；The halogen is F, Cl or Br.
Preferably, the substituent R is alkyl；The alkyl is the alkyl of 1-4 carbon atom.
Preferably, the substituent R is electron-withdrawing substituent；The electron-withdrawing substituent is nitro, cyano group, fluoroform
Base or trifluoromethoxy.
Preferably, the substituent R is CH3, F, Cl, Br or CN.
Preferably, the substituent R is as follows：
| Sequence number | R | IC50(μg/ml) |
| 1c | 2-CH3 | 27.87 |
| 1g | 4-Cl | 21.64 |
| 1h | 3-Cl | 19.06 |
| 1j | 4-Br | 15.15 |
| 1k | 3-Br | 33.37 |
To realize above-mentioned second purpose, the present invention adopts the technical scheme that：
The preparation method of the diphenyl pyrone class compound of 1,2,3-triazoles substitution as described above, reaction scheme are as follows：
Scheme 1 Reagents and comditions：(a)P2O5/Ch3SO385 DEG C of H, 2.5h；(b)K2CO3,
DMF, rt, 4h.
Scheme 2 Reagents and conditions：) a) DMSO, rt, 12h；(b)CuSO4.5H2O, rt, 16h.
Including：
(a) using 2- hydroxyls salicylic acid and phloroglucin as raw material, reaction is stirred in Eaton ' s reagents, generates 1,3- bis-
Hydroxyl diphenyl pyrone (4)；
(b) 1,3- dihydroxy diphenyl pyrone, potassium carbonate, propargyl bromide stir reaction, generation 1- hydroxyl -3- (2- in DMF
Alkynyloxy)-diphenyl pyrone (5)；
(c) sodium azide, intermediate, 1- hydroxyls -3- (2- alkynyloxies)-diphenyl pyrone, copper sulphate, sodium ascorbate exist
Reacted at room temperature in dimethyl sulfoxide (DMSO), generate target compound；The intermediate structure is as follows：
Preferably, stirring reaction temperature is 85 DEG C in the step (a), when the reaction time is 4 small.
To realize above-mentioned 3rd purpose, the present invention adopts the technical scheme that：
Application of the diphenyl pyrone class compound of 1,2,3- triazoles substitution as described above in antitumor drug is prepared.
Preferably, the tumour is lung cancer.
Preferably, the lung cancer is non-small cell lung cancer.
The diphenyl pyrone class compound that substitutes containing above-mentioned 1,2,3- triazoles of medicine of the treatment lung cancer and pharmaceutically
The pharmaceutical carrier of acceptable carrier and routine.
The invention has the advantages that：
The present invention introduces different azacyclo-s using diphenyl pyrone as basic parent nucleus, at 3-, and 1-hydroxyl-3- is prepared
(1H-1,2,3- triazole-4-yls) diphenyl pyrone class compound, test result indicates that, compound of the invention has preferable
The inhibitory activity of tumor cell proliferation, particularly compound 1c, 1g, 1h, 1j and 1k is to Non-small cell lung carcinoma cell (A495)
There is stronger cell inhibitory effect to act on, such compound can be as the drug candidate of oncotherapy.
Brief description of the drawings
Attached drawing 1 is the compounds of this invention general structure.
Embodiment
The invention will be further elucidated with reference to specific embodiments.It is to be understood that these embodiments are merely to illustrate this hair
It is bright rather than limit the scope of the invention.In addition, it should also be understood that, after described content of the invention has been read, this area skill
Art personnel can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims institute
The scope of restriction.
The synthesis of 1 the compounds of this invention of embodiment
The compounds of this invention to prepare reaction scheme as follows：
Scheme Reagents and conditions：(a)P2O5/CH3SO385 DEG C of H, 2.5h；(b)Propargyl
Bronide, L2CO3, SMF, 4h；(c) Corresponding benzyl azide, DMSO, CuSO4.5H2O, rt, 16h.
The specific preparation method of compound involved in the reaction scheme route is as follows：
(1) synthesis of 1,3- dihydroxy diphenyl pyrone (4)
2- hydroxyls salicylic acid (6.9g, 0.05mol) and phloroglucin (6.3g, 0.05mol) are dissolved in Eaton ' s reagents
In, when 85 DEG C of stirring reactions 4 are small, the reaction was complete, is cooled to room temperature, adds frozen water and is quenched excessive acid in right amount, when stirring 2 is small after it is quiet
Put, filter, neutrality is washed to after ethyl acetate dissolving, anhydrous sodium sulfate water removal, solvent evaporated, mixes a small amount of silica gel column chromatography (PE：
EA=6:1).
(2) synthesis of 1- hydroxyls -3- (2- alkynyloxies)-diphenyl pyrones (5)
1,3- dihydroxy diphenyl pyrone (4) (2.33g, 0.0102mol) is dissolved in DMF, then adds potassium carbonate
(2.82g, 0.0204mol) and propargyl bromide (1.34g, 0.0114mmol), 25 DEG C stirring 1.5 it is small when after, be stirred at room temperature 4 it is small when,
The reaction was complete for TLC detections, is poured into water, and ethyl acetate washing, anhydrous sodium sulfate water removal, then solvent evaporated, mixes a small amount of silica gel
Column chromatography (PE：EA=8:1).
(3) synthesis of target compound
Sodium azide (40mg, 0.65mmol) is dissolved in DMSO, is added to methyl benzyl bromine (100mg, 0.54mmol) room temperature
It is stirred overnight, it is disposable to add 1- hydroxyls -3- (2- alkynyloxies)-diphenyl pyrone (5) (110mg, 0.41mmol), then by five
Brochanite (catalytic amount) is soluble in water, adds sodium ascorbate (catalytic amount), quick to instill in reaction solution, is stirred overnight, instead
Should be complete, twice, anhydrous sodium sulfate water removal, solvent evaporated, mixes silica gel column chromatography (PE to dichloromethane dissolution extraction：EA=3：1),
Obtain compound 1a.
It should be noted that it is CH for substituent R in general formula3, F, Cl, Br, CN, respectively positioned at the o-, m-, right of phenyl ring
The compound of position (i.e. 1b-1n), is same as above using the substitution bromobenzyl of corresponding R group as raw material, preparation method.Prepared chemical combination
Numbering, structure and the nucleus magnetic hydrogen spectrum data of thing are shown in Table 1.
The nucleus magnetic hydrogen spectrum data of 1 target compound of table
Reagent used is that commercially available analysis is pure in above example.It should be understood that above-described embodiment only using substituent R as
CH3, Cl, Br, CN situation, but the present invention implementation be not limited to above example, using different substituents R as synthesis material, weight
Step in multiple above example, just can synthesize required compound.
The pharmacological evaluation of 2 the compounds of this invention of embodiment
(1) experiment material
1st, given the test agent
For target compound respectively with after DMSO (Merck) dissolvings, addition PBS (-) is made into the solution or uniform of 1000 μ g/ml
Suspension, then with containing DMSO PBS (-) dilution.
2nd, cell line
A549 (Non-small cell lung carcinoma cell).
3rd, other materials and key instrument
Nutrient solution：RPMI1640+15%NBS+ is dual anti-；MTT：[tetrazolium bromide] purchased from Sigma companies (St.Louis, MO,
USA)；Other reagents are that domestic analysis is pure.Full-automatic microplate reader WellscanMK-2 (Labsystems companies), CO2Constant temperature
Incubator (SANYO GS company), 96 well culture plate of import etc..
4th, experimental method
MTT (tetrazolium) method：It is 4~6 × 10 that 96 orifice plates, which add concentration per hole,4The 100 μ l of cell suspension of a/ml, put
37 DEG C, 5%CO2In incubator.After 24h, addition sample liquid, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO2Act on 72h.Per hole
The 20 μ l of MTT solution of 5mg/ml are added, add DMSO lysates after acting on 4h, 100 μ l/ holes, put in incubator, used after dissolving
The full-automatic microplate reader of MK-2 surveys 570nm OD values.
5th, experimental configuration
We have carried out synthesized target compound the test of cell line In-vitro Inhibitory Effect, using adriamycin as pair
According to obtaining the inhibitor concentration i.e. IC for making half cell death50It is worth (μ g/ml), specific experiment data are shown in Table 2.
2 target compound pair of table and Non-small cell lung carcinoma cells in vitro activity
| Compound numbers | R | IC50(μg/ml) |
| 1a | 4-CH3 | 46.73 |
| 1b | 3-CH3 | 37.90 |
| 1c | 2-CH3 | 27.87 |
| 1d | 4-F | 42.75 |
| 1e | 3-F | 121.73 |
| 1f | 2-F | 40.04 |
| 1g | 4-Cl | 21.64 |
| 1h | 3-Cl | 19.06 |
| 1i | 2-Cl | 258.30 |
| 1j | 4-Br | 15.15 |
| 1k | 3-Br | 33.37 |
| 1l | 4-CN | 427.15 |
| 1m | 3-CN | 1340.60 |
| 1n | 2-CN | 485.62 |
| Adriamycin | 36.09 |
The above results represent that compound provided by the invention has the inhibitory activity of preferable tumor cell proliferation, big absolutely
The external activity of most compounds, particularly compound 1c, 1g, 1h, 1j and 1k have Non-small cell lung carcinoma cell (A495)
Stronger cell inhibitory effect effect, such compound can be as the drug candidate of oncotherapy.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, on the premise of the method for the present invention is not departed from, can also make some improvement and supplement, these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (5)
1. a kind of diphenyl pyrone class compound of 1,2,3-triazoles substitution, it is characterised in that the 1,2,3-triazoles substitution
Diphenyl pyrone class compound structure general formula is as follows：
The substituent R is as follows：
2. the preparation method of the diphenyl pyrone class compound of 1,2,3-triazoles substitution, its feature exist according to claim 1
In including the following steps：
(a) using 2- hydroxyls salicylic acid and phloroglucin as raw material, reaction is stirred in Eaton ' s reagents, generates 1,3- dihydroxy
Diphenyl pyrone；
(b) 1,3- dihydroxy diphenyl pyrone, potassium carbonate, propargyl bromide stir reaction in DMF, generate 1- hydroxyls -3- (2- alkynyls
Oxygen)-diphenyl pyrone；
(c) sodium azide, intermediate, 1- hydroxyls -3- (2- alkynyloxies)-diphenyl pyrone, copper sulphate, sodium ascorbate are in diformazan
Reacted at room temperature in base sulfoxide, generate target compound；The intermediate structure is as follows：
The substituent R is identical with claim 1.
3. the diphenyl pyrone class compound that 1,2,3- triazoles described in claim 1 substitute answering in antitumor drug is prepared
With.
4. application according to claim 3, it is characterised in that the tumour is lung cancer.
5. application according to claim 4, it is characterised in that the lung cancer is non-small cell lung cancer.
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| DE102009022618A1 (en) * | 2009-05-26 | 2010-12-02 | Leibniz-Institut Für Pflanzenbiochemie | New hydropyrone derivatives useful as biocide, antibiotics, fungicide, antioomycetes, inhibitor for enzymes, disinfectant, textile modifier and wood preservative |
| CN101914084A (en) * | 2010-07-30 | 2010-12-15 | 中国人民解放军第二军医大学 | Derivative of diphenylpyrone nitrogen heterocyclic ring as well as preparation method and application thereof |
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| DE102009022618A1 (en) * | 2009-05-26 | 2010-12-02 | Leibniz-Institut Für Pflanzenbiochemie | New hydropyrone derivatives useful as biocide, antibiotics, fungicide, antioomycetes, inhibitor for enzymes, disinfectant, textile modifier and wood preservative |
| CN101914084A (en) * | 2010-07-30 | 2010-12-15 | 中国人民解放军第二军医大学 | Derivative of diphenylpyrone nitrogen heterocyclic ring as well as preparation method and application thereof |
Non-Patent Citations (3)
| Title |
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| Synthesis and In Vitro Antitumor Activities of Xanthone Derivatives Containing 1,4-Disubstituted-1,2,3-triazole Moiety;Yan Zou，等;《Arch Pharm Res》;20121231;第35卷(第12期);第2093-2104页 * |
| Synthesis of xanthone derivatives based on a-mangostin and their biological evaluation for anti-cancer agents;Xiang Fei，等;《Bioorganic & Medicinal Chemistry Letters》;20140325;第24卷;第2062-2065页 * |
| 苯并吡喃酮衍生物的设计、合成及其生物活性研究;胡丽娜;《第二军医大学硕士学位论文》;20110915;第15-16、25-26、28-29页 * |
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