CN106188080A - A kind of D phenylalanine ring substituent norcantharidin derivative and preparation method and application - Google Patents
A kind of D phenylalanine ring substituent norcantharidin derivative and preparation method and application Download PDFInfo
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- CN106188080A CN106188080A CN201610542762.3A CN201610542762A CN106188080A CN 106188080 A CN106188080 A CN 106188080A CN 201610542762 A CN201610542762 A CN 201610542762A CN 106188080 A CN106188080 A CN 106188080A
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- ring substituent
- phenylalanine
- substituent norcantharidin
- phenylalanine ring
- derivative
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- -1 D phenylalanine ring substituent norcantharidin derivative Chemical class 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- JAABVEXCGCXWRR-FBXFSONDSA-N rel-norcantharidin Chemical group C1C[C@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@@H]1O2 JAABVEXCGCXWRR-FBXFSONDSA-N 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical group C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- XLVXXKZBDHWNMK-UHFFFAOYSA-N N-[(6-bromochromen-4-ylidene)amino]aniline Chemical compound C1(=CC=CC=C1)NN=C1C=COC2=CC=C(C=C12)Br XLVXXKZBDHWNMK-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 7
- 208000035126 Facies Diseases 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 6
- 229940067157 phenylhydrazine Drugs 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- XVNBWGGBXOJIDR-UHFFFAOYSA-N 6-bromochromen-4-one Chemical compound O1C=CC(=O)C2=CC(Br)=CC=C21 XVNBWGGBXOJIDR-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 230000006837 decompression Effects 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 230000003292 diminished effect Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- 239000012265 solid product Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000007259 addition reaction Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000011049 filling Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 230000001629 suppression Effects 0.000 abstract description 6
- 208000032839 leukemia Diseases 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 125000003226 pyrazolyl group Chemical group 0.000 abstract description 4
- 241001597008 Nomeidae Species 0.000 abstract description 3
- 150000003217 pyrazoles Chemical class 0.000 abstract description 3
- 230000003993 interaction Effects 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 10
- 125000001711 D-phenylalanine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 5
- 229930182832 D-phenylalanine Natural products 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 150000004777 chromones Chemical class 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HPPYHLAUVVJOLY-UHFFFAOYSA-N 2-bromochromen-4-one Chemical compound C1=CC=C2OC(Br)=CC(=O)C2=C1 HPPYHLAUVVJOLY-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C1C(NC(*)*)=O)(C2OC1C=C2)C=O Chemical compound CC(C1C(NC(*)*)=O)(C2OC1C=C2)C=O 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Abstract
The invention discloses oneDPhenylalanine ring substituent norcantharidin derivative and preparation method and application, it is characterised in that: by 1,3 dipole-diople interaction methods existDC in phenylalanine ring substituent norcantharidin structure5And C6Position introduces pyrazole ring, reacts importing chromone structure, the synthesis pyrazoles containing chromone structure with chromone derivativeDPhenylalanine ring substituent norcantharidin derivative, this derivant has good inhibitory action for tumor cell line, wherein for leukaemia, there is more preferable suppression ratio and selectivity, preparing the aspects such as antitumor drug, there is extraordinary prospects for commercial application.
Description
Technical field:
The invention belongs to pharmaceutical technology field, be specifically related to a kind of pyrazoles D phenylalanine containing chromone structure and take
For norcantharidin derivative and preparation method and application.
Background technology:
D phenylalanine ring substituent norcantharidin, chemical structural formula is as follows:
D phenylalanine ring substituent norcantharidin R=(R) CH2Ph
1,3-Dipolar Cycloaddition becomes synthesis five member ring heterocyclic compound with its good region and main selectivity
Topmost method, is also a class reaction more active in heterocyclic drug chemical research.In recent years, due to chromone widely
Biological activity, the most anticancer, antibacterial, suppression platelet aggregation etc. and receive much attention.So, either from pharmacology still from conjunction
Angled consideration, this heterocyclic compounds has the highest synthesis to be worth.
Summary of the invention:
A first aspect of the present invention purpose is to provide a kind of D phenylalanine ring substituent norcantharidin derivative.
The technical scheme that the present invention takes is as follows:
A kind of D phenylalanine ring substituent norcantharidin derivative, its structural formula is as follows:
In formula: R=(R)-CH2Ph。
This compound relevant experimental data is as follows:
Applicant it has been investigated that: introduce at D phenylalanine ring substituent norcantharidin and import on the basis of five yuan of pyrazole rings
The structure of chromone can change pharmacologically active.Determined by further experiment: use chromone derivative in the structure of pyrazoles
Replace, D phenylalanine ring substituent norcantharidin carried out structure of modification, preparation containing chromone structure pyrazoles D phenylpropyl alcohol
Propylhomoserin ring substituent norcantharidin derivative, has extraordinary pharmaceutically active.
A second aspect of the present invention purpose is to provide the preparation side of a kind of D phenylalanine ring substituent norcantharidin derivative
Method, it is characterised in that comprise the following steps:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24
～48 hours, furan and maleic anhydride occur Diels-Alder to react, and prepare dehydronorcantharidiimide element (compound 1)；
(2), the synthesis of D phenylalanine ring substituent norcantharidin:
Dehydronorcantharidiimide element 4.2 grams (25mmol) and D-phenylalanine 4.13 grams (25mmol) are added through molecular sieve
In the DMF solvent 15 milliliters being dried, it is stirred at reflux 12 hours, after being cooled to room temperature, adds ethyl acetate 60 milliliters dilution, saturated
Ammonium chloride solution washs 6 times, and each 30 milliliters, organic facies anhydrous magnesium sulfate is dried, the organic facies decompression distillation rotation after filtration
Dry, obtain white solid product (compound 3) by re-crystallizing in ethyl acetate；
(3), the synthesis of 6-bromo chromone phenylhydrazone:
Use the method that 6-bromo chromone generates Schiff's base with phenylhydrazine dehydration, concrete operations: the phenylhydrazine taking 2mmol adds
Entering to fill in the flask of 10mL oxolane, boiling water bath return stirring, to dissolving, is then slowly added dropwise into 20mL dissolved with 2mmol
The ethanol solution of 6-bromo chromone, continues boiling water bath return stirring 1h, drips 10 hydrochloric acid, have pale yellow precipitate to occur.
Boiling water bath return stirring 5h continuously, stops water-bath, adds the stirring of people's 20mL distilled water, and pale yellow precipitate darkens, and sucking filtration obtains 6-
Bromo chromone phenylhydrazone, yellowish red color needle-like product.Rinse repeatedly with absolute ether, be vacuum dried to obtain product 6-bromo chromone phenylhydrazone
(compound 4)；
(4), chromone structure is imported:
By 1mmol D phenylalanine ring substituent norcantharidin and 1.1mmol6-bromo chromone phenylhydrazone in 20mL ethanol,
Adding 1.2mL toluene-sodium-sulfonchloramide, reflux 9 hours, after TLC detection reaction completes, obtain pale yellow precipitate, filtration under diminished pressure goes out precipitation, heavy
Shallow lake recrystallizing methanol, obtains product D phenylalanine ring substituent norcantharidin derivative (compound 5) after vacuum drying.
The reaction equation that the present invention relates to is as follows:
It is anti-in preparation that a third aspect of the present invention purpose is to provide a kind of D phenylalanine ring substituent norcantharidin derivative
Application in terms of tumour medicine.Pass through experimental verification: above-claimed cpd, thin for different tumor strain such as human liver cancer cells, oral cancer
Born of the same parents, stomach cancer cell, ovarian cancer cell, leukaemia, colon-cancer cell etc., inhibited, wherein for HL60 (leukemia
Cell) there is more preferably suppression ratio and selectivity, antitumor drug can be manufactured separately, can also resist with other as active component
Tumour medicine prepares anti-tumor compositions, has extraordinary prospects for commercial application.
Beneficial effects of the present invention is as follows:
Applicant is found by research: lead on the basis of D phenylalanine ring substituent norcantharidin introduces five yuan of pyrazole rings
Enter the structure of chromone, the derivant of generation, there is good pharmaceutically active, through further experiment and analysis, research is different miscellaneous
Ring is assembled in same a part and on affecting produced by pharmacologically active, is taken at D phenylalanine by 1,3 dipole-diople interaction methods
For C in norcantharidin structure5And C6Position introduces pyrazole ring, reacts importing chromone structure with chromone derivative, and synthesis is containing chromone
The pyrazoles D phenylalanine ring substituent norcantharidin derivative of structure, this derivant, in terms of preparing antitumor drug, has
Extraordinary prospects for commercial application.
Detailed description of the invention:
Below in conjunction with embodiment, the present invention is described further, but embodiment should not be construed as the model limiting the present invention
Enclose.
Embodiment 1:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24
～48 hours, furan and maleic anhydride occur Diels-Alder to react, and prepare dehydronorcantharidiimide element (compound 1)；
(2), the synthesis of D phenylalanine ring substituent norcantharidin:
Dehydronorcantharidiimide element 4.2 grams (25mmol) and D-phenylalanine 4.13 grams (25mmol) are added through molecular sieve
In the DMF solvent 15 milliliters being dried, it is stirred at reflux 12 hours, after being cooled to room temperature, adds ethyl acetate 60 milliliters dilution, saturated
Ammonium chloride solution washs 6 times, and each 30 milliliters, organic facies anhydrous magnesium sulfate is dried, the organic facies decompression distillation rotation after filtration
Dry, obtain white solid product (compound 3) by re-crystallizing in ethyl acetate；
(3) synthesis of 6-bromo chromone phenylhydrazone:
Use the method that 6-bromo chromone generates Schiff's base with phenylhydrazine dehydration, concrete operations: the phenylhydrazine taking 2mmol adds
Entering to fill in the flask of 10mL oxolane, boiling water bath return stirring, to dissolving, is then slowly added dropwise into 20mL dissolved with 2mmol6-
The ethanol solution of bromo chromone, continues boiling water bath return stirring 1h, drips 10 hydrochloric acid, have pale yellow precipitate to occur.Even
Continuous boiling water bath return stirring 5h, stops water-bath, adds the stirring of people's 20mL distilled water, and pale yellow precipitate darkens, after decompression sucking filtration
Obtain yellowish red color needle-like product.Rinse repeatedly with absolute ether, be vacuum dried to obtain product 6-bromo chromone phenylhydrazone (4).
(4), chromone structure is imported:
By 1mmol D phenylalanine ring substituent norcantharidin and 1.1mmol6-bromo chromone phenylhydrazone in 20mL ethanol,
Adding 1.2mL toluene-sodium-sulfonchloramide, reflux 9 hours, after TLC detection reaction completes, obtain pale yellow precipitate, filtration under diminished pressure goes out precipitation, heavy
Shallow lake recrystallizing methanol, obtains product (compound 5) after vacuum drying.
Compound 5 title: D phenylalanine ring substituent norcantharidin derivative；
Chemical formula: C33H23BrN3O7；
Physico-chemical parameter: yellow crystal, productivity 62%, m.p.104 105 DEG C；
Structural confirmation:
1H NMR(CD3OD) δ: 7.32 7.16 (m, 13H, Ar H), 6.47 (s, 1H, C=C H), 5.16 (d, J=
9.60Hz, 1H, H5), 4.74 (d, J=17.60Hz, 1H, H4), 4.56 (d, J=17.60Hz, 1H, H1), 4.02 (d, J=
9.60Hz, 1H, H6), 3.43 (d, J=7.20Hz, 1H, H3), 3.29 (d, J=7.20Hz, 1H, H2), 3.15 3.25 (m, 2H,
PhCH2)；
IR 3397 (N C=O), 3085 (ArH), 1721 (C=O), 1559 (C=N), 1309 (C O C) cm‐1；
M/e:652 (100.0%), 654 (97.5%)；
Anal.calcd.for C33H23BrN3O7: C, 60.64；H,3.56；N,6.42.
Application Example: use mtt assay detection test-compound to different tumor strains anti-tumor activity.
Compound (5) prepared by above-described embodiment, respectively with different tumor strains (tumor cell Bel-7402, KB,
SGC7901, HO8901, HL-60, ECA109) it is experimental subject, test compound (5) is made for the vitro inhibition of different tumor strains
With: experiment uses tetramethyl azo azoles salt trace enzyme reaction colorimetry (mtt assay), and activity half-inhibition concentration represents (IC50)。
Specific experiment step is as follows:
By compound 5 with DMSO dissolve, dilution, tumor cell Bel-7402 (human liver cancer cell), KB (cancer cell of oral cavity),
SGC7901 (stomach cancer cell), HO8901 (ovarian cancer cell), HL-60 (leukaemia), ECA109 (colon-cancer cell) are in 96 holes
Planting into 4000/200 μ L/ holes on plate, every hole adds compound 2 μ L, final concentration of 12.0 μMs, 6.0 μMs, 3.0 μMs, 1.5 μMs, is total to
It is same as 37 DEG C, 5%CO2Cell culture incubator is hatched 72 hours, with DMSO (1%) as blank.After 72 hours, add the denseest
Degree is the MTT of 0.25mg/mL, is placed in 37 DEG C, 5%CO2In cell culture incubator 4 hours, blotting solvent afterwards, every hole adds 100 μ
L DMSO, measures absorbance (OD value) with enzyme linked immunological instrument at 570nm, and the data obtained is used for calculating IC50Value.Variable concentrations
Test-compound carries out scalping with 96 orifice plates, according to the suppression ratio of gained, calculates IC50Value, result see table.
Table 1, the D phenylalanine ring substituent norcantharidin derivative IC to six kinds of tumor cell lines50Value.
By upper table data it can be seen that the compound prepared of the present invention, for various tumor cell strains, there is suppression and make
With, wherein for HL60 (leukaemia), there is more preferable suppression ratio and selectivity, antitumor drug, also can be manufactured separately
Anti-tumor compositions can be prepared as active component and other antitumor drug, there is extraordinary prospects for commercial application.
Claims (4)
1. one kindD-phenylalanine ring substituent norcantharidin derivative, its structural formula is as follows:
In formula:。
2. one kindDThe preparation method of-phenylalanine ring substituent norcantharidin derivative, it is characterised in that comprise the following steps: will
Maleic anhydride and ether be synthesized dehydronorcantharidiimide element, dehydronorcantharidiimide element andD-phenylalanine is synthesizedD-
Phenylalanine ring substituent norcantharidin, then uses 6-bromo chromone to synthesize 6-bromo chromone phenylhydrazone with phenylhydrazine dehydration,
After willD-phenylalanine ring substituent norcantharidin and 6-bromo chromone phenylhydrazone carry out dipolar addition reaction, synthesisD-phenylalanine takes
For norcantharidin derivative.
One the most according to claim 2DThe preparation method of-phenylalanine ring substituent norcantharidin derivative, its feature
It is, comprises the following steps:
(1), the synthesis of dehydronorcantharidiimide element:
Maleic anhydride is finely ground, add ether, under room temperature condition, stirring is to dissolving, and instills furan, is stirred at room temperature 24 ~ 48 little
Time, furan and maleic anhydride occur Diels-Alder to react, prepare dehydronorcantharidiimide element；
(2),DThe synthesis of-phenylalanine ring substituent norcantharidin:
By dehydronorcantharidiimide element 4.2 grams andD-phenylalanine 4.13 grams adds the DMF solvent 15 milliliters through molecular sieve drying
In, it is stirred at reflux 12 hours, is cooled to after room temperature add ethyl acetate 60 milliliters dilution, saturated ammonium chloride solution washing 6 times, often
Secondary 30 milliliters, organic facies anhydrous magnesium sulfate is dried, and the organic facies decompression distillation after filtration is spin-dried for, and obtains by re-crystallizing in ethyl acetate
White solid product；
(3), the synthesis of 6-bromo chromone phenylhydrazone:
The phenylhydrazine taking 2mmol adds in the flask filling 10mL oxolane, and boiling water bath return stirring, to dissolving, the most slowly drips
Add the 20mL ethanol solution dissolved with 2mmol 6-bromo chromone, continue boiling water bath return stirring 1h, drip 10 hydrochloric acid,
Pale yellow precipitate is had to occur；Boiling water bath return stirring 5h continuously, stops water-bath, adds the stirring of people's 20mL distilled water, pale yellow precipitate
Darkening, sucking filtration obtains 6-bromo chromone phenylhydrazone, yellowish red color needle-like product；Rinse repeatedly with absolute ether, be vacuum dried to produce
Thing 6-bromo chromone phenylhydrazone；
(4), chromone structure is imported:
By 1mmolD-phenylalanine ring substituent norcantharidin and 1.1mmol6-bromo chromone phenylhydrazone are in 20mL ethanol, then add
Entering 1.2mL toluene-sodium-sulfonchloramide, reflux 9 hours, after TLC detection reaction completes, obtain pale yellow precipitate, filtration under diminished pressure goes out precipitation, and precipitation is used
Recrystallizing methanol, obtains product after vacuum dryingD-phenylalanine ring substituent norcantharidin derivative.
4. one kindDThe application in terms of the preparing antitumor drug of-phenylalanine ring substituent norcantharidin derivative.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610542762.3A CN106188080B (en) | 2016-07-06 | 2016-07-06 | A kind of D-phenylalanine ring substituent norcantharidin derivative and the preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610542762.3A CN106188080B (en) | 2016-07-06 | 2016-07-06 | A kind of D-phenylalanine ring substituent norcantharidin derivative and the preparation method and application thereof |
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| Publication Number | Publication Date |
|---|---|
| CN106188080A true CN106188080A (en) | 2016-12-07 |
| CN106188080B CN106188080B (en) | 2018-08-10 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602578A (en) * | 2017-11-07 | 2018-01-19 | 绍兴文理学院 | A kind of preparation method and applications of the D valine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
| CN107674082A (en) * | 2017-11-07 | 2018-02-09 | 绍兴文理学院 | A kind of preparation method and applications of the D phenylalanine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002076989A1 (en) * | 2001-03-23 | 2002-10-03 | The University Of Newcastle Research Associates Limited | Protein phosphate inhibitors |
| CN103554122A (en) * | 2013-11-15 | 2014-02-05 | 绍兴文理学院 | Chromone structure-containing pyrazole norcantharidin derivative as well as preparation method and application thereof |
| CN103554123A (en) * | 2013-11-15 | 2014-02-05 | 绍兴文理学院 | Chromone structure-containing pyrazole norcantharidin derivatives, and preparation method and application thereof |
| CN103896954A (en) * | 2013-11-15 | 2014-07-02 | 绍兴文理学院 | Pyrazol norcantharidin derivative as well as preparation method and application thereof |
-
2016
- 2016-07-06 CN CN201610542762.3A patent/CN106188080B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002076989A1 (en) * | 2001-03-23 | 2002-10-03 | The University Of Newcastle Research Associates Limited | Protein phosphate inhibitors |
| CN103554122A (en) * | 2013-11-15 | 2014-02-05 | 绍兴文理学院 | Chromone structure-containing pyrazole norcantharidin derivative as well as preparation method and application thereof |
| CN103554123A (en) * | 2013-11-15 | 2014-02-05 | 绍兴文理学院 | Chromone structure-containing pyrazole norcantharidin derivatives, and preparation method and application thereof |
| CN103896954A (en) * | 2013-11-15 | 2014-07-02 | 绍兴文理学院 | Pyrazol norcantharidin derivative as well as preparation method and application thereof |
Non-Patent Citations (6)
| Title |
|---|
| DA-FENG CHEN ET AL.: "Improved synthesis and characterization of L-histidine norcantharimide, a novel potent protein phosphatase 2A inhibitor", 《JOURNAL OF CHINESE PHARMACEUTICAL SCIENCES》 * |
| DENG LIPING ET AL.: "Mass spectra of novel 5,6-dehydronorcantharidin derivatives substituted by aromatic amine", 《JOURNAL OF SHAOXING UNIVERSITY》 * |
| 田少雷等: "抗肿瘤药物研究I : 去甲斑鳌素氨基酸衍生物的合成与抗癌活性", 《药学学报》 * |
| 邓莉平等: "新型吡唑去甲斑蝥酰亚胺衍生物的核磁共振波谱分析", 《绍兴文理学院学报》 * |
| 黄文盈等: "新型含色酮异噁唑类去甲斑蝥衍生物的合成", 《绍兴文理学院学报》 * |
| 黄永华等: "去甲基斑蝥素衍生物的合成,碘-125标记及在动物体内的分布", 《合成化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602578A (en) * | 2017-11-07 | 2018-01-19 | 绍兴文理学院 | A kind of preparation method and applications of the D valine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
| CN107674082A (en) * | 2017-11-07 | 2018-02-09 | 绍兴文理学院 | A kind of preparation method and applications of the D phenylalanine ring substituent norcantharidin derivatives of the structure containing pyridazinone |
| CN107602578B (en) * | 2017-11-07 | 2019-07-16 | 绍兴文理学院 | A kind of preparation method and applications of the D-Val ring substituent norcantharidin derivative of the structure containing pyridazinone |
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