CN114957360B - Acetyl glycoside orange ketone and anti-tumor application - Google Patents
Acetyl glycoside orange ketone and anti-tumor application Download PDFInfo
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- 150000002576 ketones Chemical class 0.000 title claims abstract description 29
- -1 Acetyl glycoside Chemical class 0.000 title abstract description 21
- 230000000259 anti-tumor effect Effects 0.000 title abstract description 16
- 229930182470 glycoside Natural products 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 201000007270 liver cancer Diseases 0.000 claims abstract description 16
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 16
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 6
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 6
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 29
- 230000002401 inhibitory effect Effects 0.000 abstract description 13
- LBNSLOFBVWHESK-BCGHKPRLSA-N [hydroxy-[(2R,3S,4R,5R,6S)-3,4,5-triacetyloxy-3,4,5,6-tetrahydroxyoxan-2-yl]methyl] acetate hydrobromide Chemical compound Br.CC(=O)OC(O)[C@H]1O[C@H](O)[C@@](O)(OC(C)=O)[C@](O)(OC(C)=O)[C@@]1(O)OC(C)=O LBNSLOFBVWHESK-BCGHKPRLSA-N 0.000 abstract description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 abstract description 10
- 239000000348 glycosyl donor Substances 0.000 abstract description 9
- GBDMODVZBPFQKI-UHFFFAOYSA-N 6-hydroxy-1-benzofuran-3-one Chemical compound OC1=CC=C2C(=O)COC2=C1 GBDMODVZBPFQKI-UHFFFAOYSA-N 0.000 abstract description 4
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 abstract description 4
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 abstract description 4
- 150000003935 benzaldehydes Chemical class 0.000 abstract description 3
- 235000019256 formaldehyde Nutrition 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000003756 stirring Methods 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 11
- MGKPCLNUSDGXGT-UHFFFAOYSA-N 1-benzofuran-3-one Chemical compound C1=CC=C2C(=O)COC2=C1 MGKPCLNUSDGXGT-UHFFFAOYSA-N 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 8
- 229910052782 aluminium Inorganic materials 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000011888 foil Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OMUOMODZGKSORV-UVTDQMKNSA-N aurone Chemical compound O1C2=CC=CC=C2C(=O)\C1=C\C1=CC=CC=C1 OMUOMODZGKSORV-UVTDQMKNSA-N 0.000 description 6
- 229930015036 aurone Natural products 0.000 description 6
- RXRFEELZASHOLV-JAJWTYFOSA-N [(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] acetate Chemical compound CC(=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RXRFEELZASHOLV-JAJWTYFOSA-N 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000009987 spinning Methods 0.000 description 4
- OEDNZAYZPQLHRI-MFOYZWKCSA-N (2z)-6-hydroxy-2-(quinolin-4-ylmethylidene)-1-benzofuran-3-one Chemical compound C1=CC=C2C(/C=C3/C(=O)C4=CC=C(C=C4O3)O)=CC=NC2=C1 OEDNZAYZPQLHRI-MFOYZWKCSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- FJYHPGCVLUAPLZ-YBEGLDIGSA-N (2z)-2-[(3,4-dimethoxyphenyl)methylidene]-1-benzofuran-3-one Chemical compound C1=C(OC)C(OC)=CC=C1\C=C/1C(=O)C2=CC=CC=C2O\1 FJYHPGCVLUAPLZ-YBEGLDIGSA-N 0.000 description 2
- YUCCNWHJQXNUQE-PXNMLYILSA-N (2z)-2-[(3,4-dimethoxyphenyl)methylidene]-6-hydroxy-1-benzofuran-3-one Chemical compound C1=C(OC)C(OC)=CC=C1\C=C/1C(=O)C2=CC=C(O)C=C2O\1 YUCCNWHJQXNUQE-PXNMLYILSA-N 0.000 description 2
- FIBUPWAMVDZIAE-IUXPMGMMSA-N (2z)-6-hydroxy-2-[(1-methylindol-3-yl)methylidene]-1-benzofuran-3-one Chemical compound C12=CC=CC=C2N(C)C=C1\C=C/1C(=O)C2=CC=C(O)C=C2O\1 FIBUPWAMVDZIAE-IUXPMGMMSA-N 0.000 description 2
- BACCSXNLWHXKRV-APSNUPSMSA-N 3-[(z)-(6-hydroxy-3-oxo-1-benzofuran-2-ylidene)methyl]chromen-4-one Chemical compound C1=CC=C2C(=O)C(/C=C3/C(=O)C4=CC=C(C=C4O3)O)=COC2=C1 BACCSXNLWHXKRV-APSNUPSMSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- WGZOOBJRZOYJIO-JYOAFUTRSA-N OC(C=C1)=CC(O/C2=C\C3=CSC=N3)=C1C/2=O Chemical compound OC(C=C1)=CC(O/C2=C\C3=CSC=N3)=C1C/2=O WGZOOBJRZOYJIO-JYOAFUTRSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000208838 Asteraceae Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 241000013557 Plantaginaceae Species 0.000 description 1
- 241001107098 Rubiaceae Species 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000000386 donor Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
The invention relates to an acetyl glycoside orange ketone and an anti-tumor application, which react with 6-hydroxy-2H-benzofuran-3-one under the action of 50% KOH by using different heterocyclic formaldehydes and substituted benzaldehydes to obtain compounds A1-A7; A1-A7 is placed in a two-phase solvent of dichloromethane and water, and reacts with glycosyl donor of 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide under the catalysis of tetrabutylammonium bromide to obtain compounds B1-B7. The result of the determination of the anti-tumor activity shows that 2 compounds have inhibitory activity on Hela cervical cancer cells; 2 compounds have inhibitory activity on MCF-7 breast cancer cells; 1 compound has inhibitory activity on HT-29 colon cancer cells, 1 compound has inhibitory activity on HepG2 liver cancer cells, 5 compounds have inhibitory activity on Hep3B liver cancer cells, and 5 compounds have inhibitory activity on Huh7 liver cancer cells.
Description
Technical Field
The invention relates to an acetylglucosidic orange ketone with anti-tumor activity and application of the acetylglucosidic orange ketone in inhibiting growth of cancer cells, such as cervical cancer Hela, colorectal cancer HT-29, breast cancer MCF-7, liver cancer HepG2 and Hep3B, huh7.
Background
The aurone is a flavonoid isomer, and mainly exists in dicotyledonous plants of Scrophulariaceae, compositae, rubiaceae, etc. Its natural yield is very low and has not previously been considered important by researchers. Modern pharmacological researches show that the aurone has various pharmacological activities of resisting bacteria, inflammation, oxidation, tumor, enzyme inhibition, parasites, hepatitis C, alzheimer disease, diabetes and the like. Heterocyclic compounds are important building blocks in pharmaceutical molecules, since their good biological activity is very important in pharmaceutical chemistry. These heterocycles vary greatly in acid-base nature, hydrogen bond donor capacity, topopolar surface area, dipole moment, ionization potential.
In order to find more derivatives of the aurone with high efficiency and low toxicity, in recent years, some derivatives which are subjected to heterocyclic modification aiming at the aurone B ring have been successful in anti-tumor research, and good drug effect is obtained while the structure type of the aurone is enriched, but the anti-tumor activity of the acetylglycoside aurone is not reported.
Based on comprehensive analysis of related patents and documents at home and abroad, the invention synthesizes a series of acetylglucosyl orange ketone and researches the inhibition activity of the compounds on six tumor strains, so that candidate drugs with obvious curative effect, good specificity or wide anti-tumor spectrum can be discovered in the later period.
Disclosure of Invention
The invention aims to provide an acetyl glucoside type orange ketone and an anti-tumor application, wherein the orange ketone reacts with 6-hydroxy-2H-benzofuran-3-one under the action of 50% KOH by using different heterocyclic formaldehydes and substituted benzaldehydes to obtain compounds A1-A7; placing the compounds A1-A7 in a two-phase solvent of dichloromethane and water, and reacting with glycosyl donors of 2,3,4, 6-tetraacetyloxy-alpha-D-glucopyranose bromide under the catalysis of tetrabutylammonium bromide to obtain the compounds B1-B7; the antitumor activity of the obtained compounds B1 to B7 was measured, and the results showed that: 2 compounds have inhibitory activity on Hela cervical cancer cells; 2 compounds have inhibitory activity on MCF-7 breast cancer cells; 1 compound has inhibitory activity on HT-29 colon cancer cells, 1 compound has inhibitory activity on HepG2 liver cancer cells, 5 compounds have inhibitory activity on Hep3B liver cancer cells, and 5 compounds have inhibitory activity on Huh7 liver cancer cells.
The invention relates to an acetylglycoside orange ketone, which has the structural formula:
wherein:
the compound B1 is [ (Z) -2- (9-ethyl-9H-carbazol-4-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ', 3', 4 ', 6' -tetra-O-acetyl) -6-O-beta-D-glucopyranoside ];
compound B2 is [ (Z) -2- (quinolin-8-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ];
the compound B3 is [ (Z) -2- (4H-chromone-3-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ', 3', 4 ', 6' -tetra-O-acetyl) -6-O-beta-D-glucopyranoside ];
compound B4 is [ (Z) -2- (quinolin-4-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ];
compound B5 is [ (Z) -2- (3, 4-dimethoxybenzylidene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ];
compound B6 is [ (Z) -2- (thiazol-4-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ];
the compound B7 is [ (Z) -2- (1-methyl-1H-indol-3-yl) benzofuran-3 (2H) -one ] - [ (2 ', 3', 4 ', 6' -tetra-O-acetyl) -6-O-beta-D-glucopyranoside ].
The application of the compounds B1 and B2 in the acetylglucosides orange ketone in preparing the anti-Hela cervical cancer medicine.
Application of B1 and B2 in acetylglucosides orange ketone in preparing medicines for resisting MCF-7 breast cancer.
Application of B2 in acetylglucosidic orange ketone in preparation of anti-HT-29 colon cancer drugs.
The application of B4 in the acetylglucosidic orange ketone in preparing the anti-HepG 2 liver cancer medicine.
The application of the B1-B5 in the acetylglucosidic orange ketone in preparing anti-Hep 3B liver cancer drugs.
The application of B1-B5 in the acetylglucosidic orange ketone in preparing the Huh7 liver cancer resisting medicine.
The invention relates to an acetyl glucoside orange ketone and an anti-tumor application, and the structure of the acetyl glucoside orange ketone is shown as a general formula (I)
The invention relates to an acetyl glucoside orange ketone and an anti-tumor application, and a preparation method of a compound B1-B7 is carried out according to the following steps:
a. dispersing 1mmol of 6-hydroxy benzofuran-3 (2H) -one in 5ml of methanol, adding 1ml of 50% KOH solution, stirring at room temperature for 10min, adding 1.2mmol of heterocyclic formaldehyde, stirring at room temperature overnight, removing methanol under reduced pressure after TLC monitoring reaction is finished, adding 10ml of hot water for dilution, regulating pH to 5-6 with glacial acetic acid to obtain solid precipitate, filtering and washing the precipitate, and recrystallizing in methanol to obtain products A1-A7;
b. in a 25mL round bottom flask, 0.2mmol of the product A1-A7 obtained in the step a and 212mg of glycosyl donor 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide are respectively added, dissolved in 4mL of dichloromethane, stirred for 5 minutes, 17.3mg of tetrabutylammonium bromide and 213mg of potassium carbonate 1.2mmol are added, 3mL of clear water is added, then the reaction vial is wrapped by aluminum foil, the reaction mixture is stirred at room temperature for 72 hours, the reaction is monitored by thin layer chromatography, after the reaction is completed, the dichloromethane is dried in a spinning way under the condition of reduced pressure, the residue is diluted by distilled water, filtered, and the filter cake is repeatedly leached by clear water, thus obtaining the pure compound B1-B7.
The invention relates to an acetyl glucoside orange ketone and an anti-tumor application, and the synthetic route is as follows:
Detailed Description
The present invention is further illustrated by examples, but the present invention is not limited to these examples;
reagent: all reagents were commercially available in analytical purity.
Example 1
Preparation of Compounds A1-A7:
1mmol of 6-hydroxy benzofuran-3 (2H) -one (150.3 mg) is dissolved in 5ml of methanol, 1ml of 50% KOH solution is added under stirring, stirring is carried out for 10min at room temperature, 1.2mmol of substituted benzaldehyde or heterocyclic formaldehyde is added, reaction is carried out for 8H at room temperature, TLC monitors that the reaction is finished, 20ml of hot water is added for dilution, and glacial acetic acid is added dropwise for regulating pH to 5-6, the obtained solid precipitate is filtered and washed, and recrystallized in methanol to obtain products A1-A7, and the names of the products A1-A7 are as follows:
compound A1 is (Z) -6-hydroxy-2- (9-ethyl-9H-carbazol-4-ylmethylene) benzofuran-3 (2H) -one;
compound A2 is (Z) -6-hydroxy-2- (quinolin-8-ylmethylene) benzofuran-3 (2H) -one;
compound A3 is (Z) -6-hydroxy-2- (4H-chromone-3-ylmethylene) benzofuran-3 (2H) -one;
compound A4 is (Z) -6-hydroxy-2- (quinolin-4-ylmethylene) benzofuran-3 (2H) -one;
compound A5 is (Z) -6-hydroxy-2- (3, 4-dimethoxybenzylidene) benzofuran-3 (2H) -one;
compound A6 is (Z) -6-hydroxy-2- (thiazol-4-ylmethylene) benzofuran-3 (2H) -one;
compound A7 is (Z) -6-hydroxy-2- (1-methyl-1H-indol-3-ylmethylene) benzofuran-3 (2H) -one.
Example 2
Preparation of the compound [ (Z) -2- (9-ethyl-9H-carbazol-4-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ] B1:
in a 25mL round bottom flask, adding A1 obtained in example 1 is (Z) -6-hydroxy-2- (9-ethyl-9H-carbazol-4-ylmethylene) benzofuran-3 (2H) -one and glycosyl donor 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide 212mg,0.4mmol dissolved in 4mL dichloromethane, stirring for 5 minutes, adding tetrabutylammonium bromide 17.3mg 0.04mmol and potassium carbonate 213mg 1.2mmol, adding 3mL clear water, then the reaction vial is wrapped with aluminum foil, stirring the reaction mixture at room temperature for 72 hours, monitoring the reaction by thin layer chromatography, after the reaction is completed, spinning the dichloromethane under reduced pressure, diluting the residue with distilled water, filtering, repeatedly leaching the filter cake with clear water to obtain pure compound B1, yield 68%, yellow solid, melting point: 250.9-251.5 ℃;
1 H NMR(400MHz,DMSO-d 6 )δ8.79(d,J＝1.7Hz,1H),8.24(d,J＝7.7Hz,1H),8.12(dd,J＝8.7,1.7Hz,1H),7.77(dd,J＝14.9,8.6Hz,2H),7.68(d,J＝8.3Hz,1H),7.53(ddd,J＝8.3,7.0,1.2Hz,1H),7.35–7.24(m,2H),7.11(s,1H),6.92(dd,J＝8.5,2.1Hz,1H),5.85(d,J＝7.9Hz,1H),5.43(t,J＝9.6Hz,1H),5.17(dd,J＝9.7,7.9Hz,1H),5.07(t,J＝9.7Hz,1H),4.50(q,J＝7.1Hz,2H),4.46–4.36(m,1H),4.27–4.15(m,2H),2.07(s,3H),2.05(d,J＝3.5Hz,6H),2.00(s,3H),1.35(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ181.48,169.99,169.65,169.39,169.16,166.78,163.12,145.68,140.46,140.13,129.36,126.54,125.74,124.41,122.82,122.60,122.10,120.59,119.71,116.38,113.96,113.09,109.87,109.78,100.11,96.54,71.89,71.18,70.48,67.97,61.69,37.26,20.51,20.45,20.38,20.33,13.80.HRMS(ESI)m/z：calcd for C 37 H 35 NO 12 [M+H] + 686.2232,found 686.2225。
example 3
Preparation of the compound [ (Z) -2- (quinolin-8-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ] (B2):
in a 25mL round bottom flask, add A2 obtained in example 1 as (Z) -6-hydroxy-2- (quinolin-8-ylmethylene) benzofuran-3 (2H) -one and glycosyl donor 2,3,4, 6-tetraacetoxy- α -D-glucopyranose bromide 212mg,0.4mmol dissolved in 4mL of dichloromethane, after stirring for 5 minutes, add tetrabutylammonium bromide 17.3mg 0.04mmol and potassium carbonate 213mg 1.2mmol, add 3mL of clear water again, then wrap the reaction vial with aluminum foil, stir the reaction mixture at room temperature for 72 hours, monitor the reaction by thin layer chromatography, after completion of the reaction spin-dry dichloromethane under reduced pressure, dilute the residue with distilled water, filter, repeatedly rinse the filter cake with clear water to obtain pure compound B2, yield 78%, brown solid, melting point: 214.3-215.0 ℃;
1 H NMR(400MHz,DMSO-d 6 )δ9.08–9.00(m,1H),8.68(dd,J＝7.5,1.3Hz,1H),8.48(dd,J＝8.3,1.5Hz,1H),8.30(s,1H),8.12(d,J＝8.3Hz,1H),7.86–7.74(m,2H),7.70–7.63(m,1H),7.26(d,J＝1.7Hz,1H),6.92(d,J＝10.6Hz,1H),5.83(d,J＝7.9Hz,1H),5.42(t,J＝9.6Hz,1H),5.22–5.11(m,1H),5.06(t,J＝9.8Hz,1H),4.46–4.33(m,1H),4.25–4.14(m,2H),2.07(s,3H),2.05(s,3H),2.04(s,3H),1.99(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ181.99,169.93,169.61,169.34,169.10,167.39,163.50,150.75,147.83,145.68,136.94,131.75,130.48,129.36,128.13,126.59,126.05,122.26,115.86,113.55,105.96,100.02,96.55,71.85,71.22,70.46,67.89,61.64,20.44,20.41,20.33,20.29.HRMS(ESI)m/z：calcd for C32H29NO12[M+H] + 620.1763,found 620.1750。
example 4
Preparation of the compound [ (Z) -2- (4H-chromone-3-ylmethylene) -6-hydroxybenzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ] (B3):
in a 25mL round bottom flask, 212mg0.4mmol of (Z) -2- (4H-chromone-3-ylmethylene) -6-hydroxybenzofuran-3 (2H) -one obtained in example 1 and 2124 mmol of glycosyl donor 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide are added, dissolved in 4mL of dichloromethane. After stirring for 5 minutes, 17.3mg of tetrabutylammonium bromide, 0.04mmol and 213mg of potassium carbonate, 1.2mmol of clear water and 3ml of clear water are added, then the reaction vial is wrapped with aluminum foil, the reaction mixture is stirred at room temperature for 72 hours, the reaction is monitored by thin layer chromatography, after the reaction is finished, dichloromethane is dried by spinning under reduced pressure, the residue is diluted with distilled water and filtered, and the filter cake is repeatedly rinsed with clear water, thus obtaining pure compound B3, yield 62 percent, yellow solid, melting point: 221.8-222.2 ℃;
1 H NMR(400MHz,DMSO-d 6 )δ9.09(s,1H),8.08(d,J＝7.9Hz,1H),7.83(t,J＝7.9Hz,1H),7.71(dd,J＝15.1,8.5Hz,2H),7.51(t,J＝7.6Hz,1H),7.13(s,1H),6.88(d,J＝9.0Hz,2H),5.78(d,J＝7.8Hz,1H),5.45(t,J＝9.6Hz,1H),5.23–4.98(m,2H),4.35(d,J＝9.9Hz,1H),4.21(q,J＝12.8Hz,2H),2.15–1.91(m,12H). 13 C NMR(101MHz,CDCl 3 )δ181.86,175.06,170.50,170.21,169.47,169.30,167.16,163.77,158.59,155.90,147.81,134.29,126.52,126.21,125.95,123.60,118.37,118.03,116.99,113.41,101.90,100.49,98.37,72.56,72.49,71.01,68.14,61.95,20.74,20.71,20.67×2.HRMS(ESI)m/z：calcd for C 32 H 28 O 14 [M+H] + 637.1552,found 637.1534。
example 5
Preparation of the compound [ (Z) -6-hydroxy-2- (quinolin-4-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ] (B4):
in a 25mL round bottom flask, adding the A4 obtained in example 1 as (Z) -6-hydroxy-2- (quinolin-4-ylmethylene) benzofuran-3 (2H) -one and glycosyl donor 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide 212mg0.4mmol, dissolving in 4mL of dichloromethane, stirring for 5 minutes, adding tetrabutylammonium bromide 17.3mg 0.04mmol and potassium carbonate 213mg 1.2mmol, adding 3mL of clear water, then wrapping the reaction vial with aluminum foil, stirring the reaction mixture at room temperature for 72 hours, monitoring the reaction by thin layer chromatography, after completion of the reaction, spin-drying the dichloromethane under reduced pressure, diluting the residue with distilled water, filtering, repeatedly rinsing the filter cake with clear water to obtain pure compound B4 in 62% yield, yellow solid, melting point: 196.2-196.7 ℃;
1 H NMR(400MHz,CDCl 3 )δ9.03(d,J＝5.0Hz,1H),8.50(d,J＝8.5Hz,1H),8.35(t,J＝6.3Hz,2H),7.92(t,J＝7.7Hz,1H),7.80(d,J＝8.4Hz,2H),7.49(s,1H),6.98(d,J＝2.0Hz,1H),6.90(d,J＝10.4Hz,1H),5.39–5.24(m,3H),5.20(t,J＝9.2Hz,1H),4.35–4.16(m,2H),4.01(d,J＝9.9Hz,1H),2.07(d,J＝2.2Hz,6H),2.06(s,3H),2.05(s,3H). 13 C NMR(101MHz,CDCl 3 )δ182.34,170.48,170.26,169.49,169.28,168.36,164.59,151.37,146.57,140.93,131.91,128.94,127.46,126.98,126.86,123.65,122.19,116.07,114.27,103.23,100.72,98.24,72.66,72.53,71.03,68.09,61.96,20.88,20.78,20.74,20.71.HRMS(ESI)m/z：calcd for C 32 H 29 NO 12 [M+H] + 620.1763,found 620.1752。
example 6
Preparation of the compound [ (Z) -2- (3, 4-dimethoxybenzylidene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ] (B5):
in a 25mL round bottom flask, adding the obtained A5 of example 1 as (Z) -6-hydroxy-2- (3, 4-dimethoxy benzylidene) benzofuran-3 (2H) -one and glycosyl donor 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide 212mg0.4mmol, dissolving in 4mL dichloromethane, stirring for 5 min, adding tetrabutylammonium bromide 17.3mg 0.04mmol and potassium carbonate 213mg 1.2mmol, adding 3mL clear water, then wrapping the reaction vial with aluminum foil, stirring the reaction mixture at room temperature for 72H, monitoring the reaction by thin layer chromatography, after completion of the reaction, spinning the dichloromethane under reduced pressure, diluting the residue with distilled water, filtering, repeatedly rinsing the filter cake with clear water to obtain pure compound B5, yield 74%, yellow solid, melting point: 112.8-113.1 ℃;
1 H NMR(400MHz,DMSO-d 6 )δ9.26(d,J＝1.9Hz,1H),8.37(d,J＝1.9Hz,1H),7.78(d,J＝8.5Hz,1H),7.17(d,J＝2.1Hz,1H),6.99(s,1H),6.96–6.86(m,1H),5.82(d,J＝7.9Hz,1H),5.43(t,J＝9.6Hz,1H),5.19–5.11(m,1H),5.05(t,J＝9.7Hz,1H),4.40–4.32(m,1H),4.22(dd,J＝12.4,5.6Hz,1H),4.14(dd,J＝12.3,2.5Hz,1H),3.43(s,1H),2.04(s,6H),2.03(s,3H),1.99(s,3H). 13 C NMR(151MHz,CDCl3)δ182.99,170.61,170.31,169.53,169.38,167.43,163.55,151.10,149.23,146.66,126.15,125.97,125.24,117.36,114.14,113.60,112.88,111.38,100.59,98.32,72.60,72.49,71.09,68.27,62.04,56.21,56.12,20.90,20.81,20.77,20.73.HRMS(ESI)m/z:calcd for C 31 H 32 O 14 [M+H] + 629.1865,found 629.1846。
example 7
Preparation of the compound [ (Z) -2- (thiazol-4-ylmethylene) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ] (B6):
in a 25mL round bottom flask, add A6 obtained in example 1 as (Z) -6-hydroxy-2- (thiazol-4-ylmethylene) benzofuran-3 (2H) -one and glycosyl donor 2,3,4, 6-tetraacetoxy- α -D-glucopyranose bromide 212mg,0.4mmol, dissolve in 4mL of dichloromethane, after stirring for 5 minutes, add tetrabutylammonium bromide 17.3mg 0.04mmol and potassium carbonate 213mg 1.2mmol, add 3mL of clear water again, then wrap the reaction vial with aluminum foil, stir the reaction mixture at room temperature for 72 hours, monitor the reaction by thin layer chromatography, after completion of the reaction spin-dry dichloromethane under reduced pressure, dilute the residue with distilled water, filter, repeatedly rinse the filter cake with clear water to obtain pure compound B6, yield 64%, yellow solid, melting point: 118.4-118.8 ℃;
1 H NMR(400MHz,DMSO-d 6 )δ9.26(d,J＝1.9Hz,1H),8.37(d,J＝1.9Hz,1H),7.78(d,J＝8.5Hz,1H),7.17(d,J＝2.1Hz,1H),6.99(s,1H),6.96–6.86(m,1H),5.82(d,J＝7.9Hz,1H),5.43(t,J＝9.6Hz,1H),5.19–5.11(m,1H),5.05(t,J＝9.7Hz,1H),4.40–4.32(m,1H),4.22(dd,J＝12.4,5.6Hz,1H),4.14(dd,J＝12.3,2.5Hz,1H),2.04(s,6H),2.03(s,3H),1.99(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ181.89,169.98,169.61,169.31,169.09,167.39,163.56,155.11,148.22,147.07,126.04,124.95,115.97,113.39,104.71,99.98,96.52,71.81,71.18,70.45,67.85,61.54,20.46,20.40,20.32,20.28.HRMS(ESI)m/z:calcd for C 26 H 25 NO 12 S[M+H] + 576.1170,found576.1159。
example 8
Preparation of the compound [ (Z) -2- (1-methyl-1H-indol-3-yl) benzofuran-3 (2H) -one ] - [ (2 ", 3", 4 ", 6" -tetra-O-acetyl) -6-O- β -D-glucopyranoside ] (B7):
in a 25mL round bottom flask, add the A7 obtained in example 1 as (Z) -6-hydroxy-2- (1-methyl-1H-indol-3-ylmethylene) benzofuran-3 (2H) -one and glycosyl donor 2,3,4, 6-tetraacetoxy-alpha-D-glucopyranose bromide 212mg,0.4mmol, dissolve in 4mL dichloromethane, after stirring for 5 minutes, add tetrabutylammonium bromide 17.3mg 0.04mmol and potassium carbonate 213mg 1.2mmol, add 3mL clear water, then the reaction vial is wrapped with aluminum foil, stir the reaction mixture at room temperature for 72 hours, monitor the reaction by thin layer chromatography, spin dry dichloromethane under reduced pressure after completion of the reaction, dilute the residue with distilled water, filter, and repeatedly filter cake with clear water to obtain pure compound B7, yield 61%, orange solid, melting point: 238.1-239.7 ℃;
1 H NMR(600MHz,CDCl 3 )δ7.81(s,1H),7.77(d,J＝7.7Hz,1H),7.59(d,J＝8.4Hz,1H),7.21(q,J＝7.9Hz,2H),7.18–7.14(m,1H),6.78(s,1H),6.67(dt,J＝8.5,1.6Hz,1H),5.29–5.18(m,2H),5.18–5.04(m,2H),4.21(dd,J＝12.4,5.2Hz,1H),4.13(d,J＝12.3Hz,1H),3.88(s,1H),3.75(s,3H),1.99(d,J＝1.3Hz,6H),1.97–1.94(m,6H). 13 C NMR(151MHz,CDCl 3 )δ181.23,170.55,170.26,169.49,169.33,166.16,163.04,145.66,137.10,134.75,127.91,125.70,123.34,121.68,119.27,118.33,112.68,110.04,108.78,107.65,100.47,98.47,72.64,72.42,71.13,68.25,62.01,33.64,20.81,20.74,20.72,20.69.HRMS(ESI)m/z:calcd for C 32 H 31 NO 12 [M+H] + 622.1919,found 622.1909。
the anti-tumor activity screening of the acetylglucosidic orange ketone is determined by the following method:
cell viability was measured by MTT assay:
the experimental process comprises the following steps: cells grown in logarithmic growth phase were aspirated, washed 1 time with PBS, digested with pancreatin, stopped with medium, gently blown, counted, seeded in 96-well plates (100. Mu.L/well) at the corresponding cell density, cultured overnight, added with compounds (20. Mu.L/well), each compound set up a concentration gradient, 3 wells per concentration, CO 2 Culturing in an incubator at 37 ℃ for 48 hours, sucking and removing old culture medium, adding 100 mu L of MTT, culturing for 2 hours, incubating at 37 ℃ for 2 hours, and measuring a light absorption value (OD) at 570nm by using an MB enzyme-labeled instrument;
the calculation formula is as follows:
percent cell viability = (compound OD-blank OD/control OD-blank OD) ×100%;
cell inhibition ratio% = 1-cell viability% = [1- (compound OD-blank OD/control OD-blank OD)]100% by weight, using graphpad, fitting by formula to obtain IC 50 ；
Sample treatment: dissolving a sample by using DMSO, preserving at a low temperature, and controlling the concentration of the DMSO in a final system within a range which does not influence the detection activity;
data processing and result description: the primary screen is selected to be at a single concentration, for example, a monomer compound concentration of 50. Mu.M; the activity of the extract was measured at 50. Mu.g/. Mu.L; for samples exhibiting activity under certain conditions, e.g., inhibition (Inhibition) of greater than 50%, the activity dose dependence, i.e., IC, was further tested 50 The value is obtained by nonlinear fitting of the sample concentration through the activity of the sample, and the software used for calculation is Graphpad Prism 4; typically, each sample was provided with multiple wells (n.gtoreq.3) in the test, expressed in the results as standard deviation (Standard Deviation, SD); table 1 shows the results of the antitumor activity of the acetylglucosides orange ketone of the invention, wherein the blank indicates no measurable value;
table 1: antitumor Activity of heterocyclic hesperidone and its hesperidone analogues
From the table it can be seen that: the B1 and B2 in the acetylglucosides orange ketone have a certain inhibition effect on Hela cervical cancer cells; b1 and B2 have certain inhibition effect on MCF-7 breast cancer cells; b2 has a certain inhibition effect on HT-29 colon cancer cells; b4 has certain inhibition effect on HepG2 liver cancer cells; B1-B5 has certain inhibition effect on Hep3B liver cancer cells; the B1-B5 has a certain inhibition effect on Huh7 liver cancer cells.
Claims (7)
1. An acetylglycoside orange ketone is characterized in that the structural formula of the compound is as follows:
2. use of the compounds B1, B2 in the acetylglucosides orange ketone of claim 1 for preparing a medicament for treating Hela cervical cancer.
3. Use of B1, B2 in acetylglucosidic orange ketone as claimed in claim 1 for the preparation of a medicament for the treatment of MCF-7 breast cancer.
4. Use of B2 in acetylglucosidic orange ketone according to claim 1 for the preparation of a medicament against HT-29 colon cancer.
5. Use of B4 in acetylglucosidic orange ketone according to claim 1 for preparing anti-HepG 2 liver cancer medicament.
6. Use of B1-B4 in acetylglucosidic orange ketone according to claim 1 for preparing anti-Hep 3B liver cancer medicament.
7. Use of B1-B4 in acetylglucosidic orange ketone according to claim 1 for preparing anti-Huh 7 liver cancer medicine.
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Non-Patent Citations (3)
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| Andrea Baier等.Selected flavonoid compounds as promising inhibitors of protein kinase CK2 a and CK2α' , the catalytic subunits of CK2.《Phytochemistry》.2016,第136卷第39-45页. * |
| 叶发青主编.《"药物化学"》.浙江大学出版社,2016,(第第1版版),第66-69页. * |
| 西尔弗曼编.《有机药物化学》.化学工业出版社,2007,(第第2版版),第17-23页. * |
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