CN113045527B - Dihydrothromone derivative and synthesis method and application thereof - Google Patents
Dihydrothromone derivative and synthesis method and application thereof Download PDFInfo
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- CN113045527B CN113045527B CN202110303737.0A CN202110303737A CN113045527B CN 113045527 B CN113045527 B CN 113045527B CN 202110303737 A CN202110303737 A CN 202110303737A CN 113045527 B CN113045527 B CN 113045527B
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- 238000001308 synthesis method Methods 0.000 title abstract description 4
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical class C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- -1 2- (methyl (phenyl) amino) ethyl Chemical group 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims abstract description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 7
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 28
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- FTVWIRXFELQLPI-ZDUSSCGKSA-N (S)-naringenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 FTVWIRXFELQLPI-ZDUSSCGKSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229940117954 naringenin Drugs 0.000 claims description 6
- WGEYAGZBLYNDFV-UHFFFAOYSA-N naringenin Natural products C1(=O)C2=C(O)C=C(O)C=C2OC(C1)C1=CC=C(CC1)O WGEYAGZBLYNDFV-UHFFFAOYSA-N 0.000 claims description 6
- 235000007625 naringenin Nutrition 0.000 claims description 6
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 6
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 230000035755 proliferation Effects 0.000 abstract description 5
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- DTVHYJUSWNEKRE-UHFFFAOYSA-N 7-[tert-butyl(dimethyl)silyl]oxy-5-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one Chemical compound CC(C)(C)[Si](C)(C)OC1=CC2=C(C(=O)CC(O2)C2=CC=C(O)C=C2)C(O)=C1 DTVHYJUSWNEKRE-UHFFFAOYSA-N 0.000 description 2
- KISVAPBYRBGWFH-UHFFFAOYSA-N CC(C)(C)[Si](C)(C)OC1=CC=C(C(C2)OC3=CC(O)=CC(O)=C3C2=O)C=C1 Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(C(C2)OC3=CC(O)=CC(O)=C3C2=O)C=C1 KISVAPBYRBGWFH-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- VIIZJXNVVJKISZ-UHFFFAOYSA-N 2-(n-methylanilino)ethanol Chemical compound OCCN(C)C1=CC=CC=C1 VIIZJXNVVJKISZ-UHFFFAOYSA-N 0.000 description 1
- AMSDWLOANMAILF-UHFFFAOYSA-N 2-imidazol-1-ylethanol Chemical compound OCCN1C=CN=C1 AMSDWLOANMAILF-UHFFFAOYSA-N 0.000 description 1
- LIKATVDTYUPQJO-UHFFFAOYSA-N CC(C)(C)[Si](C)(C)OC1=CC(O)=C(C(CC(C(C=C2)=CC=C2OCC2CCCC2)O2)=O)C2=C1 Chemical compound CC(C)(C)[Si](C)(C)OC1=CC(O)=C(C(CC(C(C=C2)=CC=C2OCC2CCCC2)O2)=O)C2=C1 LIKATVDTYUPQJO-UHFFFAOYSA-N 0.000 description 1
- BSXPHGPPIZKUBB-UHFFFAOYSA-N CC(C)(C)[Si](C)(C)OC1=CC=C(C(C2)OC3=CC(OCCN(C)C4=CC=CC=C4)=CC(O)=C3C2=O)C=C1 Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(C(C2)OC3=CC(OCCN(C)C4=CC=CC=C4)=CC(O)=C3C2=O)C=C1 BSXPHGPPIZKUBB-UHFFFAOYSA-N 0.000 description 1
- IOGJIEVDTSRVAA-UHFFFAOYSA-N CC(C)COC1=CC=C(C(C2)OC3=CC(O[Si](C)(C)C(C)(C)C)=CC(O)=C3C2=O)C=C1 Chemical compound CC(C)COC1=CC=C(C(C2)OC3=CC(O[Si](C)(C)C(C)(C)C)=CC(O)=C3C2=O)C=C1 IOGJIEVDTSRVAA-UHFFFAOYSA-N 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125872 compound 4d Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- ISQVBYGGNVVVHB-UHFFFAOYSA-N cyclopentylmethanol Chemical compound OCC1CCCC1 ISQVBYGGNVVVHB-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a dihydrochromone derivative and a synthesis method and application thereof. The chemical structure of the dihydrochromone derivative is shown as the following formula (a), R 1 Is hydrogen, TBS, isobutyl or cyclopentylmethyl, R 2 Is hydrogen, 2- (methyl (phenyl) amino) ethyl or 2- (1H-imidazol-1-yl) ethyl. The dihydrochromone derivative can effectively inhibit the proliferation of tumor cells, thereby providing a new lead compound for developing antitumor drugs.
Description
The technical field is as follows:
the invention belongs to the field of organic compounds, and particularly relates to a dihydrochromone derivative, and a synthesis method and application thereof.
Background art:
malignant tumor is the most serious disease endangering human health, the incidence rate of the malignant tumor is second to cardiovascular and cerebrovascular diseases, the malignant tumor is the second largest killer of human health, and the mortality rate of the malignant tumor exceeds the cardiovascular and cerebrovascular diseases even, and the malignant tumor is the first of all diseases. Therefore, the search and development of new drugs for treating tumors are currently a major issue.
The invention content is as follows:
the first object of the present invention is to provide a dihydrochromone derivative having activity of inhibiting tumor cell proliferation.
The invention performs derivatization on naringenin to obtain a compound with a novel structure, namely a dihydrochromone derivative, and has antitumor activity, thereby realizing the aim of the invention.
The chemical structure of the dihydrochromone derivative is shown as any one of the following formulas (a):
in the formula (a), R 1 Is hydrogen, TBS, isobutyl or cyclopentylmethyl, R 2 Is hydrogen, 2- (methyl (phenyl) amino) ethyl or 2- (1H-imidazol-1-yl) ethyl.
The dihydrochromone derivative of the invention is preferably one of the following compounds:
when R is 1 Is hydrogen, R 2 When the derivative is 2- (methyl (phenyl) amino) ethyl, the chemical structure of the dihydrochromone derivative is as follows:
when R is 1 Is TBS, R 2 When hydrogen is present, the chemical structure of the dihydrochromone derivative is as follows:
when R is 1 Is TBS, R 2 When the derivative is 2- (1H-imidazole-1-yl) ethyl, the chemical structure of the dihydrochromone derivative is as follows:
when R is 1 Is isobutyl, R 2 When hydrogen is present, the chemical structure of the dihydrochromone derivative is as follows:
when R is 1 Is cyclopentylmethyl, R 2 When hydrogen is present, the chemical structure of the dihydrochromone derivative is as follows:
experiments show that the dihydrochromone derivative can inhibit tumor cell proliferation, can be used for preparing a tumor proliferation inhibitor, and has an obvious anti-tumor effect.
Therefore, the second object of the present invention is to provide the use of the above dihydrochromone derivative in the preparation of antitumor drugs.
It is a third object of the present invention to provide an antitumor agent comprising the above dihydrochromone derivative as an active ingredient.
The anti-tumor drug is preferably a drug for resisting cervical cancer, colon cancer, breast cancer, lung cancer, liver cancer or melanoma.
More preferably, the structural formula of the dihydrochromone derivative is shown as follows:
preferably, the anti-tumor drug comprises a dihydrochromone derivative and medically acceptable auxiliary materials.
The fourth object of the present invention is to provide a method for synthesizing the above dihydrochromone derivative, wherein the method (shown in the reaction formula i) comprises the following steps:
firstly, dissolving naringenin in a DMF solvent, reacting with tert-butyldimethylsilyl chloride (TBSCl) under the catalysis of imidazole and 4-dimethylaminopyridine to obtain a compound a and a compound 4, and reacting the compound a and the compound 4 with alcohol respectively under the catalysis of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound b and a compound 4d, then, after TBAF deprotection, compound c and compound e are obtained, wherein R is 1 Is TBS, isobutyl or cyclopentylmethyl, R 2 Is 2- (methyl (phenyl) amino) ethyl or 2- (1H-imidazol-1-yl) ethyl.
The reaction formula of the above method is as follows:
the dihydrochromone derivative can effectively inhibit the proliferation of tumor cells, thereby providing a new lead compound for developing antitumor drugs.
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1 synthesis of intermediate a:
YPS (naringenin) (10g, 36.76mmol) was weighed, and transferred to a 500-ml round-bottom flask equipped with a stirrer, and 30ml of methylene chloride was further added thereto, followed by stirring at room temperature for 10min. Imidazole (5 g, 73.52mmol) and 4-dimethylaminopyridine (0.9g, 7.4 mmol) are added successively and stirred at room temperature for 30min until the solution is clear. Tert-butyldimethylsilyl chloride (5.6 g, 37.33mmol) was added slowly in portions, stirred at room temperature overnight, and TLC monitored the progress of the reaction. The next day, when the reaction conversion rate reached about 80% or more, the reaction was quenched by adding 30ml of saturated sodium bicarbonate solution, extracted three times with 30ml of dichloromethane, the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, the solvent was spin-dried, and passed through a column to obtain a yellow oily solid (compound a), yield: 55.8 percent. IR (near, cm) -1 ):3358,2956,2932,2888,2859,1641,1569,1518,1469,1371,1345,1309,1269,1181,1089,1068,1018,836,784. 1 H NMR(600MHz,Chloroform-d)δ11.95(s,1H),7.33(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.99(dd,J＝19.2,2.4Hz,2H),5.35(dd,J＝13.2,3.0Hz,1H),5.20(s,1H),3.09(dd,J＝17.4,13.2Hz,1H),2.77(dd,J＝17.4,3.0Hz,1H),0.96(s,9H),0.24(s,6H). 13 C NMR(150MHz,Chloroform-d)δ196.2,165.0,163.8,162.8,156.1,130.5,127.9,115.6,103.5,101.2,99.8,78.8,43.2,25.4,18.1,-4.4.HRMS(CI + )m/z calculated for C 21 H 27 O 5 Si 1 [M+H] + 387.1622,found 387.1617.
EXAMPLE 2 Synthesis of Compound 4
YPS (10g, 36.76mmol) was weighed, and transferred to a 500-ml round-bottom flask equipped with a stirrer, and 30ml of methylene chloride was added thereto, followed by stirring at room temperature for 10min. Imidazole (5 g, 73.52mmol) and 4-dimethylaminopyridine (0.9g, 7.4 mmol) are added successively and stirred at room temperature for 30min until the solution is clear. Tert-butyldimethylsilyl chloride (5.6 g, 37.33mmol) was added slowly in portions, stirred at room temperature overnight, and TLC monitored the progress of the reaction. Next day, when the reaction conversion rate reached about 80% or more, the reaction was quenched by adding 30ml of saturated sodium bicarbonate solution, extracted three times with 30ml of dichloromethane, the organic phases were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, the solvent was spin-dried, and the product was passed through a column to obtain an off-white crystalline solid (compound 4), yield: 33.4 percent. IR (near, cm) -1 ):3278,2957,2925,2855,1714,1641,1512,1464,1379,1340,1269,1165,1085,915,837,808,779. 1 H NMR(600MHz,Chloroform-d)δ12.05(s,1H),7.31(d,J＝8.4Hz,2H),6.88(d,J＝9.0Hz,2H),6.41(s,1H),5.99(dd,J＝9.6,2.4Hz,2H),5.35(dd,J＝13.2,2.4Hz,1H),3.09(dd,J＝17.4,13.2Hz,1H),2.78(dd,J＝17.4,3.0Hz,1H),0.99(s,9H),0.21(s,6H). 13 C NMR(150MHz,Chloroform-d)δ196.3,164.9,164.3,163.4,156.3,130.8,127.7,120.4,103.1,96.7,95.6,79.1,43.2,25.7,18.2,-4.4.HRMS(CI + )m/z calculated for C 21 H 27 O 5 Si 1 [M+H] + 387.1622,found387.1618.
EXAMPLE 3 Synthesis of Compound 5a
The first step is as follows: 2- (4-hydroxyphenyl) -5-hydroxy-7- (tert-butyldimethylsilyloxy) chroman-4-one (compound a,3.8g, 9.84mmol) was weighed out, transferred to a 250ml round-bottomed flask equipped with a stirrer, and 10ml of tetrahydrofuran was added thereto and stirred at room temperature for about 10min until it was dissolved. Triphenylphosphine (3.8g, 14.76mmol) and isobutanol (1.36ml, 9.84mmol) were added in this order and stirred at room temperature for 10min. General formula (N) 2 After ice-cooling for 10min, diisopropyl azodicarboxylate (3.0 ml, 14.76mmol) was added dropwise, the mixture was stirred and gradually returned to room temperature, and the progress of the reaction was monitored by TLC. After 3h reaction is completed, adding 10ml water to quench the reaction, extracting with 10ml ethyl acetate three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, spin-drying the solvent, and passing through a column to obtain yellow oily solid with yield: and (4) 64.3%.
The second step: 2- (4-Isobutoxyphenyl) -5-hydroxy-7- (tert-butyldimethylsilyloxy) chroman-4-one (2.6 g, 5.88mmol) was weighed, transferred to a 100ml round-bottomed flask equipped with a stirrer, and 10ml of dichloromethane was added thereto, and stirred at room temperature for about 10min until it was dissolved. General formula (N) 2 After ice-cooling for 10min, tetrabutylammonium fluoride (2.9ml, 2.94mmol) was added dropwise, the mixture was stirred and gradually returned to room temperature, and the progress of the reaction was monitored by TLC. After 1h reaction was complete, the reaction was quenched by addition of 5ml saturated sodium bicarbonate solution, extracted three times with 5ml dichloromethane, the organic phases were combined, washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, the solvent was dried by spinning, and the column was passed over to give a yellow powdery solid (compound 5 a), yield: 56.0 percent. IR (near, cm) -1 ):3321,2964,2917,1631,1593,1566,1519,1466,1377,1348,1295,1270,1213,1177,1096,1054,1027,883,827,735. 1 H NMR(400MHz,Chloroform-d)δ12.00(s,1H),7.33(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.05(dd,J＝9.2,2.0Hz,2H),5.35(dd,J＝12.8,2.8Hz,1H),5.05(s,1H),3.73(d,J＝6.4Hz,2H),3.08(dd,J＝17.2,13.2Hz,1H),2.78(dd,J＝17.2,3.2Hz,1H),2.10–2.03(m,1H),1.00(d,J＝6.4Hz,6H). 13 C NMR(150MHz,Chloroform-d)δ195.9,167.6,164.0,162.8,156.0,130.6,127.9,115.6,102.9,95.5,94.5,78.8,74.7,43.1,27.9,19.0.HRMS(CI + )m/z calculated for C 19 H 21 O 5 [M+H] + 329.1384,found 329.1379.
EXAMPLE 4 Synthesis of Compound 5b
The first step is as follows: 2- (4-hydroxyphenyl) -5-hydroxy-7- (tert-butyldimethylsilyloxy) chroman-4-one (3.8g, 9.84mmol) was weighed, transferred to a 100ml round-bottomed flask equipped with a stirrer, and 10ml of tetrahydrofuran was added thereto, followed by stirring at room temperature for about 10min until it was dissolved. Triphenylphosphine (3.8g, 14.76mmol) and cyclopentylmethanol (1.1ml, 9.84mmol) were added in this order and stirred at room temperature for 10min. General formula N 2 After ice-cooling for 10min, diisopropyl azodicarboxylate (3.0 ml, 14.76mmol) was added dropwise, the mixture was stirred and gradually returned to room temperature, and the progress of the reaction was monitored by TLC. After the reaction is completed for 3h, 10ml of water is added to quench the reaction, the mixture is extracted three times by 10ml of ethyl acetate, organic phases are combined, washed by saturated saline solution, dried by anhydrous sodium sulfate, filtered, solvent is dried by spinning, and the mixture is subjected to column chromatography to obtain yellow oily solid, wherein the yield is as follows: 58.0 percent.
The second step is that: 2- (4- (Cyclopentylmethoxy) phenyl) -5-hydroxy-7- (tert-butyldimethylsilyloxy) chroman-4-one (2.6 g, 5.56mmol) was weighed into a 100ml round bottom flask with a stir bar, 5ml dichloromethane was added and stirred at room temperature for about 10min until it dissolved. General formula (N) 2 After ice-cooling for 10min, tetrabutylammonium fluoride (2.8ml, 2.78mmol) was added dropwise, the mixture was stirred and gradually returned to room temperature, and the progress of the reaction was monitored by TLC. After 1h reaction was complete, the reaction was quenched by addition of 5ml saturated sodium bicarbonate solution, extracted three times with 5ml dichloromethane, the organic phases were combined, washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, the solvent was dried by spinning, and the column was passed over to give a yellow powdery solid (compound 5 b) in yield: 46.8 percent. IR (near, cm) -1 ):3238,2960,2869,1735,1646,1596,1519,1460,1382,1358,1307,1273,1210,1166,1087,889,833,776,743. 1 H NMR(400MHz,Chloroform-d)δ12.00(s,1H),7.33(d,J＝8.4Hz,2H),6.88(d,J＝8.8Hz,2H),6.05(dd,J＝9.6,2.4Hz,2H),5.35(dd,J＝13.2,3.2Hz,1H),5.00(s,1H),3.84(d,J＝6.8Hz,2H),3.08(dd,J＝16.8,12.8Hz,1H),2.78(dd,J＝17.2,2.8Hz,1H),2.39–2.28(m,1H),1.85–1.78(m,2H),1.65–1.60(m,4H),1.35–1.28(m,2H). 13 C NMR(150MHz,Chloroform-d)δ195.9,167.7,164.0,162.8,156.0,130.6,127.9,115.6,102.9,95.5,94.6,78.8,72.6,43.1,38.6,29.3,25.3.HRMS(CI + )m/z calculated for C 21 H 21 O 5 [M-H] - 353.1395,found 353.1400.
EXAMPLE 5 Synthesis of Compound 6a
2- (4- (tert-butyldimethylsilyloxy) phenyl) -5,7-dihydroxychroman-4-one (100mg, 0.26mmol) was weighed out, transferred to a 50ml round bottom flask equipped with a stirrer, added 1ml tetrahydrofuran and stirred at room temperature for about 10min until it dissolved. Triphenylphosphine (102mg, 0.39mmol) and 1- (2-hydroxyethyl) imidazole (0.03ml, 0.26mmol) were added sequentially, and the mixture was stirred at room temperature for 10min. General formula (N) 2 After ice-cooling for 10min, diisopropyl azodicarboxylate (0.08ml, 0.39mmol) was added dropwise, stirred and gradually returned to room temperature, and the progress of the reaction was monitored by TLC. After 4h reaction was complete, 2ml water was added to quench the reaction, extracted three times with 2ml ethyl acetate, the organic phases were combined, washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered, the solvent was spun dry and the column was passed over to give a yellow powdery solid (compound 6 a), yield: 64.1 percent. IR (near, cm) -1 ):3297,2957,2923,2853,1721,1638,1573,1510,1451,1376,1306,1260,1196,1162,1092,1036,915,834,803,742. 1 HNMR(400MHz,Chloroform-d)δ12.00(s,1H),7.58(s,1H),7.30(d,J＝8.0Hz,2H),7.07(s,1H),7.00(s,1H),6.88(d,J＝8.0Hz,2H),6.02(d,J＝2.8Hz,2H),5.34(d,J＝11.6Hz,1H),4.32(t,J＝4.8Hz,2H),4.20(t,J＝4.8Hz,2H),3.08(dd,J＝16.8,12.8Hz,1H),2.79(dd,J＝17.2,2.8Hz,1H),0.99(s,9H),0.21(s,6H). 13 C NMR(125MHz,Chloroform-d)δ196.1,165.8,164.0,162.9,156.2,137.3,130.6,129.4,127.5,120.3,119.2,103.5,95.3,94.5,79.0,67.3,46.0,43.1,29.6,25.5,-4.5.HRMS(CI + )m/z calculated for C 26 H 33 N 2 O 5 Si[M+H] + 481.2153,found 481.2149.
EXAMPLE 6 Synthesis of Compound 6b
The first step is as follows: 2- (4- (tert-butyldimethylsilyloxy) phenyl) -5,7-dihydroxychroman-4-one (100mg, 0.26mmol) was weighed out, transferred to a 50ml round bottom flask equipped with a stirrer, added 1ml tetrahydrofuran and stirred at room temperature for about 10min until it dissolved. Triphenylphosphine (102mg, 0.39mmol) and N-methyl-N-hydroxyethylaniline (0.04ml, 0.26mmol) were added in this order, and stirred at room temperature for 10min. General formula (N) 2 After ice-cooling for 10min, diisopropyl azodicarboxylate (0.08ml, 0.39mmol) was added dropwise, stirred and gradually returned to room temperature, and the progress of the reaction was monitored by TLC. After 4h reaction is completed, adding 2ml water to quench the reaction, extracting with 2ml ethyl acetate three times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, spin-drying the solvent, and passing through a column to obtain a yellow powdery solid with yield: 85.9 percent.
The second step is that: 2- (4- (tert-butyldimethylsilyloxy) phenyl) -5-hydroxy-7- (2- (methyl (phenyl) amino) ethoxy) chroman-4-one (80mg, 0.2mmol) was weighed out and transferred to a 50ml round bottom flask with a stirrer, 1ml dichloromethane was added and stirred at room temperature for about 10min until it was dissolved. General formula (N) 2 After ice-cooling for 10min, tetrabutylammonium fluoride (0.02ml, 0.02mmol) was added dropwise, stirring was continued and the temperature was gradually returned to room temperature, and the progress of the reaction was monitored by TLC. After 1h reaction was complete, quench the reaction by adding 2ml of saturated sodium bicarbonate solution, extract three times with 2ml of dichloromethane, combine the organic phases, wash with saturated brine solution, dry over anhydrous sodium sulfate, filter, spin dry the solvent, and column pass to give a yellow powdery solid (compound 6 b) in yield: 36.7 percent. IR (near, cm) -1 ):3513,3292,2923,2848,1631,1568,1507,1444,1374,1349,1293,1260,1194,1172,1077,1036,822,800,742,686. 1 H NMR 1 H NMR(400MHz,Chloroform-d)δ11.99(s,1H),7.31(d,J＝8.0Hz,2H),7.23(d,J＝7.2Hz,2H),6.88(d,J＝8.0Hz,2H),6.73(t,J＝8.0Hz,3H),6.02(d,J＝9.6Hz,2H),5.34(d,J＝10.8Hz,1H),4.14(t,J＝5.6Hz,2H),3.74(t,J＝5.6Hz,2H),3.07(dd,J＝17.2,4.0Hz,1H),3.02(s,3H),2.78(dd,J＝17.2,3.2Hz,1H),0.88(s,1H). 13 C NMR(125MHz,Chloroform-d)δ195.9,166.9,164.0,162.8,156.1,148.6,130.4,129.2,127.8,116.7,115.6,112.1,103.1,95.4,94.5,78.8,65.8,51.5,43.1,39.0.HRMS(CI + )m/z calculated for C 24 H 24 NO 5 [M+H] + 406.1649,found 406.1645.
Example 7 investigation of Effect of dihydrochromone derivatives on tumor cell inhibition
The tumor-inhibiting effect of the compounds of the present invention was demonstrated by the following test methods.
These effects indicate that the compounds of the present invention have a significant tumor cell inhibitory effect and are useful for the treatment of cancer. The specific test method is as follows:
1. purpose and principle of experiment
Purpose of the experiment: the MTT method is adopted to detect the inhibition effect of the synthesized dihydrochromone derivative on the proliferation of tumor cells.
The experimental principle is as follows: MTT colorimetry is a method for detecting survival and growth of cells, and its principle is that succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-violet crystalline formazan, which is deposited in cells, while dead cells lack this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in living cells, an enzyme linked immunosorbent assay detector is used for detecting an absorbance value (OD value) under 570nM, the number of the living cells can be reflected according to the absorbance value, and in a certain range, the smaller the OD value is, the weaker the cell activity is, and the better the proliferation inhibition effect of the medicine is.
2. Basic information of reagent
3. Reagent preparation
1. RPMI-1640 complete medium
Preparing 1L of RPMI-1640 culture medium, taking a corresponding amount of RPMI-1640 powder, dissolving in a beaker containing 800ml of triple distilled water, and stirring for 4h until the powder is completely dissolved. 2g of NaHCO were added 3 And stirring until the mixture is completely dissolved. Adjusting the pH value with 1 mol/L hydrochloric acid to 7.2-7.4, and metering to 1L. Filtering with a filter membrane with pore diameter of 0.22 μm, filtering with high pressure filter, packaging, and storing at 4 deg.C. When in use, 5% of serum is added to form a complete culture medium, and the culture medium can be used for cell culture.
2、MTT
Wrapping 50ml of centrifuge tube with tinfoil paper in dark place, precisely weighing 250mg of MTT powder, adding into centrifuge tube, adding 50ml of PBS to completely dissolve MTT powder, filtering with 0.22 μm filter membrane for sterilization, subpackaging, and storing at-20 deg.C in dark place.
3. Compound configuration
The autoclaved EP tube was used to weigh the compounds, and the corresponding amount of DMSO was added to the EP tube to make the liquid a 100mM stock solution, and diluted to 30mM,10mM,3mM, and 1mM, respectively. When in use, the culture medium is diluted by 1000 times with a corresponding amount of the culture medium, and working solution with the concentration of 0.1 mu M,0.3 mu M,1 mu M,10 mu M,30 mu M and 100 mu M can be prepared.
4. Procedure of experiment
(1) Collecting cervical cancer cell (Hela), breast cancer cell (MCF-7), lung cancer cell (NCI-H292), melanoma cell (B16-F10), colon cancer cell (HCT-116), and hepatocarcinoma cell (HepG 2) in logarithmic growth phase, digesting, and adjusting cell number concentration to 2.5 × 10 4 one/mL, 100. Mu.l/well into 96-well plates. At 37 ℃,5% CO 2 Culturing overnight in a cell culture box until the cells adhere to the wall.
(2) The original culture medium was aspirated, and different concentrations of the dihydrochromone derivative series of compounds were added to each group, with gradient concentrations of each compound being 0.1. Mu.M, 0.3. Mu.M, 1. Mu.M, 10. Mu.M, 30. Mu.M, 100. Mu.M, 3 replicates per treatment. The cells were cultured in a cell culture incubator for 72 hours with 0.1% DMSO as a control, naringenin as a positive control, and no cells or compounds as a blank control.
(3) Mu.l of MTT solution was added to each well and incubated for 4h in an incubator.
(4) The medium was discarded, 100. Mu.l of DMSO was added to each well, and formazan crystals were sufficiently dissolved by shaking for 15 min.
(5) The absorbance at 570nm was measured using an enzyme linked immunosorbent assay.
(6) The cell growth inhibition rate was calculated according to the following formula:
inhibition rate = [ (As-Ab)/(Ac-Ab) ]. Times.100%
As: absorbance of assay well (cell, MTT, compound)
Ac: absorbance of control wells (cell, MTT, no Compound)
Ab: absorbance of blank wells (cell and Compound free, MTT containing)
The results are shown in Table 1 below.
TABLE 1 half inhibitory concentration of the compound on tumor cell growth
As can be seen from Table 1, the synthesized dihydrochromone derivative can effectively inhibit the growth of tumor cells, and the activity of the derivative is obviously improved compared with the activity of a naringenin control group.
Claims (8)
1. A dihydrochromone derivative having a chemical structure as shown in any one of formula (a):
（a）
in the formula (a), R 1 Is hydrogen, TBS, isobutyl or cyclopentylmethyl, R 2 Is hydrogen, 2- (methyl (phenyl) amino) ethyl or 2- (1H-imidazol-1-yl) ethyl, R 1 、R 2 Not hydrogen at the same time.
2. The dihydrochromone derivative of claim 1, wherein the dihydrochromone derivative is selected from one of the following compounds:
when R is 1 Is hydrogen, R 2 When the derivative is 2- (methyl (phenyl) amino) ethyl, the chemical structure of the dihydrochromone derivative is as follows:
；
when R is 1 Is TBS, R 2 When hydrogen, the chemical structure of the dihydrochromone derivative is as follows:
；
when R is 1 Is TBS, R 2 When the derivative is 2- (1H-imidazole-1-yl) ethyl, the chemical structure of the dihydrochromone derivative is as follows:
；
when R is 1 Is isobutyl, R 2 When hydrogen is present, the chemical structure of the dihydrochromone derivative is as follows:
when R is 1 Is cyclopentylmethyl, R 2 When hydrogen is present, the chemical structure of the dihydrochromone derivative is as follows:
3. the use of a dihydrochromone derivative of claim 1 or 2 in the preparation of an anti-tumor medicament against cervical cancer, colon cancer, breast cancer, lung cancer, liver cancer or melanoma.
4. The use of claim 3, wherein the dihydrochromone derivative has the formula:
。
5. an antitumor agent characterized by comprising the dihydrochromone derivative as described in claim 1 or 2 as an active ingredient.
6. The antitumor agent as claimed in claim 5, wherein the structural formula of said dihydrochromone derivative is as follows:
7. the antitumor agent as claimed in claim 5, wherein said antitumor agent comprises a dihydrochromone derivative and a pharmaceutically acceptable excipient.
8. A method for synthesizing a dihydrochromone derivative is characterized by comprising the following steps:
the reaction formula is as follows:
（i）
first, naringenin is dissolvedIn a DMF solvent, reacting with tert-butyldimethylsilyl chloride under the catalysis of imidazole and 4-dimethylaminopyridine to obtain a compound a and a compound 4, reacting the compound a and the compound 4 with alcohol respectively under the catalysis of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound b and a compound d, and then removing TBS protecting groups by using TBAF to obtain a compound c and a compound e, wherein R is 1 Is isobutyl or cyclopentylmethyl, R 2 Is 2- (methyl (phenyl) amino) ethyl or 2- (1H-imidazol-1-yl) ethyl.
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