CN113321673A - Preparation method and application of neobynine boric acid compound - Google Patents
Preparation method and application of neobynine boric acid compound Download PDFInfo
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- CN113321673A CN113321673A CN202110678041.6A CN202110678041A CN113321673A CN 113321673 A CN113321673 A CN 113321673A CN 202110678041 A CN202110678041 A CN 202110678041A CN 113321673 A CN113321673 A CN 113321673A
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- -1 boric acid compound Chemical class 0.000 title claims abstract description 20
- 239000004327 boric acid Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 16
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 9
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 9
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 9
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 9
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000000543 intermediate Substances 0.000 claims description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- 238000003786 synthesis reaction Methods 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- INYYVPJSBIVGPH-UHFFFAOYSA-N 14-episinomenine Natural products C1CN(C)C2CC3=CC=C(OC)C(O)=C3C31C2C=C(OC)C(=O)C3 INYYVPJSBIVGPH-UHFFFAOYSA-N 0.000 claims description 3
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 claims description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 3
- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229930002966 sinomenine Natural products 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- IKOGEPVQXKWROD-UHFFFAOYSA-N 1-methyl-2H-quinoline hydroiodide Chemical compound I.C1=CC=C2N(C)CC=CC2=C1 IKOGEPVQXKWROD-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 241000872931 Myoporum sandwicense Species 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229910052786 argon Inorganic materials 0.000 claims 1
- 150000001642 boronic acid derivatives Chemical class 0.000 claims 1
- 239000000284 extract Substances 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 238000003828 vacuum filtration Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 38
- 210000004027 cell Anatomy 0.000 abstract description 15
- 230000000259 anti-tumor effect Effects 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 8
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 abstract description 8
- 229960000303 topotecan Drugs 0.000 abstract description 8
- 210000004881 tumor cell Anatomy 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 5
- 238000012216 screening Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229930013930 alkaloid Natural products 0.000 description 4
- 150000003797 alkaloid derivatives Chemical class 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 125000005619 boric acid group Chemical group 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LUYISICIYVKBTA-UHFFFAOYSA-N 6-methylquinoline Chemical compound N1=CC=CC2=CC(C)=CC=C21 LUYISICIYVKBTA-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- INYYVPJSBIVGPH-QHRIQVFBSA-N Sinomenine Chemical compound C([C@@H]1N(CC2)C)C3=CC=C(OC)C(O)=C3[C@@]32[C@@H]1C=C(OC)C(=O)C3 INYYVPJSBIVGPH-QHRIQVFBSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- GKJSZXGYFJBYRQ-UHFFFAOYSA-N 6-chloroquinoline Chemical compound N1=CC=CC2=CC(Cl)=CC=C21 GKJSZXGYFJBYRQ-UHFFFAOYSA-N 0.000 description 1
- RMDCSDVIVXJELQ-UHFFFAOYSA-N 6-fluoroquinoline Chemical compound N1=CC=CC2=CC(F)=CC=C21 RMDCSDVIVXJELQ-UHFFFAOYSA-N 0.000 description 1
- 241000563984 Ampelopsis Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 235000009388 Parthenocissus quinquefolia Nutrition 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- BMGMQYRPZOGZFU-YFKPBYRVSA-N [(1r)-1-amino-3-methylbutyl]boronic acid Chemical compound CC(C)C[C@H](N)B(O)O BMGMQYRPZOGZFU-YFKPBYRVSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000002841 anti-cancer assay Methods 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960003648 ixazomib Drugs 0.000 description 1
- MXAYKZJJDUDWDS-LBPRGKRZSA-N ixazomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MXAYKZJJDUDWDS-LBPRGKRZSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- PZIIKMBOSNKNFZ-UHFFFAOYSA-N neocryptolepine Natural products C1=CC=C2N(C)C3=NC4=CC=CC=C4C3=CC2=C1 PZIIKMBOSNKNFZ-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 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 1
- 238000011160 research Methods 0.000 description 1
- 229940127020 second-generation proteasome inhibitor Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (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 relates to a neohederin boric acid compound, a preparation method thereof and application thereof in preparing antitumor drugs, wherein the chemical general formulas of the compound are shown as structural formulas (I) and (II). The screening result of the in vitro antitumor activity shows that the compounds shown in the formulas I and II have broad-spectrum antitumor activity and show stronger inhibition activity on cell lines of human liver cancer (HepG2), human pancreatic cancer (SW1990), human ovarian cancer (A2780), human breast cancer (MCF7) and human colon cancer (SW 480). Wherein the compounds N-3 and N-4 have strong inhibitory action on 5 tumor cell lines tested, IC50The values are 0.26-0.89. mu.M and 0.22-0.91. mu.M, respectively; the compound N-1, N-3, N-4 has strong inhibiting effect on human pancreatic cancer (SW1990) cell line, IC50Respectively 0.97, 0.45 and 0.63 mu M, which are obviously superior to the control drug topotecan; meanwhile, the compound N-3, N-4 also has strong inhibiting effect on human breast cancer (MCF7) cell line, IC500.80 and 0.65 mu M respectively, which is obviously superior to the control drug topotecan. Therefore, the neobynine boric acid compound is expected to be developed into a novel antitumor drug.
Description
Technical Field
The invention relates to a neobyttrine boric acid compound, a preparation method of the compound and an application of the compound in the aspect of tumor resistance. Belongs to the field of medicine technology.
Background
The natural alkaloid as an important nitrogenous organic matter in the biological world has the biological activities of resisting tumor, resisting bacteria, diminishing inflammation, resisting virus, resisting arrhythmia, relieving pain, relieving spasm and the like. Therefore, taking natural alkaloid as a lead, and further structural modification or reconstruction by combining the structure-activity relationship is one of important ways for developing new drugs. Sinomenine is an alkaloid separated from African medicinal plant caulis Seu folium Ampelopsis Brevipedunculatae, and has antimalarial, antibacterial, and antitumor biological activities. The neobyssurine as an anti-tumor active compound has narrow anti-tumor spectrum and weaker activity, and needs to be further structurally optimized or modified, so that the aims of enhancing the anti-tumor activity and expanding the anti-tumor spectrum are fulfilled. The boric acid group has wide application in the aspects of new drug design, chemistry, material science, energy research and the like due to the unique chemical property. Since 2003, 5 boron-containing drugs have been approved by the FDA, of which Bortezomib, Bortezomib
The dipeptide boric acid which is used as a first type of proteasome inhibitor and can be used for treating multiple myeloma is a first boron-containing medicament on the market; ixazomib Esazomib
As a second generation proteasome inhibitor, a dipeptidyl leucine boronic acid, which can reversibly bind to the CT-L proteolytic (β 5) site of the 20S proteasome, was used as the first oral drug for multiple myeloma treatment.
Therefore, the natural alkaloid of Sinomenine is used as a lead structure, and a boric acid group is introduced to obtain a high-activity anti-tumor-activity lead compound. According to the invention, a boric acid group is introduced into the 9 th position of the neohederin, a series of different substituted neohederin boric acid derivatives are designed and synthesized, and the inhibitory activity of the neohederin on various tumor cells is measured. Wherein the partial compound shows better anti-tumor activity, the inhibition activity to the growth of some tumor cells is better than that of a clinical drug topotecan, and the compound can be developed as a novel anti-tumor drug.
Disclosure of Invention
The invention provides a new byttylline boric acid compound, and simultaneously provides a preparation method of the new compound and application of the new compound in the direction of tumor resistance.
The neobyssurine boric acid compound of the invention is two compounds shown in the following general formulas (I) and (II):
wherein R in the formulae (I) and (II)1Can be hydrogen, methyl, methoxy, fluorine, chlorine; r2Can be hydrogen, methyl, methoxy, fluorine, chlorine; r3Can be hydrogen, methyl, methoxy, fluorine, chlorine; r4Can be hydrogen, methyl, methoxy, fluorine or chlorine.
The preparation method of the neobynine boric acid compound is carried out according to the following chemical formula 1:
different substituted quinolines are used as starting materials to react with methyl iodide at 90 ℃ to generate quinoline intermediates A1-A4; then reacting the mixture with a potassium hydroxide and hydrogen peroxide solution at normal temperature for 48 hours, and opening the ring to obtain an intermediate B1-B4; then reacting with 5-Br indole to generate an intermediate C1-C4; then the intermediate C1-C4 reacts with pinacol diboron in a1, 4-dioxane solvent under the catalysis of a palladium catalyst to obtain a target product N-1, N-3, N-5, N-7; the final product N-1, N-3, N-5, N-7 was in THF/H2Hydrolyzing with sodium periodate and 1M hydrochloric acid in solvent of O (4:1) to obtain target products N-2, N-4,N-6,N-8。
the neobynine boric acid compound can play a role in preparing antitumor drugs, and is more specifically as follows: can be applied to the preparation of medicaments for treating liver cancer, pancreatic cancer, ovarian cancer, breast cancer and colon cancer of human. The results of in vitro antitumor activity screening show that the neobynine boric acid compound has broad-spectrum antitumor activity and shows stronger inhibitory activity on cell lines of human liver cancer (HepG2), human pancreatic cancer (SW1990), human ovarian cancer (A2780), human breast cancer (MCF7) and human colon cancer (SW 480). Wherein the compounds N-3 and N-4 have strong inhibitory action on 5 tumor cell lines tested, IC50The values are 0.26-0.89. mu.M and 0.22-0.91. mu.M, respectively; the compound N-1, N-3, N-4 has strong inhibiting effect on human pancreatic cancer (SW1990) cell line, IC50Respectively 0.97, 0.45 and 0.63 mu M, which are obviously superior to the control drug topotecan; meanwhile, the compound N-3, N-4 also has strong inhibiting effect on human breast cancer (MCF7) cell line, IC500.80 and 0.65 mu M respectively, which is obviously superior to the control drug topotecan.
Therefore, the neocryptolepine boric acid compound can be used for preparing antitumor drugs, has a novel structure, cheap and available raw materials and high product purity, shows a strong inhibition effect on the proliferation of various tumor cell strains, and has an excellent application prospect.
The above-described aspects of the present invention will be described in further detail with reference to specific embodiments. This is not to be construed as limiting the invention.
Detailed Description
Example 1: synthesis of target Compound N-1
The synthesis of the compound N-1 of the present invention is performed according to chemical formula 2:
synthesis of intermediate a 1: quinoline (0.1mol) and methyl iodide (0.15mol) were mixed in an appropriate amount of isopropanol under nitrogen blanket and heated to reflux at 90 ℃ for 3 hours. After the reaction was cooled to room temperature, the precipitate was isolated by suction filtration under reduced pressure, washed with a mixed reagent of isopropanol/ethyl acetate (1/1), and the washed solid was dried to give intermediate a 1.
Synthesis of intermediate B1: an aqueous solution of potassium hydroxide (30mL) and a solution of 1, 2-dichloroethane (30mL) were mixed and then hydrogen peroxide (30%) and 1-methylquinoline iodide (intermediate A1, 15mmol of intermediate dissolved in 15mL of water) were slowly added to the mixed solution at 0 ℃. The resulting mixture was stirred at room temperature for 48 hours, then the organic layer was separated, and the aqueous layer was extracted with dichloromethane (30mL) several times, then the combined organic layers were dried over anhydrous sodium sulfate, and the organic layer was further concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to give intermediate B1.
Synthesis of intermediate C1: intermediate B1(5mmol), 5-Br indole (5mmol) and p-toluenesulfonic acid (p-TSA,5mmol) were added to absolute ethanol (10mL) and the mixture was stirred at reflux in a 50mL round bottom flask at 85 ℃ for 24 h. After cooling to room temperature, the reaction mixture was washed with 1M sodium hydroxide (50mL), and the aqueous layer was extracted with dichloromethane (80mL) several times. The combined organic phases were then dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography. Impurities were first removed by bulk mixed solvent of petroleum ether/ethyl acetate (2/1), followed by column chromatography with mixed eluent of dichloromethane/methanol (50/1), and intermediate C1 was obtained.
Synthesis of N-1: under the protection of nitrogen, intermediate C1(0.1mol), pinacol diboride (0.11mol), potassium acetate (0.3mol) and Pd (dppf) Cl were added to a dry solvent of 1, 4-dioxane2(0.01mol), the reaction mixture was stirred at 110 ℃ for 12 hours. After completion of the reaction, the solvent was removed under vacuum, and the residue was extracted with dichloromethane and saturated sodium chloride solution (15mL × 3), respectively. Mixing the organic extractsDried over sodium sulfate, the dried organic layer was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to give the product N-1. The detection data of the product obtained by the reaction are as follows: yield: 56 percent; a yellow solid;1H NMR(400MHz,Chloroform-d)δ:8.52(d,J＝7.8Hz,2H),8.01(d,J＝8.0Hz,1H),7.95(d,J＝7.9Hz,1H),7.78–7.69(m,3H),7.44(t,J＝6.6Hz,1H),4.35(s,3H),1.40(s,12H).13C NMR(100MHz,Chloroform-d)δ:158.01,157.02,136.95,136.11,130.53,130.13,128.39,128.19,128.06,123.75,122.26,121.21,117.17,114.35,83.70,33.25,29.83,25.09.MS-ESI m/z:calcd for C22H23BN2O3[M+H]+:359.2480；found:359.2477.
example 2: synthesis of target Compound N-2
Synthesis of N-2: dissolving N-1(0.1mol) in THF/H2O (4: 110 ml) in a mixed solvent. Adding appropriate amount of NaIO to the obtained solution4(0.5mol), followed by the addition of an appropriate amount of 1.0M HCl and then the reaction mixture was stirred at ambient temperature for 24 h. After the reaction was completed, THF was removed by concentration under reduced pressure, and then H was added thereto2And washing the O and dichloromethane, performing reduced pressure suction filtration, and drying to obtain a crude product. And separating and purifying by column chromatography to obtain the product N-2. The detection data of the product obtained by the reaction are as follows: yield: 65 percent; a yellow solid;1H NMR(400MHz,DMSO-d6)δ:9.05(s,1H),8.62(s,1H),8.24(d,J＝8.0Hz,1H),8.08(d,J＝8.6Hz,1H),8.00–7.96(m,2H),7.58(t,J＝8.1Hz,2H),4.37(s,3H).13C NMR(100MHz,DMSO-d6)δ:159.34,158.09,136.21,135.52,131.90,131.70,130.43,130.27,128.04,124.74,123.84,121.73,115.90,114.21,88.45,24.80.MS-ESI m/z:calcd for C16H13BN2O2[M+H]+:277.1020；found:277.1405.
example 3: synthesis of target Compound N-3
Just as in example 1, 6-methylquinoline was used instead of quinoline. The detection data of the product obtained by the reaction are as follows: yield: 43 percent; a yellow solid;1H NMR(400MHz,Chloroform-d)δ:8.52(s,1H),8.47(s,1H),8.00(dd,J＝8.1,1.3Hz,1H),7.72(d,J＝7.8Hz,2H),7.64(d,J＝8.7Hz,1H),7.57(dd,J＝8.7,2.0Hz,1H),4.35(s,3H),2.54(s,3H),1.40(s,12H).13C NMR(100MHz,Chloroform-d)δ:157.96,156.89,136.02,135.17,132.14,131.99,129.61,128.22,128.13,127.97,123.75,121.29,117.08,114.24,83.70,33.30,25.10,24.79，20.9.MS-ESI m/z:calcd for C23H25BN2O2[M+H]+:373.2750；found:373.1868.
example 4: synthesis of target Compound N-4
Just as in example 2, compound N-3 was used in place of N-1. The detection data of the product obtained by the reaction are as follows: yield: 65 percent; a red solid;1H NMR(400MHz,DMSO-d6)δ:8.81(s,1H),8.58(s,1H),7.97–7.92(m,1H),7.92–7.85(m,2H),7.66(dd,J＝8.8,2.1Hz,1H),7.51(d,J＝7.9Hz,1H),4.29(s,3H).13C NMR(100MHz,DMSO-d6)δ:157.04,155.87,134.95,134.73,132.01,131.07,129.20,128.12,127.65,126.95,123.27,120.46,116.04,114.83,32.76,20.30.MS-ESI m/z:calcd for C17H15BN2O2[M+H]+:291.1290；found:291.1164.
example 5: synthesis of target Compound N-5
Just as in example 1, 6-chloroquinoline was used instead of quinoline. The detection data of the product obtained by the reaction are as follows: yield: 76%; a yellow solid;1H NMR(400MHz,Chloroform-d)δ:8.50(s,1H),8.39(s,1H),8.04–7.99(m,1H),7.91(d,J＝2.0Hz,1H),7.70(d,J＝8.1Hz,1H),7.67–7.64(m,2H),4.33(s,3H),1.40(s,12H).13C NMR(100MHz,Chloroform-d)δ:158.39,156.88,136.62,135.36,130.46,129.32,128.78,128.43,127.63,126.87,123.59,122.06,117.39,115.76,83.79,53.56,33.36,25.10.MS-ESI m/z:calcd for C22H22BClN2O2[M+H]+:393.6900；found:393.1331.
example 6: synthesis of target Compound N-6
Just as in example 2, compound N-5 was used in place of N-1. The detection data of the product obtained by the reaction are as follows: yield: 67%; a red solid;1H NMR(400MHz,DMSO-d6)δ:8.88–8.84(m,1H),8.56(d,J＝12.3Hz,1H),8.31–8.24(m,1H),7.97–7.93(m,2H),7.84(dd,J＝9.2,2.5Hz,1H),7.53(dd,J＝8.1,2.0Hz,1H),4.30(d,J＝2.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ:157.24,155.82,135.51,135.15,130.06,128.42,128.14,127.83,127.17,125.90,123.11,121.52,117.05,116.33,48.57,32.99.MS-ESI m/z:calcd for C16H12BClN2O2[M+H]+:311.5440；found:311.0599.
example 7: synthesis of target Compound N-7
Just as in example 1, 6-fluoroquinoline was used instead of quinoline. The detection data of the product obtained by the reaction are as follows: yield: 68 percent; a yellow solid;1H NMR(400MHz,Chloroform-d)δ:8.50(s,1H),8.43(s,1H),8.05–7.98(m,1H),7.70(dd,J＝8.6,3.0Hz,2H),7.62(dd,1H),7.53–7.47(m,1H),4.35(s,3H),1.40(s,12H).13C NMR(100MHz,Chloroform-d)δ:157.75(d,J＝242Hz),157.71(d,J＝151Hz),136.58,133.55,129.41,128.44,127.17(d,J＝4Hz),123.38,121.88(d,J＝9Hz),118.85,118.61,117.25,115.96(d,J＝9Hz),114.31(d,J＝22Hz),83.77,33.49,25.10.MS-ESI m/z:calcd for C22H22BFN2O2[M+H]+:377.2384；found:377.1405.
example 8: synthesis of target Compound N-8
Just as in example 2, compound N-7 was used in place of N-1. The detection data of the product obtained by the reaction are as follows: yield: 78 percent; a red solid;1H NMR(400MHz,DMSO-d6)δ:8.85(d,J＝9.0Hz,1H),8.55(d,J＝16.2Hz,1H),8.04–7.97(m,1H),7.95(d,J＝6.4Hz,2H),7.77–7.68(m,1H),7.55–7.50(m,1H),4.30(s,3H).13C NMR(100MHz,DMSO-d6)δ:158.04,155.76(d,J＝20Hz),135.48,135.22,133.28(d,J＝2Hz),127.84,127.42(d,J＝4Hz),122.89(d,J＝2Hz),121.18(d,J＝9Hz),118.70,118.44,117.12(d,J＝7Hz),116.16(d,J＝2Hz),113.93(d,J＝22Hz),48.58,33.09.MS-ESI m/z:calcd for C16H12BFN2O2[M+H]+:295.0924；found:295.0893.
example 9 test method and results of antitumor Activity of Compounds N-1 to N-8
In vitro anti-tumor assays were performed using standard MTT methods. Topotecan was used as a positive control drug to test the antiproliferative activity of the target compounds N-1 to N-8 on human liver cancer (HepG2), human pancreatic cancer (SW1990), human ovarian cancer (a2780), human breast cancer (MCF7) and human colon cancer (SW480) cell lines. The compounds were dissolved in DMSO to prepare a mother liquor at a concentration of 20mM and diluted to the appropriate concentration with different media. The concentration of DMSO in the dilution solution should be less than 0.01% (v/v) to reduce the toxicity of DMSO on cells and reduce the test error. Tumor cells of different cell lines were cultured in RPMI-1640 medium containing 10% Fetal Bovine Serum (FBS), and various cancer cells grown logarithmically were collected, digested with pancreatin/EDTA digest and formulated into appropriate cell suspensions. 100uL of the cell suspension was added to a 96-well plate (typically 5000 cells per well) and placed at 37 ℃ with 5% CO2The incubator is used for 24 h. Then adding different concentrationsThe compound solution was assayed and after 72h incubation, the old medium was discarded and the cells were washed twice with PBS. mu.L of MTT (5mg/mL) in fresh medium was added and the culture was continued for 2 h. After this time, the medium was discarded and 200 μ L DMSO was added, and shaken on a shaker for 10min until formazan was completely dissolved. Finally, measuring the light absorption value at 492nm by a microplate reader and calculating IC50The value is obtained. All experiments were performed in triplicate or in triplicate. The results of the antitumor activity tests of the compounds N-1 to N-8 are shown in Table 1.
TABLE 1 in vitro antitumor Activity of Compounds N-1 to N-8
Note: (1) the screening method comprises the following steps: standard MTT colorimetric method; (2) acting time: 72 hours; (3) the compound numbers N-1 to N-8 are the products obtained in the foregoing examples 1 to 8, respectively.
The screening result of in vitro antitumor activity shows that the neobynine boric acid compound has broad-spectrum antitumor activity and shows stronger inhibitory activity on cell lines of human liver cancer (HepG2), human pancreatic cancer (SW1990), human ovarian cancer (A2780), human breast cancer (MCF7) and human colon cancer (SW 480). Wherein the compounds N-3 and N-4 have strong inhibitory action on 5 tumor cell lines tested, IC50The values are 0.26-0.89. mu.M and 0.22-0.91. mu.M, respectively; the compound N-1, N-3, N-4 has strong inhibiting effect on human pancreatic cancer (SW1990) cell line, IC50Respectively 0.97, 0.45 and 0.63 mu M, which are obviously superior to the control drug topotecan; meanwhile, the compound N-3, N-4 also has strong inhibiting effect on human breast cancer (MCF7) cell line, IC500.80 and 0.65 mu M respectively, which is obviously superior to the control drug topotecan. Therefore, the neobynine boric acid compound is expected to be developed into a novel antitumor drug.
Claims (8)
1. A neocelandine boric acid compound is represented by formula (I) and (II).
Wherein R in the formulae (I) and (II)1Can be hydrogen, methyl, methoxy, fluorine, chlorine; r2Can be hydrogen, methyl, methoxy, fluorine, chlorine; r3Can be hydrogen, methyl, methoxy, fluorine, chlorine; r4Can be hydrogen, methyl, methoxy, fluorine or chlorine.
2. The synthetic route of neobynine boronic acid compounds according to claim 1, characterized in that it comprises the following steps:
synthesis of intermediates A1-A4:
quinoline (0.1mol) and methyl iodide (0.15mol) were mixed in an appropriate amount of isopropanol under nitrogen blanket and heated to reflux at 90 ℃ for 3 hours. After the reaction is cooled to room temperature, a precipitate is obtained by vacuum filtration separation, washed with a mixed reagent of isopropanol/ethyl acetate (1/1), and then the washed solid is dried to obtain an intermediate A1-A4.
Synthesis of intermediates B1-B4:
an aqueous solution of potassium hydroxide (30mL) and a solution of 1, 2-dichloroethane (30mL) were mixed, and then hydrogen peroxide (30%) and 1-methylquinoline iodide (intermediates A1-A4, 15mmol of intermediate dissolved in 15mL of water) were slowly added to the mixed solution at 0 ℃. Then, the resulting mixture was stirred at room temperature for 48 hours, then, an organic layer was separated, and an aqueous layer was extracted with methylene chloride (30mL) plural times, then, the combined organic layers were dried over anhydrous sodium sulfate, and further, the organic layer was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to obtain intermediates B1 to B4.
And (3) synthesizing intermediates C1-C4:
intermediate B1-B4 (5mmol), 5-Br indole (5mmol) and p-toluenesulfonic acid (p-TSA,5mmol) were added to absolute ethanol (10mL) and the mixture was stirred at 85 ℃ in a 50mL round-bottom flask at reflux for 24 h. After cooling to room temperature, the reaction mixture was washed with 1M sodium hydroxide (50mL), and the aqueous layer was extracted with dichloromethane (80mL) several times. The combined organic phases were then dried over anhydrous sodium sulfate and the organic layer was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography, first removing impurities with a large amount of mixed solvent of petroleum ether/ethyl acetate (2/1), and then column chromatography with a mixed eluent of dichloromethane/methanol (50/1), and intermediates C1 to C4 were obtained.
Synthesis of N-1, N-3, N-5, N-7:
under the protection of argon, adding intermediate C1-C4(0.1mol), pinacol diborate (0.11mol), potassium acetate (0.3mol) and Pd (dppf) Cl into a dry solvent of 1, 4-dioxane2(0.01mol), the reaction mixture was stirred at 110 ℃ for 12 hours. After completion of the reaction, the solvent was removed under vacuum, and the residue was extracted with dichloromethane and saturated sodium chloride solution (15mL × 3), respectively. The combined organic extracts were dried over anhydrous sodium sulfate, the dried organic layer was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography to give the product N-1, N-3, N-5, N-7.
Synthesis of N-2, N-4, N-6, N-8:
dissolving N-1, N-3, N-5, N-7(0.1mol) in THF/H2O (4: 110 ml) in a mixed solvent. Adding appropriate amount of NaIO to the obtained solution4(0.5mol), followed by the addition of an appropriate amount of 1.0M HCl and then the reaction mixture was stirred at ambient temperature for 24 h. After the reaction was completed, THF was removed by concentration under reduced pressure, and then H was added thereto2And washing the O and dichloromethane, performing reduced pressure suction filtration, and drying to obtain a crude product. Separating and purifying by column chromatography to obtain the products N-2, N-4, N-6 and N-8.
3. The neobynine boric acid compound as claimed in claim 1, used for preparing antitumor drugs.
4. The use of the Sinomenine boronic acid compound of claim 1 in the preparation of a medicament for the treatment of human liver cancer (HepG 2).
5. The use of the neobynine boronic acid compound according to claim 1 in the preparation of a medicament for the treatment of human pancreatic cancer (SW 1990).
6. The use of a neobynine boronic acid compound according to claim 1 in the manufacture of a medicament for the treatment of human ovarian cancer (a 2780).
7. The use of the neobynine boronic acid compound of claim 1 in the preparation of a medicament for the treatment of human breast cancer (MCF 7).
8. The use of the neobynine boronic acid compound of claim 1 in the manufacture of a medicament for the treatment of human colon cancer (SW 480).
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