CN109053573A - A kind of substituted nitrogen heterocyclic benzanthrones compound and its application - Google Patents
A kind of substituted nitrogen heterocyclic benzanthrones compound and its application Download PDFInfo
- Publication number
- CN109053573A CN109053573A CN201810683695.6A CN201810683695A CN109053573A CN 109053573 A CN109053573 A CN 109053573A CN 201810683695 A CN201810683695 A CN 201810683695A CN 109053573 A CN109053573 A CN 109053573A
- Authority
- CN
- China
- Prior art keywords
- compound
- substituted
- application
- atg4b
- benzanthrones
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 nitrogen heterocyclic benzanthrones compound Chemical class 0.000 title claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000012822 autophagy inhibitor Substances 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 3
- 206010061592 cardiac fibrillation Diseases 0.000 claims description 3
- 230000002600 fibrillogenic effect Effects 0.000 claims description 3
- 230000002107 myocardial effect Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 208000019065 cervical carcinoma Diseases 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 13
- 230000004900 autophagic degradation Effects 0.000 abstract description 12
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 2
- 229910052711 selenium Inorganic materials 0.000 abstract description 2
- 101000753468 Homo sapiens Cysteine protease ATG4B Proteins 0.000 description 23
- 102100021903 Cysteine protease ATG4B Human genes 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 19
- 238000000034 method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 102100021901 Cysteine protease ATG4A Human genes 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 101000753414 Homo sapiens Cysteine protease ATG4A Proteins 0.000 description 6
- 241000699660 Mus musculus Species 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000011580 nude mouse model Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 101150034092 ATG4 gene Proteins 0.000 description 5
- 101100271280 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cpr-1 gene Proteins 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001962 electrophoresis Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 210000003712 lysosome Anatomy 0.000 description 3
- 230000001868 lysosomic effect Effects 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- 102000004533 Endonucleases Human genes 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 208000026037 malignant tumor of neck Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OVNWORSPZLORHV-UHFFFAOYSA-N 3-ethyl-3-methylpent-1-yne Chemical compound CCC(C)(CC)C#C OVNWORSPZLORHV-UHFFFAOYSA-N 0.000 description 1
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Chinese gallotannin Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102100021902 Cysteine protease ATG4C Human genes 0.000 description 1
- 102100027713 Cysteine protease ATG4D Human genes 0.000 description 1
- 101100170601 Drosophila melanogaster Tet gene Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101000753453 Homo sapiens Cysteine protease ATG4C Proteins 0.000 description 1
- 101000936854 Homo sapiens Cysteine protease ATG4D Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000004957 autophagosome Anatomy 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- NKLPQNGYXWVELD-UHFFFAOYSA-M coomassie brilliant blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
- 238000005314 correlation function Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001976 enzyme digestion Methods 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000009465 prokaryotic expression Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General 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)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of substituted nitrogen heterocyclic benzanthrones compound and its applications, have structure shown in formula I.Wherein, R1, R2, R3, R4Substituent group is independently selected from H, halogen ,-CF3、‑CN、‑NO2、‑OH、‑NH2, the substituted or non-substituted substituted or non-substituted aryl of heteroaryl or-L- of the alkyl of-L-C1-C6, the alkenyl of-L-C1-C6 ,-L-, wherein L is key, O, S ,-S (=O) ,-S (=O)2、NH、C(O)、CH2,-NHC (O) O, one of-HC (O) or-C (O) NH or a variety of;X is O, S, Se;Y is-CH2,-NH- ,-O-;Z is-CH2,-NH-;N is 1-18.The compound can effectively block cell autophagy, can be used as autophagy inhibitor;There is preferable inhibitory activity simultaneously, can be applied in preparation tumor.
Description
Technical field
The invention belongs to biomedicine fields.Inhibit the active inhibition of autophagy specifically, having the present invention relates to one kind
Agent and its application.
Background technique
Cell autophagy, which is that eukaryocyte is specific, passes through lysosome to impaired into the cell organelle and long-lived proteins
The cell biological processes that approach is degraded.The weight of cell homeostasis and response environment variation is maintained as eukaryocyte
Approach is wanted, the generation of autophagy and its Level tune participate in the important pathological processes of cell.Autophagy exception and a variety of disease phases
It closes, such as tumour, neurodegenerative disease, cardiovascular disease, autoimmune disease, bacterium and virus infection.At present with hydroxyl
Change the autophagy inhibitor based on chloroquine and enter preclinical phase research successively, targeting autophagy is likely to become the new way of oncotherapy
Diameter.But the action principle for being applied to clinical autophagy inhibitor at this stage mainly inhibits lysosome correlation function, side effect compared with
More, specificity is not high.Therefore, highly selective small molecule autophagy inhibitor is found to be of great significance to oncotherapy.ATG4
Play important role in autophagy process, it can be with digestion precursor LC3 (pro-LC3) for LC3-I, while ATG4 can also be gone
The LC3-II of esterified two types, to make autophagosome and lysosome fusion.There are four family members by ATG4 in mammalian cells:
ATG4A, ATG4B, ATG4C and ATG4D.Wherein, ATG4B is as studying most commonly used member by pass in ATG4 family member
Note.In recent years, many basic research show the growth for inhibiting ATG4B that can inhibit tumour cell.Therefore, by screening Gao Te
Anisotropic ATG4B micromolecular inhibitor inhibits cell autophagy to be of great significance all kinds of oncotherapies.
Summary of the invention
The object of the present invention is to provide aza benzanthrones compound autophagy capable of inhibiting cell.
It is a further object of the present invention to provide above compounds to prepare anti-tumor drug, chronic myelocytic leukemia medicine
Application in object, resisting myocardial fibrillation drug.
The purpose of the present invention is achieved through the following technical solutions:
A kind of substituted nitrogen heterocyclic benzanthrones compound has structure as follows:
Wherein, R1, R2To be monosubstituted, disubstituted or polysubstituted, R3, R4To be monosubstituted, substituent group be independently selected from H, halogen ,-
CF3、-CN、-NO2、-OH、-NH2, the substituted or non-substituted heteroaryl of the alkyl of-L-C1-C6, the alkenyl of-L-C1-C6 ,-L-,
Or the aryl that-L- is substituted or non-substituted, wherein L is key, O, S ,-S (=O) ,-S (=O)2、NH、C(O)、CH2、-NHC(O)O、-
One of HC (O) or-C (O) NH or a variety of, X is O, S, one of Se, and Y is-CH2, one of-NH- ,-O-, Z is-
CH2,-NH-, n 1-18.
Preferably, the R1, R2, R3For hydrogen, X O, Y are-NH-, and Z is-N-, R4For ethyl, it is named as S130, is changed
Learn structural formula are as follows:
The compound is used as autophagy inhibitor.
Application of the compound in preparation tumor.
The compound is applied in preparation treatment colon cancer or uterine neck cancer drug.
The compound is applied in preparation treatment chronic myelocytic leukemia drug.
The compound is applied in preparing resisting myocardial fibrillation drug.
The present invention obtains enzyme ATG4B and ATG4A albumen and the bottom of high-purity by prokaryotic expression and affinity purification technology
Object FRET-GATE16 albumen judges that compound presses down by the method for fluorescence resonance energy transfer and the method for SDS-PAGE
The ability of ATG4 enzyme activity processed.
The method that the present invention also utilizes surface plasma resonance (SPR) is examined by albumen with small molecular phase interaction instrument
Survey the affinity of small molecule compound and ATG4B.
The present invention also provides the related experiments of the cellular level to the compound, have detected cellular level compound to swollen
The growth inhibitory activity of oncocyte.
The present invention observes influence of the compound to nude mice by subcutaneous tumor formation by establishing internal model of nude mice bearing tumor.
Compared with prior art, the present invention has the advantage that
(1) autophagy inhibitor in the present invention can specifically inhibit the activity of autophagy GAP-associated protein GAP ATG4B, effectively hinder
Disconnected cell autophagy.
(2) inhibitor of the present invention is higher than reported inhibitor NSC185058 compound potency.
(3) the azepine benzanthrones compound in the present invention can be used for preparing anti-tumor drug, to colon cancer cell
HCT116 and cervical cancer cell HeLa have preferable inhibitory activity, have a good application prospect.
Detailed description of the invention
Fig. 1 is that compound S130 can inhibit ATG4B to the restriction enzyme digestion and electrophoresis figure of substrate protein FRET-GATE16.
Fig. 2 (a) is to inhibit the IC50 of ATG4B enzymatic activity bent with fluorescence resonance energy transfer method detection compound S130
Line;Fig. 2 (b) is the IC50 curve for inhibiting ATG4A enzymatic activity with fluorescence resonance energy transfer method detection compound S130.
Fig. 3 is the IC50 value of the compound S130 and ATG4B albumen that are measured using the method for surface plasma resonance (SPR)
Figure.
Fig. 4 (a) is inhibiting effect figure of the cellular level compound S130 to HeLa tumor cell survival;Fig. 4 (b) is thin
Inhibiting effect figure of the horizontal compound S130 of born of the same parents to HCT116 tumor cell survival;Fig. 4 (c) is cellular level compound S130
To the inhibiting effect figure of HL60 tumor cell survival.
Fig. 5 (a) is for compound S130 intraperitoneal injection to colon cancer cell HCT116 in model of nude mice bearing tumor after 3 weeks
The inhibiting effect figure of size;Fig. 5 (b) is that compound S130 intraperitoneal injection is thin to colon cancer in model of nude mice bearing tumor after 3 weeks
The inhibiting effect figure of the volume of born of the same parents HCT116.
Fig. 6 is the hydrogen spectrogram of compound S130.
Specific embodiment
Below with reference to specific example, the present invention is further explained.It should be understood that these implementation be merely to illustrate the present invention without
For limiting the scope of the invention.
Embodiment 1: the preparation of compound S130
The preparation method of compound S130, as shown in route (1):
Specifically, the preparation method comprises the steps of:
1) it weighs phenanthrenequione (50mmol), anhydrous second is added in 500mL round-bottomed flask in methoxy semicarbazide hydrochloride (50mmol)
Alcohol 150mL, flow back 4h, is spin-dried for solvent, obtains yellow solid.
2) yellow solid obtained by previous step is dissolved in 200mL toluene, addition diethyl butyn DMAD (2.2eq,
110mmol), 140 DEG C are warming up to, is reacted 8 days.It is cooled to room temperature, 100mL water is added, 50mL ethyl acetate extracts, and shakes, analysis
Yellow particle shape solid out, water phase and organic phase filter together, are washed with Et2O, obtain 6.0g yellow solid.
3) previous step yellow solid is transferred in 500mL round-bottomed flask, MeOH 80mL, H2O160mL is added, weighs
KOH (5eq) is added in above-mentioned solution, is warming up to 140 DEG C, reaction is for 24 hours;After being spin-dried for MeOH, with 2N HCl tune pH=1, generate yellow
Color solid filters filtration cakes torrefaction obtained by (obtained solid easily blocks filter paper) in batches.
4) previous step yellow solid is transferred in 250mL round-bottomed flask, liquid diphenylmethane ether 50mL is added, is warming up to 190
DEG C, 2h is reacted, after being cooled to room temperature, is filtered, ether washing dries to recrystallize after obtaining brown solid using nitrobenzene
5) it weighs hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus PyBoP (1.9eq) and is dissolved in 25mL DMF
In, 65 DEG C are warming up to, by previous step brown solid, after ammonia (2eq) is dissolved in 30mL DMF, slow (30min) is added dropwise to above-mentioned molten
In liquid, after dripping, the reaction was continued 1h.After reaction, after 65 DEG C of water-baths are spin-dried for solvent, DCM is added, saturation NaHCO3 successively extracts
It takes, Na2SO4 is dried, filtered, and is spin-dried for solvent, and column chromatographic analysis purifies (eluent system: DCM:MeOH=20:1).It finally obtains
1.5g yellow solid, as S130.1H NMR (400MHz, DMSO) δ 9.10 (s, 2H), 8.84 (d, J=7.4Hz, 1H), 8.63
(d, J=8.1Hz, 1H), 8.38 (d, J=8.5Hz, 1H), 8.33 (dd, J=7.9,1.2Hz, 1H), 8.06 (s, 1H), 7.92
(s, 1H), 7.70 (s, 1H), 3.50 (dd, J=12.2,6.2Hz, 2H), 3.17 (d, J=6.7Hz, 6H), 2.02-1.92 (m,
2H),1.22(s,6H).
Embodiment 2: the expression and purification of recombinant protein and with SDS-PAGE method detection compound S130 to ATG4B enzymatic activity
Inhibition
By recombinant plasmid FRET-GATE16 (Min Li, Xi Chen, Qi-Zhuang Ye, Andreas Vogt, Xiao-
Ming Yin:A high-throughput FRET-based assay for determination of
Atg4activity.Autophagy 2012,8 (3): 401-12) conversion, will into e. coli bl21 (DE3) CodonPlus
Recombinant plasmid ATG4B, ATG4BC74SWith ATG4A (Li M, Hou Y, Wang J, Chen X, Shao ZM, Yin XM:
Kinetics comparisons of mammalian Atg4homologuesindicate selective
Preferences toward diverse Atg8substrates.J Biol Chem 2011,286:7327-38) it goes to
In BL21 (DE3) PLYSs.LB plate picking monoclonal is inoculated into LB liquid medium, 37 DEG C, 220rpm be incubated overnight, 1:
100 carry out amplification cultivation, and the IPTG that 0.5mM is added when OD600 reaches 0.6-0.8 is induced, and 16 DEG C, receive after 16h culture
Bacterium.Thalline were collected by centrifugation, and wet 5 to 10 times of bacterium weight of combination buffer (20mM Na is added3PO4, 500mM NaCl, 5mM miaow
Azoles) dilute ultrasonication thallus after thallus.Supernatant is collected by centrifugation, is purified using nickel NTA filler, supernatant of bacteria solution, which is added, makes mesh
Albumen hanging column, carry out gradient elution with the imidazole buffer of 20mM and 50mM respectively later, finally eluted with the imidazoles of 200mM
And collect eluent.It is concentrated after the eluent being collected into is crossed desalting column and is saved in -80 DEG C of refrigerators.As shown in Figure 1, by suitable
The ATG4B (3ng) of amount in 37 DEG C of incubation 30min, be added later substrate protein FRET-GATE16 (4 μ g) be incubated for altogether 0min or
The S130 of ATG4B (3ng) and 10 μM is incubated for 30min first altogether, substrate protein is added later by 30min, compound processing group
FRET-GATE16 (4 μ g) coreaction 30min.Terminated and reacted with 5X sample-loading buffer, by albuminous degeneration, using SDS-PAGE into
Row electrophoresis colours band with coomassie brilliant blue staining method after electrophoresis, rear decoloring analyzed.Overall length
FRET-GATE16 almost can be completely CFP-GATE16 and CFP two parts by the ATG4B digestion of 3ng, and the chemical combination with 10 μM
Object S130 is incubated for altogether can inhibit ATG4B to the digestion activity of substrate FRET-GATE16, illustrate S130 pure protein level energy in vitro
Effectively inhibit the enzymatic activity of ATG4B.
Inhibiting effect of the embodiment 3:FRET method detection compound S130 to ATG4B and ATG4A enzymatic activity
The compound and 0.75mgL of prescribed concentration are added in 384 hole blackboards-1ATG4B or 20mgL-1ATG4A
It is incubated for 30min altogether for 37 DEG C in Tris buffer, 50mgL is added later-1FRET-GATE16, reaction total system be 50 μ L,
Reaction time is 30min, and 0.1%DMSO final concentration is contained in the system.The RFUs ratio of 527/477nm is when reacting 30min
Measurement.Calculation formula of the ATG4B with respect to digestion activity are as follows: inhibiting rate (%)=(RFUmax-RFUX)/(RFUmax-RFUmin))*
100%, wherein RFUmaxRefer to the ratio of 527/477nm when endonuclease reaction does not occur, RFUminIt is most thorough to refer to that endonuclease reaction proceeds to
The ratio of the 527/477nm at bottom, RFUXRefer to the ratio of the 527/477nm under specific compound treatment conditions.As shown in Fig. 2,
Using the detection compound S130 is respectively 3.24 μM and 7.11 μM to the IC50 value of ATG4B and ATG4A.
IC50 value of the embodiment 4:SPR method detection compound S130 to ATG4B albumen
Using 50% glycerite initialize GLH chip (Bio-Rad Laboratories), respectively with 0.5%SDS,
50mM NaOH and 100mM HCl from both horizontally and vertically cleaning, reuse PBST (10mM Na3PO4,150mM NaCl,
0.01%Tween 20, pH7.4) buffer solution for cleaning pipeline.Make chip activation using EDAC+NHS, ATG4B protein dissolution is in pH
=3.0 NaAc solution, using the method labelled protein of amino coupled, response is about 1000Ru, is closed using ethanol amine.By one
The compound S130 (0,0.625,1.25,2.5,5 μM) of PBST solution diluted concentration gradient of the series containing 0.1%DMSO, if
Setting binding time is 60s, and Dissociation time 120s obtains a series of reaction signal of gradient concentrations.For above-mentioned gained signal,
It reduces except dynamic behavior fitting related data after lubber line error and blank control, is selected, obtains S130 to the IC50 value of ATG4B
Respectively 4.00 μM (Fig. 3).
Embodiment 5: the measurement of compound S130 inhibition tumor cell activity
The present embodiment detects the vigour changes of cell under various concentration S130 using 3 kinds of tumour cells.By cell inoculation in
In 96 orifice plates, 5000, every hole cell is incubated overnight adherent to cell.It is administered in a manner of changing liquid, various concentration will be contained
The culture medium of S130 is added in 96 orifice plates, and after continuing culture 48 hours, the CCK8 solution of 10 μ L is added.After placing 1-2 hour
It takes out, reads OD value at 450 nm, according to the cell relative viability under various concentration, compound S130 is calculated and inhibits palace
The IC50 value of neck cancer cell (HeLa), the early young grain acute leukemia cells (HL60) of colon cancer cell (HCT116) and people is respectively
16.1 μM, 7.4 μM and 4.7 μM (Fig. 4).
Embodiment 6: compound S130 can inhibit the growth of interior tumor cell
2 × 10 are subcutaneously injected using the Female nude mice of 5 week old6A HCT116 cell establishes model of nude mice bearing tumor.To be injected 2
Zhou Hou, i.e. gross tumor volume are about 50mm3When start grouping administration.Tumor-bearing mice is randomly divided into 4 groups according to gross tumor volume, 1. model
Control group;2. calorie limits (CR) group;S130 3. (20mg/kg) group;Calorie limitation 4.+S130 (20mg/kg) group, every group
6, there was no significant difference for each group tumor size (P > 0.05).Calorie is limited to the heat of normal diet 70%.Drug is used
PBS be completely dissolved after after 0.2 μm of membrane filtration degerming, intraperitoneal injection, once a day, successive administration 4 weeks, be administered volume
For 0.2mL/10g weight.Model control group is to give the physiological saline of equal volume.The gross tumor volume of detection in every 3 days.Using
Vernier caliper reads the length (mm) and width (mm) of mouse tumor, calculates gross tumor volume: Volume (mm3)=length according to following formula
(mm) × wide by 2 (mm)/2.It weighs weekly three times, to adjust administered volume.The general state of mouse after being administered is observed simultaneously.?
The 35th day after injection HCT116 cell, mouse is weighed, and is drawn materials after 3% chloral hydrate anesthesia.As shown in Fig. 5 (a) and (b), S130
Administration group can significantly inhibit the size of tumour and the volume of tumour, and calorie limitation joint S130 administration group can further suppress
The size and volume of tumour.
Claims (7)
1. a kind of substituted nitrogen heterocyclic benzanthrones compound, which is characterized in that have structure as follows:
Wherein, R1, R2To be monosubstituted, disubstituted or polysubstituted, R3, R4To be monosubstituted, R1, R2, R3, R4Substituent group be independently selected from H,
Halogen ,-CF3、-CN、-NO2、-OH、-NH2, substituted or non-substituted miscellaneous of the alkyl of-L-C1-C6, the alkenyl of-L-C1-C6 ,-L-
Aryl or the substituted or non-substituted aryl of-L-, wherein L is key, O, S ,-S (=O) ,-S (=O)2、NH、C(O)、CH2、-NHC
(O) one of O ,-HC (O) or-C (O) NH or a variety of;
X is O, S, one of Se;
Y is-CH2, one of-NH- ,-O-;
Z is-CH2, one of-NH-;
N is the natural number of 1-18.
2. compound according to claim 1, which is characterized in that its chemical structural formula are as follows:
3. the application of compound described in claims 1 or 2, which is characterized in that the compound is used as autophagy inhibitor.
4. application of the compound of any of claims 1 or 2 in preparation tumor.
5. application according to claim 4, which is characterized in that the compound is in preparation treatment colon cancer or cervical carcinoma medicine
It is applied in object.
6. compound as claimed in claim 1 or 2 is applied in preparation treatment chronic myelocytic leukemia drug.
7. compound as claimed in claim 1 or 2 is applied in preparing resisting myocardial fibrillation drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810683695.6A CN109053573A (en) | 2018-06-28 | 2018-06-28 | A kind of substituted nitrogen heterocyclic benzanthrones compound and its application |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810683695.6A CN109053573A (en) | 2018-06-28 | 2018-06-28 | A kind of substituted nitrogen heterocyclic benzanthrones compound and its application |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109053573A true CN109053573A (en) | 2018-12-21 |
Family
ID=64818135
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810683695.6A Pending CN109053573A (en) | 2018-06-28 | 2018-06-28 | A kind of substituted nitrogen heterocyclic benzanthrones compound and its application |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109053573A (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101020659A (en) * | 2007-03-02 | 2007-08-22 | 中山大学 | 9-aminoalkylamido-1-azabenznthrone derivative and its synthesis and application |
CN101564391A (en) * | 2008-04-23 | 2009-10-28 | 上海安普生物科技有限公司 | Usage of oxidized aporphine derivative and composition thereof |
CN103483256A (en) * | 2013-09-23 | 2014-01-01 | 广西师范大学 | (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone as well as synthesis method and application thereof |
CN103497155A (en) * | 2013-09-23 | 2014-01-08 | 广西师范大学 | (+)-4-(2,3-dihydroxypropyl)-formamide-6-azabenzanthrone, and synthetic method and application thereof |
CN103923010A (en) * | 2014-04-15 | 2014-07-16 | 广西师范大学 | 11-replaced oxoisoaporphine derivatives as well as synthetic method and application thereof |
CN103923009A (en) * | 2014-04-15 | 2014-07-16 | 广西师范大学 | 8-substitued oxoisoaporphine derivatives as well as synthetic method and application thereof |
CN106905217A (en) * | 2017-02-09 | 2017-06-30 | 中山大学 | A kind of autophagy key protein ATG4B enzyme inhibitors and its application |
-
2018
- 2018-06-28 CN CN201810683695.6A patent/CN109053573A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101020659A (en) * | 2007-03-02 | 2007-08-22 | 中山大学 | 9-aminoalkylamido-1-azabenznthrone derivative and its synthesis and application |
CN101564391A (en) * | 2008-04-23 | 2009-10-28 | 上海安普生物科技有限公司 | Usage of oxidized aporphine derivative and composition thereof |
CN103483256A (en) * | 2013-09-23 | 2014-01-01 | 广西师范大学 | (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone as well as synthesis method and application thereof |
CN103497155A (en) * | 2013-09-23 | 2014-01-08 | 广西师范大学 | (+)-4-(2,3-dihydroxypropyl)-formamide-6-azabenzanthrone, and synthetic method and application thereof |
CN103923010A (en) * | 2014-04-15 | 2014-07-16 | 广西师范大学 | 11-replaced oxoisoaporphine derivatives as well as synthetic method and application thereof |
CN103923009A (en) * | 2014-04-15 | 2014-07-16 | 广西师范大学 | 8-substitued oxoisoaporphine derivatives as well as synthetic method and application thereof |
CN106905217A (en) * | 2017-02-09 | 2017-06-30 | 中山大学 | A kind of autophagy key protein ATG4B enzyme inhibitors and its application |
Non-Patent Citations (7)
Title |
---|
HUANG TANG ET AL.: "Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
SHENQI WEI ET AL.: "Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase, anti-b-amyloid aggregation and enhanced autophagy activity against Alzheimer’s disease", 《BIOORGANIC & MEDICINAL CHEMISTRY 》 * |
YONG-BIAO WEI ET AL.: "Design, synthesis and anticancer activity of oxoaporphine alkaloid derivatives", 《J ENZYME INHIB MED CHEM》 * |
YONG-BIAO WEI ET AL.: "Design, synthesis and anticancer activity of oxoaporphine alkaloid derivatives", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》 * |
唐煌等: "氧化阿朴菲生物碱衍生物与DNA的相互作用及抗肿瘤活性研究", 《西北药学杂志》 * |
宋云龙等: "DNA拓扑异构酶I结构、功能及喜树碱类抗癌药物研究进展", 《中国药学杂志》 * |
陈协群等: "拓扑异构酶I抑制剂对K562细胞的杀伤与诱导凋亡作用", 《癌症》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107556317B (en) | Imidazole pyrazinamine phenyl derivative and application thereof | |
CN101880290B (en) | Preparation method of cefamandole nafate | |
CN105237564A (en) | 2-carbonyl-3-phenylpropionic acid salicylhydrazone bis(p-methylbenzyl)tin complex and preparation method and application thereof | |
CN106279303B (en) | N-4- benzene sulfonamido-N ' -1- deoxidations-(2- deoxidation -2- substituted-aminos)-β-D- glucopyranosyl thiourea compounds and application thereof | |
CN105384770A (en) | 2-oxo-propionic acid salicyloyl hydrazone and di(p-methylbenzyl)tin complex as well as preparation method and application of 2-oxo-propionic acid salicyloyl hydrazone and di(p-methylbenzyl)tin complex | |
CN111620908A (en) | Diastereoisomer of tenofovir alafenamide, preparation method and application thereof | |
CN113387892A (en) | Imidazole heterocyclic derivative containing nitrogen mustard and preparation method and application thereof | |
CN109053573A (en) | A kind of substituted nitrogen heterocyclic benzanthrones compound and its application | |
CN115477639B (en) | Polysubstituted pyrimidine compound with FGFR1 as target point, and preparation method and application thereof | |
CN103877078B (en) | SENP2 micromolecular inhibitors and its application | |
CN106892859B (en) | Benzo [c, d] indoles -2 (H) -one-polyamines conjugate and its preparation method and application | |
CN107266407B (en) | Photosensitive targeted anti-tumor prodrug capable of killing tumor cells in response to nitroreductase and preparation method and application thereof | |
CN104693123A (en) | 1H-indazole-3-aminobiphenyl compound as well as preparation method and application thereof | |
CN102391193B (en) | 1,2,4-triazole derivative and preparation method and use thereof | |
CN104788410A (en) | Phenyl ring-aromatic ring cascaded compound, and preparation method and medical application thereof | |
CN104961725B (en) | 4-alpha, beta-unsaturated carboxamidoquinoline compounds and preparation and application | |
CN108864109B (en) | Synthesis method and application of amino-containing troger base derivative and binaphthol-troger base amine Schiff base derivative | |
CN105130896B (en) | The naphthalimide derivative of a kind of substituent containing thiocarbamide, its preparation method and application | |
CN113234026B (en) | Compound with B lymphocyte tyrosine kinase inhibitory activity and application thereof | |
CN106496118B (en) | A kind of quinolines enamine ketone compound and preparation method thereof | |
Echeverría et al. | Synthesis and Biological Evaluation of Heteroaryldiamides and Heteroaryldiamines as Cytotoxic Agents, Apoptosis Inducers and Caspase‐3 Activators | |
CN106632322A (en) | Pyrazol purrocoline compound and preparation method and application thereof | |
CN111518078B (en) | Aminopyridine-containing pyrimidine compound and application thereof | |
CN112375023B (en) | Preparation and application of thiosemicarbazone compound | |
CN112194667B (en) | Substituted 1, 4-benzoxazine-diazepine compound and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181221 |