CN109503553A - A kind of light Affinity Probes molecule and preparation method thereof based on VEGFR-2 inhibitor B14 - Google Patents
A kind of light Affinity Probes molecule and preparation method thereof based on VEGFR-2 inhibitor B14 Download PDFInfo
- Publication number
- CN109503553A CN109503553A CN201811481142.9A CN201811481142A CN109503553A CN 109503553 A CN109503553 A CN 109503553A CN 201811481142 A CN201811481142 A CN 201811481142A CN 109503553 A CN109503553 A CN 109503553A
- Authority
- CN
- China
- Prior art keywords
- vegfr
- inhibitor
- photoaffinity
- probe molecule
- phenyl
- 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.)
- Granted
Links
- 239000000523 sample Substances 0.000 title claims abstract description 61
- 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000013067 intermediate product Substances 0.000 claims abstract description 19
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 14
- 238000005516 engineering process Methods 0.000 claims abstract description 14
- VLWNCJPMUMKUMF-UHFFFAOYSA-N 4-(1-hydroxypropyl)benzene-1,2-diol Chemical compound CCC(O)C1=CC=C(O)C(O)=C1 VLWNCJPMUMKUMF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005222 photoaffinity labeling Methods 0.000 claims abstract description 8
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- 150000002763 monocarboxylic acids Chemical class 0.000 claims abstract 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 108090000623 proteins and genes Proteins 0.000 claims description 16
- 102000004169 proteins and genes Human genes 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000004202 carbamide Substances 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 150000003384 small molecules Chemical class 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- ARRHNBAREWBCOU-UHFFFAOYSA-N 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea Chemical compound ClC1=C(C=C(C=C1)NC(=O)NC1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)C(F)(F)F ARRHNBAREWBCOU-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 229940045713 antineoplastic alkylating drug ethylene imines Drugs 0.000 description 13
- 238000012790 confirmation Methods 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 12
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 10
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 10
- -1 aryl azide Chemical class 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000003596 drug target Substances 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 4
- UCFSYHMCKWNKAH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YFTHTJAPODJVSL-UHFFFAOYSA-N 2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(SC=C2)C2=C1 YFTHTJAPODJVSL-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- FRYRJNHMRVINIZ-UHFFFAOYSA-N B1CCOO1 Chemical compound B1CCOO1 FRYRJNHMRVINIZ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000012650 click reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 229940121649 protein inhibitor Drugs 0.000 description 2
- 239000012268 protein inhibitor Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- DGRVQOKCSKDWIH-UHFFFAOYSA-N 1-chloro-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Cl DGRVQOKCSKDWIH-UHFFFAOYSA-N 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- LJSGLEVVMDHAGH-UHFFFAOYSA-N [4-chloro-3-(trifluoromethyl)phenyl]urea Chemical group NC(=O)NC1=CC=C(Cl)C(C(F)(F)F)=C1 LJSGLEVVMDHAGH-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000012455 bioassay technique Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Materials Engineering (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
- Pyridine Compounds (AREA)
Abstract
一种基于VEGFR‑2抑制剂B14光亲和探针分子及其制备方法，4‑溴吡啶‑2‑羧酸与1‑(4‑氯‑3‑(三氟甲基)苯基)‑3‑(4‑(4,4,5,5‑四甲基‑1,3,2‑二氧硼杂环戊烷‑2‑基)苯基)脲进行Suzuki偶联反应，得到带有单羧酸的中间产物；含有光亲和基团双吖丙啶与炔基的链接体与带有单羧酸的中间产物在EDC·HCl的缩合作用下，得到基于VEGFR‑2抑制剂B14的光亲和探针分子。本发明的B14光亲和探针分子制备方法简单，易于实现，并且收率较高。本发明的B14小分子光亲和探针能够用于确证B14的作用靶标以及验证光亲和标记技术在确证小分子靶标方面的可行性。A kind of photoaffinity probe molecule based on VEGFR-2 inhibitor B14 and preparation method thereof, 4-bromopyridine-2-carboxylic acid and 1-(4-chloro-3-(trifluoromethyl)phenyl)-3 ‑(4‑(4,4,5,5‑tetramethyl‑1,3,2‑dioxaborolane‑2‑yl)phenyl)urea was subjected to Suzuki coupling reaction to obtain a Intermediate product of acid; linker containing photoaffinity group bis-aziridine and alkynyl group and intermediate product with monocarboxylic acid under the condensation of EDC·HCl to obtain photoaffinity based on VEGFR-2 inhibitor B14 and probe molecules. The preparation method of the B14 photoaffinity probe molecule of the present invention is simple, easy to realize, and has a high yield. The B14 small molecule photoaffinity probe of the present invention can be used to confirm the action target of B14 and to verify the feasibility of the photoaffinity labeling technology in confirming the small molecule target.
Description
Technical field
The present invention relates to a kind of light Affinity Probes molecule and preparation method thereof based on VEGFR-2 inhibitor B14.
Background technique
Photoaffinity labeling technology (PAL) is to combine modern molecular biology, cell biology, pharmaceutical chemistry, analytical chemistry
Etc. multi-disciplinary advantage, with the photoaffinity probe molecule of synthesis, the centre of high activity is generated under the irradiation of special wavelength light
Body directly can carry out irreversible covalent cross-linking with the protein of drug molecule specific binding to realize to drug targets
The capture of protein molecular.It is research one of ligand and the core tool of acceptor interaction on molecular level, to illustrating ligand
Discovery with acceptor interaction mechanism and drug novel targets suffers from huge impetus.
This technology was mainly used in the confirmation of molecular drug target albumen in recent years, was based primarily upon photo-crosslinking skill
Art, bio-orthogonal technology and relevant bioassay technique etc. realize the capture and its confirmation of molecular drug target.Wherein light
The design synthesis of affinity probe molecule is that structural modification is directly carried out on the basis of not influencing target head pharmaceutical activity, is introduced respectively
Light reaction group and bio-orthogonal handle design synthesize photoaffinity probe molecule, special under the irradiation of special wavelength light
The target proteins of anisotropic irreversible covalent capture target head compound.Next it is captured by bio-orthogonal reaction to realize
Target proteins identification confirmation.
Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor) be by
The memebrane protein of VEGF gene expression belongs to tyrosine family protein, is the high molecular weight protein closely related with malignant tumour.Blood vessel
Endothelial growth factors and its receptor have overexpression in a series of tumour cells, and this receptor family includes three hypotypes:
VEGFR-1,VEGFR-2,VEGFR-3.Wherein VEGFR-2 is primarily involved in the proliferation of vascular endothelial cell, is distributed in cancer cell
Also most extensively.A series of research confirms that it can be used as effective drug targets.
Since nearly 5 years, the optical active group reported in document has aryl azide, benzophenone, double a word used for translations containing substituent group
Third pyridine, double ethylene imines this four major class.Wherein, the preferably double ethylene imines of photo-crosslinking activity.It is therefore desirable to select double ethylene imines
Synthesis photoaffinity probe molecule is designed as optical active group.
Summary of the invention
The purpose of the present invention is to provide a kind of light Affinity Probes molecule based on VEGFR-2 inhibitor B14 and its preparations
Method, B14 photoaffinity probe molecule are used to confirm the target proteins of B14 and the binding mode of itself and target proteins, and can
For verifying feasibility of the photoaffinity labeling technology in terms of target proteins confirmation.
In order to achieve the above objectives, the invention adopts the following technical scheme:
One kind being based on VEGFR-2 inhibitor B14 photoaffinity probe molecule, and structural formula is as follows:
Wherein X is O or NH.
A kind of preparation method based on VEGFR-2 inhibitor B14 photoaffinity probe molecule, which is characterized in that including following
Step:
1) 4- bromopyridine -2- carboxylic acid and 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- (tetramethyl -1 4,4,5,5-,
3,2- dioxaborolane -2- bases) phenyl) urea progress Suzuki coupling reaction, obtain the intermediate product with monocarboxylic acid；
2) the chain junctor containing the double ethylene imines of light affinity groups and alkynyl is with the intermediate product with monocarboxylic acid in EDC
Under the condensation of HCl, the photoaffinity probe molecule based on VEGFR-2 inhibitor B14 is obtained, structural formula is as follows:
Wherein X=O or NH.
A further improvement of the present invention lies in that the detailed process of the step 1) are as follows: by 4- bromopyridine -2- carboxylic acid, 1- (4-
Chloro- 3- (trifluoromethyl) phenyl) -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) urea,
Cesium carbonate and tetrakis triphenylphosphine palladium are dissolved in the mixed solution of acetonitrile and water, N2It protects, is handled after 100 DEG C of reaction 16h,
Obtain the intermediate product with monocarboxylic acid.
A further improvement of the present invention lies in that by 4- bromopyridine -2- carboxylic acid 4.95mmol, 1- (chloro- 3- of 4- (trifluoromethyl)
Phenyl) -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) urea 5.94mmol, cesium carbonate
9.90mmol and tetrakis triphenylphosphine palladium 0.25mmol is dissolved in the mixed solution 50mL of acetonitrile and water, N2Protection, 100 DEG C of reactions
It is handled after 16h, obtains the intermediate product with monocarboxylic acid.
A further improvement of the present invention lies in that the volume ratio of acetonitrile and water is 4:1 in the mixed solution of acetonitrile and water.
A further improvement of the present invention lies in that the detailed process of the step 2) are as follows: have single carboxylic for what step 1) obtained
The intermediate product of acid is dissolved in anhydrous tetrahydrofuran solution, and EDCHCl, HOBt is added, DIPEA is then added dropwise, at 0 DEG C
The chain junctor containing light affinity groups double ethylene imines and alkynyl is added after stirring 1h, after stirring for 24 hours at room temperature, is handled, is obtained
To the photoaffinity probe molecule based on VEGFR-2 inhibitor B14.
A further improvement of the present invention lies in that the intermediate product 0.145mmol with monocarboxylic acid is dissolved in the anhydrous tetrahydro of 3mL
In tetrahydrofuran solution, add EDCHCl 0.218mmol, stir evenly at 0 DEG C of HOBt 0.174mmol, is then added dropwise
DIPEA0.725mmol stirs 1h, and the chain junctor 0.145mmol containing light affinity groups double ethylene imines and alkynyl, room temperature is added
Stirring for 24 hours, is obtained based on VEGFR-2 inhibitor B14 photoaffinity probe molecule.
It is a kind of based on VEGFR-2 inhibitor B14 photoaffinity probe molecule photoaffinity labeling technical aspect application.
A further improvement of the present invention lies in that based on VEGFR-2 inhibitor B14 photoaffinity probe molecule in confirmation protein targets
Mark the application of aspect.
Compared with prior art, the invention has the following advantages:
By the present invention in that with the chain junctor simultaneously containing light affinity groups double ethylene imines and alkynyl, by itself and VEGFR-2
Protein inhibitor B14 connection obtains B14 photoaffinity probe molecule.The photoaffinity probe molecule is capable of the irreversible total of specificity
The target proteins molecule of valence combination B14, bio-orthogonal handle in following probe molecule with contain fluorescein or biotin
Another bio-orthogonal handle carry out click-reaction to confirm target proteins.B14 photoaffinity probe molecule preparation side of the invention
Method is simple, it is easy to accomplish, and yield is higher.
B14 photoaffinity probe molecule in the present invention can carry out specific covalent combination, Jin Ertong to VEGFR-2 albumen
Click-reaction is crossed to realize to the next confirmatory analysis of the target proteins of capture.It is realized using photoaffinity labeling technology to drug
The confirmation of action target albumen and some shortcomings that original confirmation target technology can be improved.In original target confirmation technology
Probe molecule cannot be stable combination drug targets molecule, be easy to cause false positive results.And original technology usually requires
Large volume of fluorophor is connected on drug molecule to be analyzed, this will lead to the reduction of probe molecule activity, solubility
Difference, the disadvantages of cell permeability is poor.And photoaffinity labeling technology is by synthesized micromolecule photoaffinity probe combination bio-orthogonal
Technology carries out target confirmation, compensates for the deficiency of original technology.B14 small molecule photoaffinity probe of the invention can be used in really
Demonstrate,prove the feasibility of the action target and verifying photoaffinity labeling technology of B14 in terms of confirming small molecule target.
Detailed description of the invention
Fig. 1 is the synthetic route chart provided by the invention based on VEGFR-2 inhibitor B14 photoaffinity probe molecule；
Wherein, compound 1 is 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- (4,4,5,5- tetramethyls -1,3,2- bis-
Oxygen boron heterocycle pentane -2- base) phenyl) urea, compound 2 is 4- bromopyridine -2- carboxylic acid, and compound 3 is 4- (4- (3- (the chloro- 3- of 4-
(trifluoromethyl) phenyl) urea groups) phenyl) pyridine carboxylic acid (B14), compound 4 is containing the double ethylene imines of light affinity groups and alkynyl
Chain junctor, compound (X) be B14 photoaffinity probe molecule.
It is marked in figure specifically:
a.CsCO3,Pd[P(C6H5)3]4,Acetonitrile,N2,80℃；b.EDC·HCl,HOBt,DIPEA,THF,
rt。
Specific embodiment
The present invention is described in further detail with specific embodiment with reference to the accompanying drawing, and described is to of the invention
It explains rather than limits.
By the present invention in that with the chain junctor containing the double ethylene imines of light affinity groups and alkynyl by VEGFR-2 protein inhibitor
Connection obtains photoaffinity probe molecule.Photoaffinity probe molecule of the present invention can be used in confirming the target proteins of B14.
The structural formula of chain junctor containing the double ethylene imines of light affinity groups and alkynyl in the present invention are as follows:Wherein, X is O or NH.
The chemical structural formula of the photoaffinity probe molecule with confirmation molecular drug target provided by the invention is specific as follows:
Wherein, X is O or NH.
Photoaffinity probe molecule of the present invention with the effect of target confirmation, comprising:
2- (the double ethylene imine -3- bases of 3- (butyl- 3- alkynes -1- base) -3H-) ethyl 4- (4- (3- (4- chloro- 3- (trifluoromethyl) benzene
Base) urea groups) phenyl) pyridine carboxylic acid.
N- (2- (the double ethylene imine -3- bases of 3- (butyl- 3- alkynes -1- base) -3H-) ethyl) -4- (4- (3- (chloro- 3- (fluoroform of 4-
Base) phenyl) urea groups) phenyl) picolinamide.
Carry out the tool that the present invention will be described in detail provides below with reference to synthetic route shown in Fig. 1 and specific synthetic example
The preparation for the photoaffinity probe molecule for thering is target confirmation to act on and method for screening active ingredients.
Referring to Fig. 1, a kind of preparation method based on VEGFR-2 inhibitor B14 photoaffinity probe molecule, including following step
It is rapid:
1) 4- bromopyridine -2- carboxylic acid and 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- (tetramethyl -1 4,4,5,5-,
3,2- dioxaborolane -2- bases) phenyl) urea progress Suzuki coupling reaction, obtain the intermediate product with monocarboxylic acid；
The concrete operations of the step 1) are as follows: by 4- bromopyridine -2- carboxylic acid, 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3-
(4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) phenyl) urea, cesium carbonate and tetrakis triphenylphosphine palladium are molten
In the mixed solution (volume ratio of acetonitrile and water is 4:1) of acetonitrile and water, N2Protection, 100 DEG C of reaction 16h.After reaction,
It filters, rotation is added appropriate ethyl acetate and water extracts except filtrate, merging organic phase, saturated common salt water washing, and anhydrous sodium sulfate is dry
It is dry, the intermediate product with monocarboxylic acid is obtained after pillar layer separation.
2) by the intermediate product with monocarboxylic acid and the chain junctor containing the double ethylene imines of light affinity groups and alkynyl in EDC
HCl is to obtain the compound that logical formula (X) indicates under the condensation of condensing agent；
The concrete operations of the step 2) are as follows: the intermediate product with monocarboxylic acid for obtaining step 1), EDCHCl,
HOBT is dissolved in anhydrous THF, and DIPEA is added dropwise under ice bath, stirs 1h, is added containing the double ethylene imines of light affinity groups and alkynyl
Chain junctor, stir at room temperature for 24 hours, after reaction, decompression rotation remove solvent, washed respectively after appropriate ethyl acetate is added
It washs, saturated sodium bicarbonate washing, saturated common salt water washing merges organic phase, and anhydrous sodium sulfate is dry, and pillar layer separation obtains
Lead to the compound that formula (X) indicates based on VEGFR-2 inhibitor B14 photoaffinity probe.
It is above-mentioned to be swollen in preparation by the anti-of target spot of VEGFR-2 kinases based on VEGFR-2 inhibitor B14 photoaffinity probe molecule
Application in tumor medicine.
Embodiment 1
In the structural formula of the B14 photoaffinity probe molecule with target confirmation effect, X is O or NH, passes through following steps
It prepares (referring to Fig. 1):
4- bromopyridine -2- carboxylic acid and 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- (tetramethyl -1,3 4,4,5,5-,
2- dioxaborolane -2- base) phenyl) urea progress Suzuki coupling reaction, obtain the intermediate product with monocarboxylic acid；Specifically
Process is as follows:
By 4- bromopyridine -2- carboxylic acid, 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- (tetramethyl -1,3 4,4,5,5-,
2- dioxaborolane -2- base) phenyl) urea, cesium carbonate and tetrakis triphenylphosphine palladium be dissolved in the mixed solution (second of acetonitrile and water
The volume ratio of nitrile and water is 4:1) in, N2Protection, 100 DEG C of reaction 16h.After reaction, it filters, rotation removes filtrate, is added appropriate
Ethyl acetate and water extraction merge organic phase, and saturated common salt water washing, anhydrous sodium sulfate is dry, and pillar layer separation uses dichloro
Methane/methanol (V/V=10/1) affords target compound, weight 0.36g, and yield 17% obtains the intermediate production with monocarboxylic acid
Object.
LC-MS(ESI,m/z):436.79[M+H]+, 434.79 [M-H]-
(probe molecule I, X=O)；Detailed process is as follows:
Intermediate product 4- (4- (3- (4- chloro- 3- (trifluoromethyl) phenyl) urea groups) phenyl) pyridine first of monocarboxylic acid will be had
Sour (0.063g, 0.145mmol) is dissolved in 3mL anhydrous tetrahydrofuran solution, add EDCHCl (0.04g, 0.218mmol),
HOBT (0.024g, 0.174mmol) is stirred evenly at 0 DEG C, is then added dropwise DIPEA (0.094g .725mmol), stirring
1h is added the chain junctor (0.02g, 0.145mmol) containing light affinity groups double ethylene imines and alkynyl, is stirred at room temperature for 24 hours, reaction
After, decompression rotation removes solvent, is added after appropriate ethyl acetate and carries out water washing, saturated sodium bicarbonate washing, saturation food respectively
Salt water washing merges organic phase, and anhydrous sodium sulfate is dry, and pillar layer separation is washed using petrol ether/ethyl acetate (V/V=1/1)
It is de- to obtain target compound, weight 0.03g, yield 41.66%.It obtains based on VEGFR-2 inhibitor B14 photoaffinity probe general formula
(X) compound indicated.
The structure of gained target compound is as follows:
Hydrogen composes nuclear magnetic resonance data are as follows:1H NMR(400MHz,DMSO-D6)δ9.28(s,1H),δ9.17(s,1H),δ
8.75-8.76(D,1H),δ8.34-8.35(d,1H),δ8.14(d,1H),δ7.97-7,99(d,1H),δ7.85-7.87(d,
2H),δ7.65-7.68(m,4H),δ4.23-4.27(t,2H),δ2.83-2.84(t,1H),δ2.05-2.09(m,2H),δ
1.91-1.94(t,2H),δ1.69-1.73(t,2H).
LC-MS(ESI,m/z):556.94[M+H]+。
Embodiment 2
In the structural formula of photoaffinity probe molecule II, X NH.
Synthesis step is the same as embodiment 1
The structure of gained target-probe molecule II is as follows:
Hydrogen composes nuclear magnetic resonance data are as follows:1H NMR(400MHz,DMSO-D6)δ9.28(s,1H),δ9.17(s,1H),δ
8.88-8.91(t,1H),δ8.66-8.68(d,1H),δ8.27-8.28(d,1H),δ8.14(d,1H),δ7.91-7,92(q,
1H),δ7.86-7.84(d,2H),δ7.65-7.67(m,4H),δ3.22-3.27(q,2H),δ2.85-2.86(t,1H),δ
2.01-2.06(m,2H),δ1.68-1.71(t,2H),δ1.62-1.66(t,2H).
LC-MS(ESI,m/z):555.96[M+H]+。
Embodiment 3
B14 photoaffinity probe molecule screens the inhibitory activity of VEGFR-2 kinases.
Using ADP-Glo luminescent method measurement B14 photoaffinity probe molecule to the inhibitory activity of VEGFR-2 kinases.
With Buffer (Tris 80mM, MgCl220mM, BSA 0.2mg/mL, DTT 2mM) dilution ATP (10mM) be 250
μM；ATP and substrate Poly (4:1Glu, Tyr) Peptide is made into ATP (125 μM)-Poly (4:1Glu, Tyr) by volume 1:1
Peptide (0.5 μ g/ μ L) mixed solution；It is 1.5ng/ μ L with Buffer dilution kinases.Untested compound is made into 6 concentration
The solution of gradient, in sequentially adding on 384 orifice plates, 2 μ L ATP-Poly (4:1Glu, Tyr) Peptide solution, 1 μ L sample are molten
Liquid, the starting reaction of 2 μ L enzyme solutions.After 30 DEG C of incubation 60min, 5 μ L of ADP-Glo reagent is added and terminates reaction.Add Kinase
ADP is converted ATP by 10 μ L of Detection reagent, in 25 DEG C of incubation 30min, uses PerkinElmer multi-function microplate reader
Chemiluminescence module measures luminous value, calculates inhibiting rate.
Numerical value processing: inhibiting rate=(positive value-administration class value)/(positive value-feminine gender value) × 100%；
The experimental result of compound is shown in Table 1:
Inhibitory activity result of the table 1B14 photoaffinity probe molecule to VEGFR-2 kinases
As it can be seen from table 1 B14 photoaffinity probe molecule prepared by the present invention has preferable suppression to VEGFR-2 kinases
System activity.
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811481142.9A CN109503553B (en) | 2018-12-05 | 2018-12-05 | Light affinity probe molecule based on VEGFR-2 inhibitor B14 and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811481142.9A CN109503553B (en) | 2018-12-05 | 2018-12-05 | Light affinity probe molecule based on VEGFR-2 inhibitor B14 and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109503553A true CN109503553A (en) | 2019-03-22 |
| CN109503553B CN109503553B (en) | 2020-08-28 |
Family
ID=65752573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811481142.9A Expired - Fee Related CN109503553B (en) | 2018-12-05 | 2018-12-05 | Light affinity probe molecule based on VEGFR-2 inhibitor B14 and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109503553B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407749A (en) * | 2019-08-30 | 2019-11-05 | 西安交通大学 | A photoaffinity linker containing disulfide bond and its preparation method and application |
| CN113061126A (en) * | 2021-03-16 | 2021-07-02 | 无锡海伦生物科技有限公司 | Preparation method and application of sorafenib photoaffinity probe molecule based on halogen intermediate |
| CN114685463A (en) * | 2021-07-01 | 2022-07-01 | 上海交通大学 | Isorhamnetin photoaffinity probe and synthetic method and application thereof |
| CN115677583A (en) * | 2022-10-31 | 2023-02-03 | 南京科络思生物科技有限公司 | Phenylhydrazine-based natural product photoaffinity probe reactant, and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532197A (en) * | 2010-12-24 | 2012-07-04 | 中国科学院上海药物研究所 | First glass photoaffinity labeling difunctional probe molecule and preparation method and application thereof |
| CN104817493A (en) * | 2015-03-11 | 2015-08-05 | 西安交通大学 | Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof |
-
2018
- 2018-12-05 CN CN201811481142.9A patent/CN109503553B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532197A (en) * | 2010-12-24 | 2012-07-04 | 中国科学院上海药物研究所 | First glass photoaffinity labeling difunctional probe molecule and preparation method and application thereof |
| CN104817493A (en) * | 2015-03-11 | 2015-08-05 | 西安交通大学 | Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ZHENGQIU LI等: "Design and Synthesis of Minimalist Terminal Alkyne-Containing Diazirine Photo-Crosslinkers and Their Incorporation into Kinase Inhibitors for Cell- and Tissue-Based Proteome Profiling", 《ANGEW. CHEM. INT. ED.》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407749A (en) * | 2019-08-30 | 2019-11-05 | 西安交通大学 | A photoaffinity linker containing disulfide bond and its preparation method and application |
| CN110407749B (en) * | 2019-08-30 | 2021-01-19 | 西安交通大学 | Photoaffinity linker containing disulfide bond, preparation method and application thereof |
| CN113061126A (en) * | 2021-03-16 | 2021-07-02 | 无锡海伦生物科技有限公司 | Preparation method and application of sorafenib photoaffinity probe molecule based on halogen intermediate |
| CN114685463A (en) * | 2021-07-01 | 2022-07-01 | 上海交通大学 | Isorhamnetin photoaffinity probe and synthetic method and application thereof |
| CN114685463B (en) * | 2021-07-01 | 2024-05-28 | 上海交通大学 | Isorhamnetin photoaffinity probe and its synthesis method and application |
| CN115677583A (en) * | 2022-10-31 | 2023-02-03 | 南京科络思生物科技有限公司 | Phenylhydrazine-based natural product photoaffinity probe reactant, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109503553B (en) | 2020-08-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109503553A (en) | A kind of light Affinity Probes molecule and preparation method thereof based on VEGFR-2 inhibitor B14 | |
| Ehmke et al. | Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure–Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X‐ray Crystal Structure Analysis with Human Cathepsin L | |
| Huang et al. | Validation of phosphodiesterase-10 as a novel target for pulmonary arterial hypertension via highly selective and subnanomolar inhibitors | |
| CN109369622A (en) | A kind of photoaffinity probe molecule based on VEGFR-2 inhibitor BD7 and preparation method thereof | |
| CN109456261A (en) | A kind of light Affinity Probes molecule and preparation method thereof based on VEGFR-2 inhibitor Sorafenib | |
| CN106543145B (en) | c-Met kinase inhibitor 3-(4-fluorophenyl)pyrimidinone-5-carboxylic acid amide derivatives, preparation method and application | |
| Nazir et al. | Novel indole based hybrid oxadiazole scaffolds with N-(substituted-phenyl) butanamides: synthesis, lineweaver–burk plot evaluation and binding analysis of potent urease inhibitors | |
| CN101928294B (en) | Nitrogen heterocyclic carbene silver complex on premise of substituted benzimidazole salt and application thereof | |
| CN113480558A (en) | Androgen receptor small-molecule fluorescent probe and preparation method and application thereof | |
| CN114133390A (en) | A kind of dehydrocamelin derivative and its preparation method and application | |
| CN111019644B (en) | Rapid quantitative detection of tumor hypoxia related enzyme by using cofactor-substrate probe platform | |
| CN104744350A (en) | A kind of pyridine substituted diaryl urea compound and its preparation method and application | |
| CN113149962A (en) | Preparation method and application of probe molecule containing photoaffinity group bisaziridine | |
| WO2021023193A1 (en) | Pyrazine-2(1h)-ketone compound preparation method | |
| CN114349703B (en) | Trifluoromethyl-4-cyano pyrazole compound, and preparation method and application thereof | |
| CN114560819B (en) | Substituted triazine compound, preparation method thereof and application thereof in amino acid, peptide, protein and cell marker | |
| CN105924385A (en) | Diarylthiourea compound with antitumor activity, and preparation method and application thereof | |
| CN113583018A (en) | Curcumin derivative connected with biotin and preparation method and application thereof | |
| CN114957136A (en) | Anti-tumor compound used as VEGFR inhibitor and application thereof | |
| CN110256465B (en) | A kind of 2,4-diaminopyrimidine containing dihydropyranothiazole and application thereof | |
| CN109485695A (en) | A kind of protein degradation targeting chimera and preparation method and application based on VEGFR-2 inhibitor S7 | |
| CN116640123B (en) | Bifunctional molecule compound for inducing degradation of HK2 protein and synthesis and application thereof | |
| CN111848657B (en) | Reversible fluorescent compounds recognized by targeting tyrosine kinases, preparation methods and applications thereof | |
| CN104817489B (en) | A kind of heterocyclic biphenyl aryl urea compound with antitumor activity and its preparation method and application | |
| CN114835640A (en) | Fibroblast growth factor receptor inhibitor, preparation method and application |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210208 Address after: 442000 No. 32 Renmin South Road, Hubei, Shiyan Patentee after: SHIYAN TAIHE Hospital Address before: Beilin District Xianning West Road 710049, Shaanxi city of Xi'an province No. 28 Patentee before: XI'AN JIAOTONG University |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200828 Termination date: 20211205 |