CN115057827A - Deferasirox derivative, synthesis method thereof and application thereof in preparation of medicines for diagnosing and treating iron-overload hepatocellular carcinoma - Google Patents
Deferasirox derivative, synthesis method thereof and application thereof in preparation of medicines for diagnosing and treating iron-overload hepatocellular carcinoma Download PDFInfo
- Publication number
- CN115057827A CN115057827A CN202210853705.2A CN202210853705A CN115057827A CN 115057827 A CN115057827 A CN 115057827A CN 202210853705 A CN202210853705 A CN 202210853705A CN 115057827 A CN115057827 A CN 115057827A
- Authority
- CN
- China
- Prior art keywords
- exph
- deferasirox
- cnac
- derivative
- derivative according
- 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
- FMSOAWSKCWYLBB-VBGLAJCLSA-N deferasirox Chemical class C1=CC(C(=O)O)=CC=C1N(N\C(N\1)=C\2C(C=CC=C/2)=O)C/1=C\1C(=O)C=CC=C/1 FMSOAWSKCWYLBB-VBGLAJCLSA-N 0.000 title claims abstract description 25
- 206010073071 hepatocellular carcinoma Diseases 0.000 title claims description 21
- 231100000844 hepatocellular carcinoma Toxicity 0.000 title claims description 21
- 206010065973 Iron Overload Diseases 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 12
- 238000001308 synthesis method Methods 0.000 title claims description 8
- 239000003814 drug Substances 0.000 title claims description 7
- 229940079593 drug Drugs 0.000 title description 3
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 238000003745 diagnosis Methods 0.000 claims abstract description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- -1 2-hydroxyphenyl Chemical group 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 7
- 229960004889 salicylic acid Drugs 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 6
- NRESDXFFSNBDGP-UHFFFAOYSA-N (4-bromophenyl)hydrazine Chemical compound NNC1=CC=C(Br)C=C1 NRESDXFFSNBDGP-UHFFFAOYSA-N 0.000 claims description 5
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 claims description 5
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229960000581 salicylamide Drugs 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- TZBHPYXJOJGKDT-UHFFFAOYSA-N 1,3-oxazin-4-one Chemical compound O=C1C=COC=N1 TZBHPYXJOJGKDT-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- NSWIROGSZPXREF-UHFFFAOYSA-N 2-(2-hydroxyphenyl)-1,3-benzoxazin-4-one Chemical compound OC1=CC=CC=C1C1=NC(=O)C2=CC=CC=C2O1 NSWIROGSZPXREF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 4
- 239000000523 sample Substances 0.000 abstract description 22
- 102000013392 Carboxylesterase Human genes 0.000 abstract description 21
- 108010051152 Carboxylesterase Proteins 0.000 abstract description 21
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 abstract description 14
- 241000252212 Danio rerio Species 0.000 abstract description 10
- 239000007850 fluorescent dye Substances 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 201000011510 cancer Diseases 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 5
- 238000013459 approach Methods 0.000 abstract description 2
- 238000011503 in vivo imaging Methods 0.000 abstract description 2
- 230000009919 sequestration Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 18
- 229910052742 iron Inorganic materials 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000007853 buffer solution Substances 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- MHSVUSZEHNVFKW-UHFFFAOYSA-N bis-4-nitrophenyl phosphate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1OP(=O)(O)OC1=CC=C([N+]([O-])=O)C=C1 MHSVUSZEHNVFKW-UHFFFAOYSA-N 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 230000009702 cancer cell proliferation Effects 0.000 description 3
- 239000013522 chelant Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000000799 fluorescence microscopy Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- XJOTXKZIRSHZQV-RXHOOSIZSA-N (3S)-3-amino-4-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S,3S)-1-[[(1R,6R,12R,17R,20S,23S,26R,31R,34R,39R,42S,45S,48S,51S,59S)-51-(4-aminobutyl)-31-[[(2S)-6-amino-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]-20-benzyl-23-[(2S)-butan-2-yl]-45-(3-carbamimidamidopropyl)-48-(hydroxymethyl)-42-(1H-imidazol-4-ylmethyl)-59-(2-methylsulfanylethyl)-7,10,19,22,25,33,40,43,46,49,52,54,57,60,63,64-hexadecaoxo-3,4,14,15,28,29,36,37-octathia-8,11,18,21,24,32,41,44,47,50,53,55,58,61,62,65-hexadecazatetracyclo[32.19.8.26,17.212,39]pentahexacontan-26-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)[C@@H](C)O)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@@H]4CSSC[C@H](NC(=O)[C@H](Cc5ccccc5)NC(=O)[C@@H](NC1=O)[C@@H](C)CC)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1cnc[nH]1)NC3=O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N2)C(=O)NCC(=O)N4)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XJOTXKZIRSHZQV-RXHOOSIZSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000009920 chelation Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229960001489 deferasirox Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 102000018511 hepcidin Human genes 0.000 description 2
- 229940066919 hepcidin Drugs 0.000 description 2
- 108060003558 hepcidin Proteins 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241001100935 Ilex purpurea Species 0.000 description 1
- 235000003366 Ilex purpurea Nutrition 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
- C09K2211/1059—Heterocyclic compounds characterised by ligands containing three nitrogen atoms as heteroatoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a deferasirox derivative ExPh 2 ‑CNAc 2 The structural formula is shown as follows:
. The deferasirox derivative is a fluorescent probe. Experiments carried out in cells and zebra fish of different growth stages prove that the deferasirox derivative ExPh of the invention 2 ‑CNAc 2 The carboxylesterase of (a) detects, images and sequesters excess fe (iii). Probe ExPh 2 ‑CNAc 2 This superior in vivo imaging and sequestration properties may be iron-overloaded hepatocytesEarly diagnosis and treatment of cancer patients provide new approaches.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a deferasirox derivative, a synthesis method thereof and application thereof in preparation of a medicine for diagnosing and treating iron-overload hepatocellular carcinoma.
Background
Iron is an essential element for promoting cell proliferation and growth, and its balance in the body is crucial. Under normal conditions, iron is taken in by diet and can only be removed by very limited mucosal cell shedding or other modes of blood loss. Because humans lack the proper physiological mechanisms to eliminate iron, excessive iron-induced production of hepcidin only limits iron absorption in the duodenum. Infection, inflammation and alcohol can affect hepcidin expression, resulting in excess iron in the liver. Meanwhile, the excessive free iron with redox activity catalyzes the generation of hydroxide anions and hydroxide radicals, increases the generation of active oxygen of cells, destroys cells and macromolecular components of cellular DNA, and thereby induces hepatocellular carcinoma. On the other hand, excessive iron provides nutrition for cancer cell proliferation and promotes cancer cell growth making the process of cancer cell proliferation much more uncontrolled in hepatocellular carcinoma patients with iron overload. Therefore, treatment of hepatocellular carcinoma patients with iron overload must fundamentally solve the problem of iron overload.
Some fluorescent probes developed for hepatocellular carcinoma have been used for chemotherapy and surgery for hepatocellular carcinoma, but iron overload, a large amount of iron accumulated in the human body, easily causes rapid spread of cancer and requires other additional treatments, thus fundamentally eliminating the effect of the excess iron. Iron chelators have also been found to be a potential primary or adjuvant treatment for cancer, and they can successfully reduce cancer cell proliferation by removing excess iron from the body in a non-invasive manner. The deferasirox designed by Nowa company is a tridentate ligand based on a triazole platform, has good selectivity on iron, and has poor affinity on trace elements such as zinc, copper and the like. It is orally active and produces 2:1 compounds with Fe (III). The research shows that: deferasirox has excellent antibacterial and chemotherapeutic activity.
In view of the above, the introduction group of the invention discovers a deferasirox derivative with novel fluorescence characteristic, and designs a fluorescent probe for combining early diagnosis and treatment of targeted iron-overload hepatocellular carcinoma patients.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a deferasirox derivative, a synthesis method thereof and application thereof in preparing a medicine for diagnosing and treating iron-overload hepatocellular carcinoma.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a deferasirox derivative, the structural formula of which is shown as follows, wherein the deferasirox derivative is a fluorescent probe and is marked as follows: ExPh 2 -CNAc 2 。
The above deferasirox derivative (i.e., fluorescent probe ExPh) 2 -CNAc 2 ) The synthesis method comprises the following steps:
1) mixing thionyl chloride and salicylic acid in toluene, adding a small amount of catalyst pyridine, heating and stirring at 45-55 ℃ for 1-1.5H, cooling to room temperature, adding thionyl chloride and salicylamide, heating and refluxing for 2-3H, cooling to room temperature, evaporating under reduced pressure to remove a solvent, recrystallizing with absolute ethyl alcohol, filtering, and drying to obtain yellow solid 2- (2-hydroxyphenyl) -4 Hbenzo [ e ] [1,3] oxazine-4-one;
2) mixing p-bromophenylhydrazine and 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazine-4-ketone in ether, heating and refluxing for 12-14H, cooling to room temperature, evaporating the solvent under reduced pressure, and purifying the residue by silica gel column chromatography to obtain yellow solid ExPh-Br;
3) dissolving ExPh-Br and 4-cyanophenylboronic acid in ethanol, adding potassium carbonate solution to adjust pH to 8-12, adding catalyst tetrakis (triphenylphosphine) palladium under nitrogen atmosphere, heating and refluxing for 8-12h, cooling the obtained mixture to room temperature, distilling under reduced pressure to remove solvent, and purifying by silica gel column chromatography to obtain white powder ExPh 2 -CN；
4) Mixing ExPh 2 dissolving-CN and acetyl chloride in dichloromethane, adding a small amount of acid-binding agent triethylamine, stirring at room temperature for reaction for 24-36h, evaporating the obtained mixture, and purifying the residue by silica gel column chromatography to obtain white solid ExPh 2 -CNAc 2 。
Specifically, in the step 1), the molar ratio of (1-1.2): 1 mixing thionyl chloride and salicylic acid in toluene; according to the mol ratio of 1-1.5: 1 thionyl chloride and salicylamide are added.
Specifically, in the step 2), the molar ratio of the p-bromophenylhydrazine to the 2- (2-hydroxyphenyl) -4H-benzo [ e ] [1,3] oxazine-4-one is 2-3: 1.
further, in step 3), the molar ratio of ExPh-Br to 4-cyanophenylboronic acid is 1: 1-1.5.
Specifically, in step 4), ExPh 2 -CN and acetyl chloride in a molar ratio of 1: 2-3.
Further, in the step 1), the molar ratio of the salicylic acid to the pyridine is 1: 0.01-0.03.
Specifically, in the step 3), the molar ratio of ExPh-Br to tetrakis (triphenylphosphine) palladium is 1: 2.9-3.5.
Specifically, in step 4), ExPh 2 -the molar ratio of-CN to triethylamine is 1: 0.72-0.9.
The invention also provides application of the deferasirox derivative in preparation of medicaments for diagnosing and treating iron-overload hepatocellular carcinoma.
A large number of researches prove that the correlation exists between the excess of the iron in the human body and the incidence and proliferation of the hepatocellular carcinoma, and the development of the diagnosis and treatment integrated fluorescent probe which can not only identify the hepatocellular carcinoma in a targeted way, but also effectively eliminate the excess iron in the hepatocellular carcinoma has great significance. Therefore, the invention designs and synthesizes a fluorescent probe ExPh 2 -CNAc 2 The probe has unique aggregation-induced emission and iron chelation characteristics of deferasirox derivatives, and can be selectively hydrolyzed by carboxylesterase, ExPh, a biomarker of hepatocellular carcinoma 2 -CNAc 2 Fluorescent precursor ExPh produced by carboxylesterase hydrolysis 2 The CN can be further chelated with Fe (III), so that enzyme activation is achieved to target hepatocellular carcinoma and efficiently chelate excessive iron in cancer cells, and the whole process can be effectively monitored through fluorescence imaging. Experiments carried out in cells and zebrafish have demonstrated that the deferasirox derivative ExPh of the invention 2 -CNAc 2 The carboxylesterase of (a), imaging and chelating potential for excess fe (iii). Probe ExPh 2 -CNAc 2 This superior in vivo imaging and sequestration profile may be early in patients with iron-overload hepatocellular carcinomaPhase diagnosis and treatment provide new approaches. Compared with the prior art, the invention has the following beneficial effects:
ExPh designed and synthesized by the invention 2 -CNAc 2 Specific targeting of hepatocellular carcinoma can be achieved; the invention can treat iron overload; the invention can be selectively hydrolyzed by carboxylesterase so as to realize accurate treatment of hepatocellular carcinoma; the present invention enables monitoring of the entire process of diagnosis and treatment by fluorescence imaging.
Drawings
FIG. 1 shows ExPh prepared according to the present invention 2 -CNAc 2 Mass spectrogram of (2);
FIG. 2 shows ExPh prepared according to the present invention 2 -CNAc 2 Nuclear magnetic hydrogen spectrum of (a);
FIG. 3 shows ExPh prepared according to the present invention 2 -CNAc 2 Nuclear magnetic carbon spectrum of (a);
FIG. 4 shows ExPh in accordance with the present invention 2 -CNAc 2 Fluorescence emission profiles at different times of reaction with carboxylesterase;
FIG. 5 shows ExPh in accordance with the present invention 2 -CNAc 2 Fluorescence emission patterns of the reaction product after reaction with carboxylesterase and different concentrations of Fe (III);
FIG. 6 shows ExPh in accordance with the present invention 2 -CNAc 2 A plot of carboxylesterase concentration;
FIG. 7 shows ExPh in accordance with the present invention 2 -CNAc 2 Imaging of different cell lines;
FIG. 8 shows ExPh in accordance with the present invention 2 -CNAc 2 Imaging of Fe (III) and carboxylesterase inhibitors at different times than HepG2 cells;
FIG. 9 shows ExPh in accordance with the present invention 2 -CNAc 2 Imaged plots of time-varying, Fe (iii) and carboxylesterase inhibitors with zebrafish.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following examples, but the scope of the present invention is not limited thereto.
In the following examples, all the raw materials were commercially available products, unless otherwise specified. Room temperature refers to 25 ± 5 ℃.
Example 1
Preparation and characterization of 2- (2-hydroxyphenyl) -4H-benzo [ e ] [1,3] oxazin-4-one
Using toluene (5 mL) as a solvent, thionyl chloride (2.60 mL, 36.23 mmol), salicylic acid (5.00 g, 36.23 mmol) were placed in a 50 mL round bottom flask, followed by pyridine (100 mL)μL, 0.72 mmol), the reaction mixture was heated at 50 ℃ with stirring for 1 h. Then cooled to room temperature. Salicylamide (4.97 g, 36.23 mmol) and thionyl chloride (2.60 mL, 36.23 mmol) were then added and the reaction mixture heated with stirring to reflux for 2 h. The resulting mixture was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Recrystallizing with anhydrous ethanol, filtering, and drying (vacuum drying at 60 deg.C for 12H) to obtain yellow solid 2- (2-hydroxyphenyl) -4H benzo [ e ]][1,3]Oxazin-4-one in 45% yield. 1 H NMR (400 MHz, Chloroform-d) δ 6.99 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.07 (dd, J = 8.4, 1.1 Hz, 1H), 12.70 (s, 1H), 8.20 (dd, J = 8.1, 1.7 Hz, 1H), 8.10 (dd, J = 8.1, 1.7 Hz, 1H), 7.79 (ddd, J = 8.8, 7.4, 1.7 Hz, 1H), 7.52 (ddq, J = 7.3, 4.3, 1.6 Hz, 3H). ESI-MS: m/z, calcd: 239.06, found: 239.80 ([M + H] + )。
Preparation and characterization of ExPh-Br
P-bromophenylhydrazine (4.35 g, 23.40 mmol) and 2- (2-hydroxyphenyl) -4H-benzo [ e ] in diethyl ether (30 mL) as solvent][1,3]Oxazin-4-one (2.80 g, 11.70 mmol) was placed in a 50 mL round bottom flask and the mixture was heated at 35 deg.C with stirring at reflux for 12 h. The resulting mixture was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. The residue was then purified by silica gel column chromatography (petroleum ether and dichloromethane at a volume ratio of 1: 1 as eluent) to give ExPh-Br as a yellow solid in 43% yield. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 10.07 (s, 1H), 8.03 (dd, J = 7.8, 1.7 Hz, 1H), 7.69 – 7.65 (m, 2H), 7.53 (dd, J = 7.6, 1.7 Hz, 1H), 7.41 – 7.35 (m, 4H), 7.05 – 6.96 (m, 3H), 6.87 (d, J = 8.2 Hz, 1H). ESI-MS: m/z, calcd: 407.03, found: 406.24 ([M - H] - )。
ExPh 2 Preparation and characterization of-CN
4-cyanophenylboronic acid (0.59 g, 3.0 mmol) and ExPh-Br (1.22 g, 3.0 mmol) were placed in a 100 mL round-bottom flask in anhydrous ethanol (30 mL) as a solvent, 4 mL of a potassium carbonate solution (2 mol/L) was added, the mixture was degassed with nitrogen for 10 minutes, tetrakis (triphenylphosphine) palladium (10 mg, 8.7 mmol) was added under nitrogen, and the mixture was stirred under heating and reflux for 8 hours. The resulting mixture was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Separating and purifying by silica gel column chromatography (with petroleum ether and dichloromethane at volume ratio of 1: 1 as eluent) to obtain white solid powder ExPh 2 CN, yield 59%.
ExPh 2 -CNAc 2 Preparation and characterization of
Using dichloromethane (30 mL) as solvent, ExPh 2 -CN (0.43 g, 1.0 mmol) and triethylamine (0.72 mmol) were placed in a 50 mL round-bottomed flask, stirred at room temperature for 24 h, and acetyl chloride (0.16 g, 2 mmol) was slowly added dropwise to the mixed solution during the reaction. The resulting mixture was distilled under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether and dichloromethane at 1: 2 by volume as eluent) to give white solid ExPh 2 -CNAc 2 The yield was 18%. The mass spectrum, nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum are respectively shown in the figures 1 to 3, and the specific data are shown as follows.
1 H NMR of ExPh 2 -CNAc 2 in DMSO-d 6 . 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.25 (dd, J = 7.8, 1.7 Hz, 1H), 7.96 – 7.87 (m, 6H), 7.61 (td, J = 7.8, 1.7 Hz, 1H), 7.57 – 7.49 (m, 5H), 7.46 (td, J = 7.6, 1.3 Hz, 1H), 7.39 – 7.26 (m, 3H), 2.29 (s, 3H), 2.07 (s, 3H). 13 C NMR of ExPh 2 -CNAc 2 in DMSO-d 6 . 13 C NMR (126 MHz, DMSO-d 6 ) δ 170.02, 169.01, 158.89, 151.03, 148.80, 148.58, 143.51, 138.77, 138.07, 133.41, 132.46, 131.79, 131.29, 129.53, 128.53, 128.14, 126.92, 126.68, 125.13, 124.61, 123.93, 123.51, 121.68, 119.22, 111.02, 21.57, 20.99. ESI-MS: m/z, calcd: 514.16, found: 515.38, 537.37 ([M + H] + , [M + Na] + )。
Example 2
Preparing a PBS buffer solution with the pH =7.4 and the concentration of 10 mM, and preparing a carboxylesterase stock solution of 1 mg/mL by using the PBS buffer solution, wherein the stock solution is marked as a solution A; ExPh prepared in example 1 2 -CNAc dissolved in DMSO to make 1 mM ExPh 2 -CNAc 2 The DMSO probe solution is marked as solution B; get 30µL solutions A and 15µSolution L, solution B, was mixed into a fluorescence cuvette, and the mixed solution was diluted to 3 mL (PBS and DMSO in the final solution in a volume ratio of 9: 1) with PBS buffer solution and DMSO to allow carboxylesterase and probe ExPh 2 -CNAc 2 Respectively at a final concentration of 10µg/mL and 5µAnd M. The reaction was carried out in a shaker at 37 ℃. The fluorescence spectra were plotted for 0-7 h on a fluorescence spectrometer (excitation wavelength: 310 nm; slit: 5 nm) (FIG. 4).
As can be seen from fig. 4: the fluorescence intensity at 370 nm gradually decreased and the fluorescence intensity at 510 nm gradually increased with the increase of the reaction time, indicating that the probe ExPh 2 -CNAc 2 Can be hydrolyzed by carboxylesterase and the fluorescence wavelength can be changed.
Example 3
Carboxylesterase concentration as abscissa, ExPh 2 -CNAc 2 Fluorescence intensity F of 370 nm Plotting a chart for the ordinate to obtain a working curve (see fig. 6); the inset shows that the probe is in carboxylesterase 0-1.25µThe g/mL range has a good linear relation, and the linear regression equation is as follows: y = 615183.6850-304184.9579X.
Example 4
Preparing a PBS buffer solution with the pH =7.4 and the concentration of 10 mM, and preparing a carboxylesterase stock solution of 1 mg/mL by using the PBS buffer solution, wherein the stock solution is marked as a solution A; ExPh prepared in example 1 2 -CNAc dissolved in DMSO to make 1 mM ExPh 2 -CNAc 2 The DMSO probe solution is marked as solution B; take 37.5µL solutions A and 30µSolution L, solution B, was mixed into a fluorescence cuvette, and the mixed solution was diluted to 3 mL (PBS and DMSO in the final solution in a volume ratio of 9: 1) with PBS buffer solution and DMSO to allow carboxylesterase and probe ExPh 2 -CNAc 2 Respectively at a final concentration of 12.5µg/mL and 10µAnd M. The reaction is carried out for 5h in a shaker at 37 ℃, and then 0-30 percent of the reactant is addedµFe (III) of M. The fluorescence spectra were plotted on a fluorescence spectrometer (FIG. 5).
As can be seen from fig. 5: the intensity of fluorescence at 510 nm gradually decreased with increasing Fe (III) concentration after 5h of reaction with the enzyme, indicating that the probe can chelate Fe (III) and quench the fluorescence at 510 nm after reaction with carboxylesterase.
Example 5
Cell fluorescence imaging experiment: preparation of 1 mM ExPh 2 -CNAc 2 In DMSO. Will 10μL ExPh 2 -CNAc 2 The DMSO solution (K) was added to 1 mL of a cell culture medium (composition: ilex purpurea fetal calf serum: DMEM medium: 100. mu.g/mL, streptomycin = 5: 45: 0.1, volume ratio, the same below) so that the probe ExPh was used 2 -CNAc 2 To a final concentration of 10μAnd M. Then incubated with HepG2 cells, Raw264.7 cells, A549 cells and HeLa cells, respectively, at 37 ℃ for 5 h. Probe ExPh 2 -CNAc 2 Green channel in HepG2 cells: (λ em = 500-550 nm，λ ex = 405 nm. Scale bar: 20 μm) was observed (see fig. 7), from which ExPh was seen 2 -CNAc 2 Has the capability of targeting hepatocellular carcinoma imaging.
Example 6
Preparation of 1 mM ExPh 2 -CNAc 2 In DMSO. Will 10μL ExPh 2 -CNAc 2 The DMSO solution was added to 1 mL of the cell culture medium to make the probe ExPh 2 -CNAc 2 To a final concentration of 10μAnd M. Then incubated with HepG2 cells at 37 ℃ for 1 h, 3h, 4h and 5h, respectively, to determine the green channel: (λ em = 500-550 nm，λ ex = 405 nm. Scale bar: 20 μm) of the fluorescent substance. We will associate with probe ExPh 2 -CNAc 2 HepG2 cells incubated for 5h at 37 ℃ were added 10μM Fe (III), the green channel fluorescence is obviously weakened. Bis (4-nitrophenyl) phosphate (BNPP) (500) using an inhibitor of carboxylesteraseμM) incubation with HepG2 cellsAfter 30 min of incubation, probe ExPh is added 2 -CNAc 2 After 5h incubation, the green channel only fluoresced weakly (see FIG. 8). ExPh Probe ExPh 2 -CNAc 2 Can be specifically hydrolyzed by carboxylesterase in cells and chelate Fe (III), and the whole process can be monitored by the change of green fluorescence.
Example 7
Zebra fish imaging experiments: preparation of 1 mM ExPh 2 -CNAc 2 In DMSO. Will 10μL ExPh 2 -CNAc 2 The DMSO solution was added to the zebrafish Holtferer buffer to give a final concentration of 10μAnd M. The fluorescence intensity of the blue and green channels was measured by incubating zebrafish for 5 min, 30 min, 3h and 5h at 28 ℃ respectively (blue channel:λ em = 432-482 nm，λ ex = 362-396 nm; scale bar: 500 μm; green channel:λ em = 460-500 nm，λ ex = 426-446 nm）。
we will associate with probe ExPh 2 -CNAc 2 Adding 10 parts of zebra fish which are incubated for 5hμM Fe (III), the green channel fluorescence is obviously weakened. BNPP (500) using an inhibitor of carboxylesteraseμM) incubating the zebra fish for 30 min and then adding a probe ExPh 2 -CNAc 2 After 5h incubation, the blue channel fluoresced significantly while the green channel fluoresced only weakly (fig. 9). ExPh Probe ExPh 2 -CNAc 2 Chelation of carboxylesterase and Fe (III) is also achieved in zebrafish.
In conclusion, probe ExPh 2 -CNAc 2 In imaging experiments of cells and zebra fish, the feasibility of the probe for specifically recognizing carboxylesterase and chelating Fe (III) is successfully demonstrated, and the probe has the potential of diagnosing and treating iron overload in hepatocellular carcinoma patients.
Claims (9)
1. A deferasirox derivative is characterized by having a structural formula shown as follows:
2. the method for synthesizing the deferasirox derivative according to claim 1, comprising the steps of:
1) mixing thionyl chloride and salicylic acid in toluene, adding a small amount of catalyst pyridine, heating and stirring at 45-55 ℃ for 1-1.5H, cooling to room temperature, adding thionyl chloride and salicylamide, heating and refluxing for 2-3H, cooling to room temperature, evaporating under reduced pressure to remove a solvent, recrystallizing, filtering and drying to obtain solid 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazine-4-one;
2) mixing p-bromophenylhydrazine and 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazine-4-ketone in ether, heating and refluxing for 12-14H, cooling to room temperature, evaporating the solvent under reduced pressure, and purifying the residue by silica gel column chromatography to obtain solid ExPh-Br;
3) dissolving ExPh-Br and 4-cyanophenylboronic acid in ethanol, adding potassium carbonate solution to adjust pH to 8-12, adding catalyst tetrakis (triphenylphosphine) palladium under nitrogen atmosphere, heating and refluxing for 8-12h, cooling to room temperature, distilling under reduced pressure to remove solvent, and purifying by silica gel column chromatography to obtain powder ExPh-Br 2 -CN；
4) Mixing ExPh 2 dissolving-CN and acetyl chloride in dichloromethane, adding a small amount of acid-binding agent triethylamine, stirring and reacting at room temperature for 24-36h, evaporating the obtained mixture, and purifying the residue by silica gel column chromatography to obtain the compound.
3. The method for synthesizing a deferasirox derivative according to claim 1, wherein in step 1), the ratio of the molar ratio of 1-1.2: 1 mixing thionyl chloride and salicylic acid in toluene; according to the mol ratio of 1-1.5: 1 thionyl chloride and salicylamide are added.
4. The synthesis method of the deferasirox derivative according to claim 1, wherein in the step 2), the molar ratio of p-bromophenylhydrazine to 2- (2-hydroxyphenyl) -4H-benzo [ e ] [1,3] oxazin-4-one is 2-3: 1.
5. the method for synthesizing the deferasirox derivative according to claim 1, wherein in the step 3), the molar ratio of ExPh-Br to 4-cyanophenylboronic acid is 1: 1-1.5.
6. The method for synthesizing deferasirox derivative according to claim 1, wherein in step 4), ExPh 2 -CN and acetyl chloride in a molar ratio of 1: 2-3.
7. The synthesis method of the deferasirox derivative according to claim 1, wherein in the step 1), the molar ratio of the salicylic acid to the pyridine is 1: 0.01-0.03.
8. The synthesis method of the deferasirox derivative according to claim 1, wherein in the step 3), the molar ratio of ExPh-Br to tetrakis (triphenylphosphine) palladium is 1: 2.9-3.5.
9. The use of the deferasirox derivative according to claim 1 for the preparation of a medicament for the diagnosis and treatment of iron-overload hepatocellular carcinoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210853705.2A CN115057827B (en) | 2022-07-20 | 2022-07-20 | Deferasirox derivative, synthesis method thereof and application thereof in preparation of iron overload hepatocellular carcinoma diagnosis and treatment drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210853705.2A CN115057827B (en) | 2022-07-20 | 2022-07-20 | Deferasirox derivative, synthesis method thereof and application thereof in preparation of iron overload hepatocellular carcinoma diagnosis and treatment drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115057827A true CN115057827A (en) | 2022-09-16 |
| CN115057827B CN115057827B (en) | 2023-06-30 |
Family
ID=83207094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210853705.2A Active CN115057827B (en) | 2022-07-20 | 2022-07-20 | Deferasirox derivative, synthesis method thereof and application thereof in preparation of iron overload hepatocellular carcinoma diagnosis and treatment drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115057827B (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008064317A1 (en) * | 2006-11-22 | 2008-05-29 | University Of Medicine And Dentistry Of New Jersey | Lipophilic opioid receptor active compounds |
| US20100240713A1 (en) * | 2007-06-05 | 2010-09-23 | Xenon Pharmaceuticals Inc. | Aromatic and heteroaromatic compounds useful in treating iron disorders |
| CN101851230A (en) * | 2009-03-31 | 2010-10-06 | 株式会社半导体能源研究所 | Luminous element, light-emitting device, means of illumination and the electronics of heterogeneous ring compound, use heterogeneous ring compound |
| CN103554040A (en) * | 2013-11-08 | 2014-02-05 | 南京靖龙药物研发有限公司 | Preparation method of deferasirox derivative |
| WO2016203488A1 (en) * | 2015-06-16 | 2016-12-22 | Havaldar Freddy H | Preparation of novel deferasirox analogues for antimalarial activity |
| CN106471007A (en) * | 2014-07-08 | 2017-03-01 | 住友化学株式会社 | Metal complex and the light-emitting component employing it |
| CN106554770A (en) * | 2015-09-29 | 2017-04-05 | 杭州杜易科技有限公司 | A kind of preparation and its application of triazole derivatives |
| CN109646679A (en) * | 2019-01-28 | 2019-04-19 | 中国科学院长春应用化学研究所 | The purposes of iron chelator and its officinal salt |
| WO2021195064A1 (en) * | 2020-03-23 | 2021-09-30 | Board Of Regents, The University Of Texas System | Cell activatable iron chelators |
-
2022
- 2022-07-20 CN CN202210853705.2A patent/CN115057827B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008064317A1 (en) * | 2006-11-22 | 2008-05-29 | University Of Medicine And Dentistry Of New Jersey | Lipophilic opioid receptor active compounds |
| US20100240713A1 (en) * | 2007-06-05 | 2010-09-23 | Xenon Pharmaceuticals Inc. | Aromatic and heteroaromatic compounds useful in treating iron disorders |
| CN101851230A (en) * | 2009-03-31 | 2010-10-06 | 株式会社半导体能源研究所 | Luminous element, light-emitting device, means of illumination and the electronics of heterogeneous ring compound, use heterogeneous ring compound |
| CN103554040A (en) * | 2013-11-08 | 2014-02-05 | 南京靖龙药物研发有限公司 | Preparation method of deferasirox derivative |
| CN106471007A (en) * | 2014-07-08 | 2017-03-01 | 住友化学株式会社 | Metal complex and the light-emitting component employing it |
| WO2016203488A1 (en) * | 2015-06-16 | 2016-12-22 | Havaldar Freddy H | Preparation of novel deferasirox analogues for antimalarial activity |
| CN106554770A (en) * | 2015-09-29 | 2017-04-05 | 杭州杜易科技有限公司 | A kind of preparation and its application of triazole derivatives |
| CN109646679A (en) * | 2019-01-28 | 2019-04-19 | 中国科学院长春应用化学研究所 | The purposes of iron chelator and its officinal salt |
| WO2021195064A1 (en) * | 2020-03-23 | 2021-09-30 | Board Of Regents, The University Of Texas System | Cell activatable iron chelators |
Non-Patent Citations (2)
| Title |
|---|
| ADAM C. SEDGWICK ET AL.: ""Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties"", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》, vol. 143, pages 1278 - 1283 * |
| 孙敏 等: ""铁鳌合剂去铁斯若的合成"", 《中国新药杂志》, vol. 18, no. 9, pages 850 - 851 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115057827B (en) | 2023-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108524482B (en) | Use of 2- (substituted phenylamino) benzoic acid FTO inhibitors for treating leukemia | |
| Zou et al. | Synthesis, characterization and vasculoprotective effects of nitric oxide-donating derivatives of chrysin | |
| EP2489661B1 (en) | Impurity of lapatinib and salts thereof | |
| EP3111940B1 (en) | Silicon phthalocyanine complex, preparation method and medicinal application thereof | |
| CN109422737B (en) | Imidazolone androgen receptor antagonist, preparation method and application thereof | |
| CN113698416B (en) | Singlet oxygen carrier for inhibiting beta-amyloid protein aggregation and preparation method and application thereof | |
| Zhan et al. | Design and synthesis of a gossypol derivative with improved antitumor activities | |
| CN115057827B (en) | Deferasirox derivative, synthesis method thereof and application thereof in preparation of iron overload hepatocellular carcinoma diagnosis and treatment drugs | |
| CN111454254B (en) | Preparation and application of benzimidazole derivative with fluorine-containing substituent | |
| CN111825620B (en) | Carbamate derivative and preparation method and application thereof | |
| CN117580836A (en) | Pyrimidine ring structure derivative and application thereof | |
| EP3612538B1 (en) | Quinone-methide precursors with bodipy chromophore, method of preparation, biological activity and application in fluorescent labelling | |
| CN112624960B (en) | NTR-1 response type fluorescent probe based on benzindole, preparation method and application | |
| Özen et al. | Synthesis of 2-(2, 3, 4-trimethoxyphenyl)-1-(substituted-phenyl) acrylonitriles: in vitro anticancer activity against MCF-7, PC-3 and A2780 cancer cell lines | |
| CN113045554A (en) | Fexotinib crystal form and preparation method thereof | |
| CN114591346B (en) | Camptothecin prodrug, preparation method, application and salt thereof | |
| CN112441963B (en) | Divalent DNJ derivative, synthetic method and application thereof | |
| CN116768906B (en) | Tri-fused ring compound and preparation method and application thereof | |
| EP3085690B1 (en) | New urea compound, manufacturing method and application thereof | |
| CN116354901B (en) | Thiazolidinedione compound and preparation method and application thereof | |
| CN109369634B (en) | Preparation method and application of 2-methoxynicotinamide derivative with antitumor activity | |
| CN113666887B (en) | 1, 4-naphthoquinone derivative, synthesis method and application | |
| CN114605440B (en) | Preparation method of carbazolyl gallium carbole derivative and application of carbazolyl gallium carbole derivative in photodynamic antibiosis and antitumor | |
| CN101157652B (en) | Antitumor activity bipyridine methyl amine compound and preparation method thereof | |
| CN108727383B (en) | L-phenylalanine substituted maleimide derivative 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |