CN115057827B - Deferasirox derivative, synthesis method thereof and application thereof in preparation of iron overload hepatocellular carcinoma diagnosis and treatment drugs - Google Patents
Deferasirox derivative, synthesis method thereof and application thereof in preparation of iron overload hepatocellular carcinoma diagnosis and treatment drugs Download PDFInfo
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- 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 abstract description 22
- 231100000844 hepatocellular carcinoma Toxicity 0.000 title claims abstract description 22
- 206010065973 Iron Overload Diseases 0.000 title claims abstract description 14
- 238000011282 treatment Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 11
- 238000003745 diagnosis Methods 0.000 title claims description 7
- 239000003814 drug Substances 0.000 title claims description 7
- 238000001308 synthesis method Methods 0.000 title description 5
- 229940079593 drug Drugs 0.000 title description 3
- 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 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 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
- 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
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- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 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 8
- 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 7
- 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
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 238000003756 stirring 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
- 238000001704 evaporation Methods 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
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 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
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 7
- 102000013392 Carboxylesterase Human genes 0.000 abstract description 21
- 108010051152 Carboxylesterase Proteins 0.000 abstract description 21
- 239000000523 sample Substances 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
- 238000003384 imaging method Methods 0.000 abstract description 8
- 239000007850 fluorescent dye Substances 0.000 abstract description 6
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- 238000002474 experimental method Methods 0.000 abstract description 5
- 238000001514 detection method Methods 0.000 abstract description 3
- 238000013399 early diagnosis Methods 0.000 abstract description 3
- 238000013459 approach Methods 0.000 abstract description 2
- 238000011503 in vivo imaging Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 33
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- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 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
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000010261 cell growth 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
- 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
- 238000001819 mass spectrum Methods 0.000 description 2
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
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- 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
- 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022979 Iron excess 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
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- 238000004113 cell culture Methods 0.000 description 1
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- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
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- 210000001198 duodenum Anatomy 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
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- 150000003852 triazoles Chemical class 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
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-
- 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
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- 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
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- 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 as follows:
. The deferasirox derivative is a fluorescent probe. Experiments in zebra fish at different growth stages and cells prove that the deferasirox derivative ExPh of the invention 2 ‑CNAc 2 Carboxylesterase detection, imaging and chelating of excess Fe (III). Probe ExPh 2 ‑CNAc 2 This superior in vivo imaging and chelation properties may provide a new approach for early diagnosis and treatment of iron overload hepatocellular carcinoma patients.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and in particular relates to a deferasirox derivative, a synthesis method thereof and application thereof in preparing medicines for diagnosing and treating iron overload hepatocellular carcinoma.
Background
Iron is an essential element that promotes cell proliferation and growth, and its balance in the body is critical. Under normal circumstances, iron is taken up by the diet and can only be removed by extremely limited mucosal cell shedding or other blood loss. Because humans lack the proper physiological mechanism to eliminate iron, excessive iron-induced hepcidin can only limit the absorption of iron by the duodenum. Infection, inflammation and alcohol affect hepcidin expression, resulting in iron excess in the liver. Meanwhile, excessive free iron with redox activity catalyzes the generation of hydroxyl anions and hydroxyl free radicals, increases the generation of active oxygen of cells, and damages macromolecular components of cells and cell DNA, thereby inducing hepatocellular carcinoma. On the other hand, excessive iron provides nutrition for cancer cell proliferation and promotes cancer cell growth, making the cancer cell proliferation process of iron-overloaded hepatocellular carcinoma patients more uncontrolled. Therefore, the treatment of patients with iron overload hepatocellular carcinoma must fundamentally solve the problem of iron overload.
Some fluorescent probes developed for hepatocellular carcinoma have been used in 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, so that the influence of excessive iron needs to be fundamentally eliminated. Iron chelators have also been found to be a potential primary or adjunct treatment for cancer, which can successfully reduce cancer cell proliferation by removing excess iron from the body in a non-invasive manner. Deferasirox designed by Nohua corporation is a tridentate ligand based on a triazole platform, has good selectivity to iron and poor affinity to trace elements such as zinc and copper. It has oral activity and produces a 2:1 compound with Fe (III). Studies have shown that: deferasirox has excellent antibacterial and chemotherapeutic activity.
In view of the above, the introduced group of the invention discovers a deferasirox derivative with novel fluorescence characteristics, and designs a fluorescence probe for combining early diagnosis and treatment of a target iron overload hepatocellular carcinoma patient.
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 medicaments for diagnosing and treating iron overload hepatocellular carcinoma.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides a deferasirox derivative, which has the following structural formula, wherein the deferasirox derivative is a fluorescent probe and is marked as follows in the application: exPh 2 -CNAc 2 。
The above-mentioned deferasirox derivative (i.e., fluorescent probe ExPh 2 -CNAc 2 ) The synthesis method of (2) comprises the following steps:
1) Mixing thionyl chloride and salicylic acid in toluene, adding a small amount of pyridine as a catalyst, 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 the solvent under reduced pressure, recrystallizing with absolute ethyl alcohol, filtering, and drying to obtain yellow solid 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazin-4-one;
2) Mixing p-bromophenylhydrazine and 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazin-4-one in diethyl 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 a 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 tetra (triphenylphosphine) palladium under nitrogen atmosphere, heating and refluxing for 8-12h, cooling the obtained mixture to room temperature, removing solvent by vacuum distillation, and purifying by silica gel column chromatography to obtain white powder ExPh 2 -CN；
4) ExPh was performed 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 step 1), the molar ratio is 1-1.2:1 mixing thionyl chloride and salicylic acid in toluene; the molar ratio is 1-1.5:1 thionyl chloride and salicylamide are added.
Specifically, in step 2), the molar ratio of p-bromophenylhydrazine to 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazin-4-one is 2-3:1.
further, in step 3), the molar ratio of the ExPh-Br to the 4-cyanophenylboronic acid is 1:1-1.5.
Specifically, in step 4), exPh 2 -the molar ratio of CN to acetyl chloride is 1:2-3.
Further, in step 1), the molar ratio of salicylic acid to pyridine is 1:0.01-0.03.
Specifically, in 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 preparing medicaments for diagnosis and treatment of iron overload hepatocellular carcinoma.
A large number of researches prove that the iron in human body is excessive and the liver cells are excessiveThe incidence rate and proliferation rate of the cancers are related, and the development of the diagnosis and treatment integrated fluorescent probe which can not only target and identify the hepatocellular carcinoma, but also effectively eliminate excessive iron in the hepatocellular carcinoma is of great significance. For this purpose, the invention designs and synthesizes a fluorescent probe ExPh 2 -CNAc 2 The probe has unique aggregation-induced emission and iron chelating property of deferasirox derivative, and can be selectively hydrolyzed by carboxylesterase, which is a biomarker of hepatocellular carcinoma, and ExPh 2 -CNAc 2 Fluorescent precursor ex ph produced by carboxylesterase hydrolysis 2 CN can be further chelated with Fe (III), thereby achieving enzyme activation targeting of hepatocellular carcinoma and efficient chelation of excess iron in cancer cells, and the whole process can be effectively monitored by fluorescence imaging. Experiments performed in cells and zebra fish demonstrate that the deferasirox derivative ex ph of the invention 2 -CNAc 2 Carboxylesterase detection, imaging and chelating of excess Fe (III). Probe ExPh 2 -CNAc 2 This superior in vivo imaging and chelation properties may provide a new approach for early diagnosis and treatment of iron overload hepatocellular carcinoma patients. Compared with the prior art, the invention has the following beneficial effects:
the invention designs and synthesizes ExPh 2 -CNAc 2 Can realize specific targeting of hepatocellular carcinoma; the invention can treat iron overload; the invention can be selectively hydrolyzed by carboxylesterase so as to realize accurate treatment of hepatocellular carcinoma; the invention can monitor the whole process of diagnosis and treatment through fluorescence imaging.
Drawings
FIG. 1 shows the ExPh prepared according to the present invention 2 -CNAc 2 Mass spectrum of (3);
FIG. 2 shows the ExPh prepared according to the present invention 2 -CNAc 2 Nuclear magnetic hydrogen spectrogram of (2);
FIG. 3 shows the ExPh prepared according to the present invention 2 -CNAc 2 Nuclear magnetic carbon spectrogram of (2);
FIG. 4 shows the ExPh of the present invention 2 -CNAc 2 Fluorescence emission patterns at different times from carboxylesterase reaction;
FIG. 5 shows the ExPh of the present invention 2 -CNAc 2 With carboxylic acid estersFluorescence emission patterns of Fe (III) with different concentrations after enzyme reaction;
FIG. 6 shows the ExPh of the present invention 2 -CNAc 2 A graph of carboxylesterase concentration;
FIG. 7 shows the ExPh of the present invention 2 -CNAc 2 Imaging with different cell lines;
FIG. 8 shows the ExPh of the present invention 2 -CNAc 2 Imaging of Fe (iii) and carboxylesterase inhibitors at different times from HepG2 cells;
FIG. 9 shows the ExPh of the present invention 2 -CNAc 2 Imaging of Fe (iii) and carboxylesterase inhibitors at different times from zebra fish.
Detailed Description
The following describes the technical scheme of the present invention in further detail with reference to examples, but the scope of the present invention is not limited thereto.
In the following examples, all materials used, unless otherwise specified, were commercially available products. Room temperature refers to 25±5 ℃.
Example 1
Preparation and characterization of 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazin-4-one
Thionyl chloride (2.60 mL,36.23 mmol) and salicylic acid (5.00 g,36.23 mmol) were placed in a 50 mL round bottom flask with toluene (5 mL) as solvent, then pyridine (100) was addedμL,0.72 mmol) and the reaction mixture was stirred with heating at 50℃for 1 h. And 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 was heated to reflux with stirring 2 h. The resulting mixture was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Recrystallizing with absolute ethanol, filtering, and drying (vacuum drying at 60deg.C 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 ] are prepared by using diethyl ether (30, mL) as a 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 to 35℃with stirring and reflux 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 column chromatography on silica gel (1:1 by volume petroleum ether and dichloromethane as eluent) to give the yellow solid, exPh-Br, 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 with anhydrous ethanol (30 mL) as solvent, 4 mL 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 atmosphere and heated under reflux with stirring for 8 h. 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 with volume ratio of 1:1 as eluent) to obtain white solid powder ExPh 2 -CN in 59% yield.
ExPh 2 -CNAc 2 Is prepared and characterized by
Exph was prepared by dissolving in dichloromethane (30 mL) 2 CN (0.43 g, 1.0 mmol) and triethylamine (0.72 mmol) were placed in a 50 mL round bottom flask and stirred at RT for 24 h, 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 subjected to silica gel column chromatographySeparating and purifying (by using petroleum ether and methylene dichloride with volume ratio of 1:2 as eluent) to obtain white solid ExPh 2 -CNAc 2 The yield was 18%. The mass spectrum, the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum are respectively shown in figures 1 to 3, and specific data are shown below.
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 PBS buffer solution with pH=7.4 and concentration of 10 mM, and preparing carboxylesterase stock solution with the PBS buffer solution of 1 mg/mL, which is marked as solution A; exPh prepared in example 1 2 Preparation of 1 mM ExPh by dissolving-CNAc in DMSO 2 -CNAc 2 Is marked as solution B; take 30µL solutions A and 15µL solution B was mixed into a fluorescence cuvette, and the mixed solution was diluted to 3 mL (volume ratio of PBS and DMSO in the final solution was 9:1) with PBS buffer and DMSO to allow carboxylesterase and probe ExPh to pass 2 -CNAc 2 Final concentration of 10 respectivelyµg/mL and 5µM. The reaction was carried out in a shaker at 37 ℃. Fluorescence spectra were plotted (FIG. 4) for 0-7 h on a fluorescence spectrometer (excitation wavelength: 310 nm; slit: 5 nm).
As can be seen from fig. 4: as the reaction time was prolonged, the fluorescence intensity at 370 and nm gradually decreased, and the fluorescence intensity at 510 and nm gradually increasedDescription of the probes ExPh 2 -CNAc 2 Can be hydrolyzed by carboxylesterase and the fluorescence wavelength can be changed.
Example 3
On the abscissa of carboxylesterase concentration, exPh 2 -CNAc 2 Fluorescence intensity F of (2) 370 nm Drawing a graph for a longitudinal sitting plot to obtain a working curve (see fig. 6); the inset shows the probe at carboxylesterase 0-1.25µThe linear regression equation has good linear relation in the g/mL range: y= 615183.6850-304184.9579X.
Example 4
Preparing PBS buffer solution with pH=7.4 and concentration of 10 mM, and preparing carboxylesterase stock solution with the PBS buffer solution of 1 mg/mL, which is marked as solution A; exPh prepared in example 1 2 Preparation of 1 mM ExPh by dissolving-CNAc in DMSO 2 -CNAc 2 Is marked as solution B; take 37.5µL solutions A and 30µL solution B was mixed into a fluorescence cuvette, and the mixed solution was diluted to 3 mL (volume ratio of PBS and DMSO in the final solution was 9:1) with PBS buffer and DMSO to allow carboxylesterase and probe ExPh to pass 2 -CNAc 2 Final concentration of 12.5 respectivelyµg/mL and 10µM. After the reaction is carried out in a shaking table at 37 ℃ for 5h, 0 to 30 percent of the reaction mixture is addedµFe (III) of M. The fluorescence spectrogram was drawn by detection on a fluorescence spectrometer (fig. 5).
As can be seen from fig. 5: the gradual decrease in fluorescence intensity at 510, nm with increasing concentration of Fe (III) following reaction with enzyme 5, h, suggests that the probe may sequester Fe (III) and quench fluorescence at 510, nm following reaction with carboxylesterase.
Example 5
Cell fluorescence imaging experiments: preparation of 1 mM ExPh 2 -CNAc 2 Is a solution of DMSO in (B). Will 10μL ExPh 2 -CNAc 2 Adding DMSO solution of (B) into 1 mL cell culture solution (composition: herba Siraitiae Grosvenorii embryo calf serum: DMEM culture medium: 100 μg/mL cyan, streptomycin=5:45:0.1, volume ratio, the same as below) to make probe ExPh 2 -CNAc 2 Is 10 in final concentrationμM. Then respectively combining with HepG2 cells, raw264.7 cells, A549 cells and HeLa cellsIncubate 5h at 37 ℃. Probe ExPh 2 -CNAc 2 In the green channel of HepG2 cellsλ em = 500-550 nm，λ ex =405 nm. Scale bar: 20. μm) is evident from the fluorescent light (see FIG. 7), from which ExPh can be seen 2 -CNAc 2 Has the capability of targeting hepatocellular carcinoma imaging.
Example 6
Preparation of 1 mM ExPh 2 -CNAc 2 Is a solution of DMSO in (B). Will 10μL ExPh 2 -CNAc 2 Adding the DMSO solution of (C) to 1 mL cell culture medium to make the probe ExPh 2 -CNAc 2 Is 10 in final concentrationμM. Then incubating 1 h, 3h, 4h and 5h with HepG2 cells at 37 ℃ to determine green channelλ em = 500-550 nm，λ ex =405 nm. Scale bar: 20. μm) of the fluorescent intensity. We will be coupled with probe ExPh 2 -CNAc 2 HepG2 cells incubated 5h at 37℃were added 10μM Fe (III), the fluorescence of the green channel is obviously weakened. Bis (4-nitrophenyl) phosphate (BNPP) (500) inhibitors of carboxylesteraseμM) the probe ExPh was added after incubation with HepG2 cells for 30 min 2 -CNAc 2 Incubation 5h, the green channel was only weakly fluorescent (see fig. 8). Description of probes ExPh 2 -CNAc 2 Can be specifically hydrolyzed by carboxylesterase in cells and sequester Fe (III), and the whole process can be monitored by changing green fluorescence.
Example 7
Zebra fish imaging experiments: preparation of 1 mM ExPh 2 -CNAc 2 Is a solution of DMSO in (B). Will 10μL ExPh 2 -CNAc 2 Adding the DMSO solution of (B) to the zebra fish Holtfreter buffer solution to obtain the final concentration of 10μM. Incubation with zebra fish at 28 ℃ for 5 min, 30 min, 3h and 5h, respectively, measured the fluorescence intensities of the blue and green channels (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 be coupled with probe ExPh 2 -CNAc 2 Zebra fish addition 10 incubated 5hμM Fe (III), the fluorescence of the green channel is obviously weakened. BNPP (500) using carboxylesterase inhibitorsμM) incubating with zebra fish for 30 min and adding probe ExPh 2 -CNAc 2 Incubation 5h, blue channel was significantly fluorescent while the green channel was only weakly fluorescent (fig. 9). Description of probes ExPh 2 -CNAc 2 Chelation of carboxylesterase and Fe (III) can also be achieved in zebra fish.
To sum up, probe ex ph 2 -CNAc 2 In imaging experiments of cells and zebra fish, the feasibility of specific recognition of carboxylesterase by the probe and chelation of Fe (III) is successfully demonstrated, and the probe has potential of diagnosis and treatment of iron overload in hepatocellular carcinoma patients.
Claims (9)
1. A deferasirox derivative, characterized by the following structural formula:
2. the method for synthesizing a deferasirox derivative according to claim 1, comprising the steps of:
1) Mixing thionyl chloride and salicylic acid in toluene, adding a small amount of pyridine as a catalyst, heating and stirring at 45-55 ℃ for 1-1.5H, cooling to room temperature, then adding thionyl chloride and salicylamide, heating and refluxing for 2-3H, cooling to room temperature, evaporating solvent under reduced pressure, recrystallizing, filtering and drying to obtain solid 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazin-4-one;
2) Mixing p-bromophenylhydrazine and 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazin-4-one in diethyl 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 tetra (triphenylphosphine) palladium under nitrogen atmosphere, heating and refluxing for 8-12h, and cooling to obtain the final productDistilling under reduced pressure at room temperature to remove solvent, and purifying by silica gel column chromatography to obtain powder ExPh 2 -CN；
4) ExPh was performed 2 -CN and acetyl chloride are dissolved in dichloromethane, a small amount of acid-binding agent triethylamine is added, the mixture is stirred at room temperature for reaction for 24-36 hours, the obtained mixture is evaporated, and then the residue is purified by silica gel column chromatography, so that the product is obtained.
3. The method for synthesizing deferasirox derivative according to claim 2, wherein in step 1), the molar ratio is 1 to 1.2:1 mixing thionyl chloride and salicylic acid in toluene; the molar ratio is 1-1.5:1 thionyl chloride and salicylamide are added.
4. The method for synthesizing a deferasirox derivative according to claim 2, wherein in the step 2), the molar ratio of the p-bromophenylhydrazine to the 2- (2-hydroxyphenyl) -4H benzo [ e ] [1,3] oxazin-4-one is 2 to 3:1.
5. the method for synthesizing a deferasirox derivative according to claim 2, 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 2, wherein in step 4), exPh 2 -the molar ratio of CN to acetyl chloride is 1:2-3.
7. The method for synthesizing deferasirox derivative according to claim 2, wherein in the step 1), the molar ratio of salicylic acid to pyridine is 1:0.01-0.03.
8. The method for synthesizing a deferasirox derivative according to claim 2, wherein in the step 3), the molar ratio of ExPh-Br to tetrakis (triphenylphosphine) palladium is 1:2.9-3.5.
9. Use of a deferasirox derivative according to claim 1 for the preparation of a medicament for diagnosis and treatment of iron overload hepatocellular carcinoma.
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