CN117003822A - SG3C bromobenzyl ether derivative, preparation method and application - Google Patents
SG3C bromobenzyl ether derivative, preparation method and application Download PDFInfo
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- CN117003822A CN117003822A CN202310991888.9A CN202310991888A CN117003822A CN 117003822 A CN117003822 A CN 117003822A CN 202310991888 A CN202310991888 A CN 202310991888A CN 117003822 A CN117003822 A CN 117003822A
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- Prior art keywords
- sg3c
- ether derivative
- bromobenzyl ether
- bromo
- phenylbenzyloxy
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- SUHUQLOULPAPRO-UHFFFAOYSA-N [bromo-[bromo(phenyl)methoxy]methyl]benzene Chemical class C=1C=CC=CC=1C(Br)OC(Br)C1=CC=CC=C1 SUHUQLOULPAPRO-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 7
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 7
- 239000012216 imaging agent Substances 0.000 claims abstract description 7
- -1 2-bromo-3-phenylbenzyloxy Chemical group 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 12
- 235000018417 cysteine Nutrition 0.000 claims description 12
- 238000003384 imaging method Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 8
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 claims description 8
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 6
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 6
- 238000005520 cutting process Methods 0.000 claims description 6
- 238000011534 incubation Methods 0.000 claims description 6
- 229920001184 polypeptide Polymers 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 239000011347 resin Substances 0.000 claims description 6
- 229920005989 resin Polymers 0.000 claims description 6
- 239000001119 stannous chloride Substances 0.000 claims description 6
- 235000011150 stannous chloride Nutrition 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 4
- 239000007790 solid phase Substances 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940009662 edetate Drugs 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 14
- 150000002632 lipids Chemical class 0.000 abstract description 7
- 238000001514 detection method Methods 0.000 abstract description 5
- 238000012151 immunohistochemical method Methods 0.000 abstract description 5
- 238000009826 distribution Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 11
- 238000002372 labelling Methods 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- PJXZIEDLTHQYBC-UHFFFAOYSA-N 2-bromo-1-(bromomethyl)-3-phenylbenzene Chemical compound BrCC1=CC=CC(C=2C=CC=CC=2)=C1Br PJXZIEDLTHQYBC-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- RZILUEQOAIVYLY-UHFFFAOYSA-N 4-[(2-bromo-3-phenylphenyl)methoxy]-5-chloro-2-hydroxybenzaldehyde Chemical compound OC1=C(C=O)C=C(C(=C1)OCC1=C(C(=CC=C1)C1=CC=CC=C1)Br)Cl RZILUEQOAIVYLY-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
- 239000004342 Benzoyl peroxide Substances 0.000 description 5
- VXKDAXXMZPTOMR-UHFFFAOYSA-N BrC1=C(C=CC=C1C)C1=CC=CC=C1 Chemical compound BrC1=C(C=CC=C1C)C1=CC=CC=C1 VXKDAXXMZPTOMR-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 235000019400 benzoyl peroxide Nutrition 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000009169 immunotherapy Methods 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- QGJDXUIYIUGQGO-UHFFFAOYSA-N 1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC(C)C(=O)N1CCCC1C(O)=O QGJDXUIYIUGQGO-UHFFFAOYSA-N 0.000 description 4
- KEGQEFDADWTVBG-UHFFFAOYSA-N 2-bromo-1-iodo-3-methylbenzene Chemical compound CC1=CC=CC(I)=C1Br KEGQEFDADWTVBG-UHFFFAOYSA-N 0.000 description 4
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000691 measurement method Methods 0.000 description 4
- 239000003068 molecular probe Substances 0.000 description 4
- 238000005192 partition Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 229960003328 benzoyl peroxide Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 description 2
- IPOSHVWRFQTHGK-UHFFFAOYSA-N 5-chloro-2,4-dihydroxybenzaldehyde Chemical compound OC1=CC(O)=C(C=O)C=C1Cl IPOSHVWRFQTHGK-UHFFFAOYSA-N 0.000 description 2
- MFBYPDKTAJXHNI-VKHMYHEASA-N Gly-Cys Chemical compound [NH3+]CC(=O)N[C@@H](CS)C([O-])=O MFBYPDKTAJXHNI-VKHMYHEASA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000002173 cutting fluid Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a SG3C bromobenzyl ether derivative, a preparation method and application thereof, SG3C-CBM is used as a ligand and is used 99m Tc-labelled complexes 99m Tc-SG3C-CBM can be used as an imaging agent to detect PD-L1 expression, thereby realizing real-time, comprehensive and convenient detection of PD-L1 expression level of tumor and overcoming the defects of immunohistochemical method. The invention provides an SG3C bromobenzyl ether derivative, a preparation method and application thereof, and the prepared product 99m The marking rate of Tc-SG3C-CBM is above 96%, the radiochemical purity is still above 92% after the sample is placed at room temperature for 6 hours, the sample is stable at room temperature in vitro, the sample is suitable for clinical application, the lipid water distribution coefficient is 0.86, the distribution condition of the medicine in the organism between the water phase and the lipid phase can be reflected, and the cell uptake shows, 99m Tc-SG3C-CBM uptake in PD-L1 positive cells was 6.46 times that in negative cells.
Description
Technical Field
The invention belongs to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine, and particularly relates to an SG3C bromobenzyl ether derivative, a preparation method and application thereof.
Background
In recent years, immunotherapy has become a research hotspot in tumor therapy, and immune escape of tumor cells plays a very important role in tumorigenesis and development. Tumor cells survive by binding programmed death ligand (PD-L1) generated on their surface to programmed death molecule 1 (PD-1) of T cells, inhibiting proliferation of T cells and releasing cytotoxins, resulting in depletion and apoptosis of tumor-specific T cells, thus escaping the immune system from attack. PD-1/PD-L1 based immunotherapy is a new generation of immunotherapy currently attracting attention, aiming at using the human body's own immune system to combat tumors, inducing apoptosis by blocking the PD-1/PD-L1 signaling pathway, has the potential to treat various types of tumors, and the expression level of PD-L1 has an important link with the effect of the final immunotherapy.
At present, the expression level of PD-L1 on the surface of a tumor is mainly measured by an immunohistochemical method, and the immunohistochemical method needs to extract tumor tissues and is an invasive method. Meanwhile, due to tumor heterogeneity, the level of PD-L1 measured by immunohistochemistry does not reflect the immune status of the tumor as a whole. And PD-L1 expression level is a dynamic indicator, which varies with the course of treatment of the tumor. Therefore, the real-time, comprehensive and convenient detection of the PD-L1 level of the tumor is an urgent problem to be solved clinically at present.
Molecular imaging can carry out qualitative or quantitative visual detection and research on pathogenic molecules, disease characteristics, molecular mechanisms of occurrence and development of diseases and the prognosis, treatment and prognosis of the diseases at molecular level through molecular probes in a living body state. Therefore, by means of the molecular probe of the specific targeting PD-L1, the molecular image can continuously and comprehensively observe the PD-L1 level of the tumor, and the defects of the immunohistochemical method in the prior art are overcome.
Nuclear medicine imaging using radionuclide-labeled molecular probes is the most developed technology in current molecular imaging, and has long been clinically applied to diagnosis and efficacy assessment of tumors. The radionuclide-labeled PD-L1 specific molecular probe can reflect the PD-L1 level of the tumor comprehensively and quantitatively in real time, and provides a judgment basis for immunotherapy. International publication No. (WO 2017/202273A 1) discloses a benzyl ether derivative, a preparation method, a pharmaceutical composition and application thereof, and has better binding capacity with PD-L1 protein. In the prior art, the radionuclide is used for labeling macromolecules such as PD-L1 antibodies or partial antibodies, and the imaging result can reflect the distribution of PD-L1 in the body, but the imaging probe is expensive to prepare, has longer in vivo elimination half-life and is not an ideal imaging probe. The prior art (CN 111943876B) discloses an N2S2 bromobenzyl ether derivative, which has the advantages of milder marking condition, boiling requirement, lower marking rate of 94 percent, and low marking rate after being placed for 6 hours at room temperature, 99m Tc-SG3C-CBM has poor stability and poor targeting to PD-L1The amplification is low, and the problem needs to be solved at present.
Disclosure of Invention
In order to solve the problems that the marking condition of the N2S2 bromobenzyl ether derivative in the prior art is not mild and needs to be boiled, after the product is placed for 6 hours at room temperature, 99m the technical problems of poor stability of Tc-SG3C-CBM, poor targeting to PD-L1 and low amplification purity are solved by the invention, which aims to provide a novel high-performance fluorescent dye suitable for the treatment of the tumor 99m Tc marked SG3C bromobenzyl ether derivative, its preparation and application.
In order to achieve the above purpose and achieve the above technical effects, the invention adopts the following technical scheme:
an SG3C bromobenzyl ether derivative, which is N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycine, having the following structural formula (i):
further, the preparation method of the SG3C bromobenzyl ether derivative comprises the following steps:
n- [2- (3-cyanobenzene-1-methoxylidene) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] serine, fmoc-glycine and FMOC-thio-tert-butyl-cysteine are taken and synthesized into N- [2- (3-cyanobenzene-1-methoxylidene) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl (S-tert-butylthio) cysteine by a solid-phase polypeptide synthesis method, tris (2-carboxyethyl) phosphine (TCEP) is added, tert-butylthio is removed, and N- [2- (3-cyanobenzene-1-methoxylidene) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl cysteine is obtained.
Further, the solid-phase polypeptide synthesis method uses resin as a carrier, and after synthesizing N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl (S-tert-butylthio) cysteine, N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl (S-tert-butylthio) cysteine is cut from the resin by using a cutting solution, wherein the cutting solution is preferably a solution containing trifluoroacetic acid.
The invention also discloses application of the SG3C bromobenzyl ether derivative as a ligand to form a complex with a nuclide marker in PD-L1 imaging.
The invention also discloses an application of the SG3C bromobenzyl ether derivative as a ligand to form a complex with a nuclide marker in PD-L1 imaging, wherein the nuclide marker is 99m Tc。
The invention also discloses a device 99m Tc marked SG3C bromobenzyl ether derivative is prepared by adopting SG3C bromobenzyl ether derivative.
Further, the said 99m The preparation method of the Tc-marked SG3C bromobenzyl ether derivative comprises the following steps:
taking the SG3C bromobenzyl ether derivative solution, adding glucoheptonate, ethylenediamine tetraacetate, stannous chloride and pertechnetum acid solution, mixing, incubating, taking out to obtain the desired product, and taking out to obtain the desired product 99m Tc-SG3C-CBM。
Further, the SG3C bromobenzyl ether derivative is dissolved in an alcohol solvent to obtain the SG3C bromobenzyl ether derivative solution, the incubation temperature is preferably 30-45 ℃, and the incubation time is preferably more than 60min
The invention also discloses a device 99m Application of SG3C bromobenzyl ether derivative marked by Tc as imaging agent in detecting PD-L1 expression.
The invention also discloses a developer, which is 99m Tc-labeled SG 3C-bromobenzyl ether derivatives.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses an SG3C bromobenzyl ether derivative, a preparation method and application thereof, wherein the SG3C bromobenzyl ether derivative comprises the following components: n- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl]-N-seryl glycyl cysteine, SG3C-CBM for short, which is used as ligand and is used 99m Complexation of Tc-tag formationArticle (B) 99m Tc-SG3C-CBM can be used as an imaging agent to detect PD-L1 expression, so as to realize real-time, comprehensive and convenient detection of PD-L1 level of tumor and overcome the defects of immunohistochemical method. 99m The lipid partition coefficient of Tc-SG3C-CBM is 0.86, which can reflect the partition condition of the medicine in organisms between the water phase and the lipid phase, and the cell uptake shows that the uptake of the medicine in PD-L1 positive cells (A375-hPD-L1) is obviously higher than that of negative cells (A375). Compared with the prior art (CN 111943876B N2S2 bromobenzyl ether derivatives, preparation method and application), the invention provides 99m The Tc-SG3C-CBM marking condition is mild, no boiling is needed, the marking rate is 96 percent, the marking rate in CN111943876B is 94 percent, and after the product is placed for 6 hours at room temperature, the product is prepared 99m Tc-SG3C-CBM has good stability, the amplification purity is more than 95 percent, and CN111943876B is only more than 90 percent; furthermore, the invention 99m The difference between uptake of Tc-SG3C-CBM in PD-L1 positive cells (A375-hPD-L1) and negative cells (A375) was compared to that in CN111943876B 99m Tc-N2S2-CBMBC and 99m the difference in uptake of Tc-blank in breast cancer cells (MDA-MB-231) is more indicative of the present invention 99m Tc-SG3C-CBM has good targeting to PD-L1.
Drawings
FIG. 1 is a mass spectrum of the marker precursor SG3C-CBM of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of the marker precursor SG3C-CBM of the present invention;
FIG. 3 is a schematic view of the present invention 99m HPLC chromatogram of Tc-SG 3C-CBM;
FIG. 4 is a schematic view of the present invention 99m HPLC chromatogram of Tc-blank.
Detailed Description
The following embodiments of the present invention are described in detail so that the advantages and features of the present invention may be more readily understood by those skilled in the art, thereby making a clearer and more definite definition of the scope of the present invention.
An SG3C bromobenzyl ether derivative, designated: n- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycine, abbreviated SG3C-CBM, having the following structural formula (I):
the preparation method of the SG3C bromobenzyl ether derivative comprises the following steps:
s1, preparing 2-bromo-3-phenyltoluene
Adding 100-5000mg of 2-bromo-3-iodotoluene into a 100mL three-necked flask under the condition of nitrogen, adding 30-70mL of aqueous solution containing dioxane (60% -90%) to dissolve the 2-bromo-3-iodotoluene, sequentially adding 50-2500mg of phenylboric acid, 100-8000mg of cesium carbonate and 10-300mg of triphenylphosphine palladium after stirring uniformly, stirring for 12-24h at 70-90 ℃, stopping the reaction, cooling to room temperature, rotationally evaporating to remove the solvent, adding water and ethyl acetate, extracting for 3 times, merging the organic phases, drying with anhydrous sodium sulfate, evaporating to dry the organic phase, and passing through a silica gel column to obtain colorless oily 2-bromo-3-phenyltoluene;
s2, preparing 2-bromo-3-phenylbenzyl bromide
Under the condition of introducing nitrogen, dissolving 100-2000mg of 2-bromo-3-phenyltoluene obtained in the step S1 and anhydrous carbon tetrachloride in a 100mL three-necked flask, adding 80-1600 mgN-Bromosuccinimide (English is fully called N-Bromosuccinimide, english is abbreviated as NBS) under stirring, heating to 80 ℃, adding 10-20mg of benzoyl peroxide (English is fully called Benzoylperoxide, english is abbreviated as BPO) for reacting at intervals of 2 hours, then cooling to room temperature, adding water and dichloromethane for extraction, merging organic phases, drying by anhydrous sodium sulfate, evaporating the organic phases to obtain 2-bromo-3-phenylbenzyl bromide yellow oily substance, and directly using the 2-bromo-3-phenylbenzyl bromide oily substance for the next reaction;
s3, preparing 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde
Under the condition of introducing nitrogen, adding 100-1000mg of 2, 4-dihydroxyl-5-chlorobenzaldehyde into a 100mL three-necked flask, adding acetonitrile to dissolve the chlorobenzaldehyde, adding 150-1000mg of sodium bicarbonate, and filling the mixture into a roomAfter warm stirring, the acetonitrile solution of 2-bromo-3-phenylbenzyl bromide (150-1500 mg) obtained in step S2 is added dropwise, the temperature is raised to 75 ℃ and stirred overnight, then cooled to room temperature, filtered, the filtrate is washed with water, then the aqueous solution is extracted with ethyl acetate for 2 times, the organic phases are combined, and anhydrous Na is used 2 SO 4 Drying, evaporating the solvent, and recrystallizing with ethyl acetate and petroleum ether to obtain 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde as pale yellow solid;
s4, preparation of 2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde
Under the condition of introducing nitrogen, 100-1000mg of 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde is dissolved, 3-8mL of LDMF is dissolved and then stirred and mixed with 100-600mg of cesium carbonate at room temperature, 3-5mL of 80-800mg of 3-cyano-benzyl bromide DMF solution is dropwise added, the temperature is raised to 85 ℃ and stirred for 12-24 hours, then the mixture is cooled to room temperature, poured into 100mL of water, extracted for 3 times by ethyl acetate, the organic phases are combined, dried and evaporated to dryness, and ethyl acetate and petroleum ether are used for recrystallization, so that 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde is obtained as a yellow solid;
s5 preparation of N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] serine
Dissolving 50-500mg of 2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde and 10-300mg of serine in ethanol, adding 20-200 mu L of acetic acid and 50-500mg of anhydrous sodium sulfate, heating and refluxing for 2-6h, cooling to room temperature, adding 5-20mL of methanol solution of 20-500mg of sodium cyanoborohydride, stirring at room temperature for reaction for 24h, evaporating the solvent, extracting the aqueous solution with ethyl acetate for 3 times, combining organic phases, and using anhydrous Na 2 SO 4 Drying and evaporating the solvent to obtain the required product.
S6, preparation of N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycinoyl glycylglycinoyl (S-t-butylthio) cysteine
By polypeptide solid phase synthesis, 50-500 mgN-fluorenylmethoxycarbonyl-S-t-butylthio cysteine is first bound to 100-800mg resin, N protecting group fluorenylmethoxycarbonyl (Fmoc) is removed, and then N protecting group is removed by binding N-fluorenylmethoxycarbonyl glycine (Fmoc-glycine) and then removing N protecting groupThe method of protecting fluorenylmethoxycarbonyl (Fmoc) is repeated twice, and is followed by sequentially connecting three glycine residues and then connecting 50-600mgN- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl]Serine, 20mL of 1% trifluoroacetic acid (99 mLCH) was added 2 Cl 2 1mL of trifluoroacetic acid) cutting fluid is added, and N is introduced 2 Bubbling for 1min, and collecting the reaction solution in an eggplant-shaped flask. Repeating the cutting operation for 5 times, collecting all the reaction liquid, and evaporating to dryness by rotation to obtain oily liquid. Adding appropriate amount of glacial ethyl ether, and separating out pale yellow solid.
S7 preparation of N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycinoyl glycylcysteine
Dissolving 5-50mgN- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl (S-tert-butylthio) cysteine in 0.5-5mL of ethanol, adding 0.5-5mL of 12.5mg/L of tris (2-carboxyethyl) phosphine (TCEP), uniformly mixing, standing at room temperature for 30-60min, and separating and purifying by semi-preparative high-efficiency liquid phase to obtain the required N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl cysteine.
The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative 99m Tc-SG 3C-CBM) and adopting SG3C bromobenzyl ether derivatives, comprising the following steps:
dissolving 50-800 μg of marking precursor (SG 3C bromobenzyl ether derivative, SG 3C-CBM) in ethanol, adding 1-10mg sodium glucoheptonate, 0.2-10mg disodium ethylenediamine tetraacetate, 5-200 μg stannous chloride and pertechnetum acid solution, shaking, incubating at 37deg.C for 45-90min to obtain the final product 99m Tc-SG3C-CBM。
The invention also discloses an application of the SG3C bromobenzyl ether derivative as a ligand to form a complex with a nuclide marker in PD-L1 imaging, which is used for preparing an imaging agent reflecting the expression level of PD-L1 on the surface of tumor cells; the nuclide label is preferably 99m Tc。
Example 1
An SG 3C-type bromobenzyl ether derivative has the following structural formula (I):
a preparation method of SG3C bromobenzyl ether derivatives comprises the following steps:
s1, preparation of 2-bromo-3-phenyltoluene:
under the condition of introducing nitrogen, 1400mg of 2-bromo-3-iodotoluene is added into a 100mL three-necked flask, 50mL of dioxane/water (volume ratio is 5/1) is added to dissolve the 2-bromo-3-iodotoluene, after stirring for 10min, 700mg of phenylboric acid, 3600mg of cesium carbonate and 160mg of triphenylphosphine palladium are sequentially added, stirring is carried out at 75 ℃ for 18h, the reaction is stopped, the temperature is reduced to room temperature, after the solvent is distilled off by rotary evaporation, water and ethyl acetate are added for extraction for 3 times, the organic phases are combined, dried by anhydrous sodium sulfate, the organic phases are evaporated, and the mixture is passed through a silica gel column to obtain 1015mg of colorless oily substance with the yield of 87.2%, 1 HNMR(400MHz，DMSO-d 6 )δ7.42-7.31(m,5H,Ar-H)，7.25-7.20(d,2H,Ar-H)，7.12-7.08(m,1H,Ar-H)，2.45(s,3H,Ar-CH 3 )。
preparation of S2, 2-bromo-3-phenylbenzyl bromide
Under the condition of introducing nitrogen, 1000mg of 2-bromo-3-phenyltoluene is added into a 100mL three-necked flask, 40mL of anhydrous carbon tetrachloride is added to be completely dissolved, 500mg of N-bromosuccinimide is added under stirring, the temperature is raised to 80 ℃, then 10mg of benzoyl peroxide is added to react for 2 hours, 10mg of BPO is added to continue to react for 2 hours, the reaction is stopped, the temperature is reduced to room temperature, water and dichloromethane are added to extract, the organic phase is combined, anhydrous sodium sulfate is used for drying, and the organic phase is evaporated to dryness to obtain 2-bromo-3-phenylbenzyl bromide yellow oily substance which is directly used for the next reaction.
Preparation of S3, 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde
Under nitrogen atmosphere, 750mg of 2, 4-dihydroxy-5-chlorobenzaldehyde was added to a 100mL three-necked flask, dissolved in 20mL of acetonitrile, and then 500mg of NaHCO was added 3 Stirring at room temperature for 5min, then dropwise adding 5mL of the acetonitrile solution of the 2-bromo-3-phenylbenzyl bromide obtained in the step, heating to 75 ℃ after the completion of the dropwise addition, and stirring overnight. The reaction solution is then cooled downFiltering at room temperature, washing the filtrate with water, extracting the aqueous solution with ethyl acetate for 2 times, and mixing the organic phases with anhydrous Na 2 SO 4 Drying, evaporating to dryness, recrystallizing with ethyl acetate and petroleum ether to obtain light yellow solid 640mg with yield of 37.9%, 1 HNMR(400MHz，DMSO-d 6 )δ11.20(s,1H,-OH)，10.05(s,1H,-CHO)，7.72(d,1H,Ar-H)，7.61(d,1H,Ar-H)，7.51-7.32(m,7H,Ar-H)，6.78(s,1H,Ar-H)，5.28(s,2H,-CH 2 -)。
preparation of S4, 2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde
460mg of 2-hydroxy-4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde was dissolved in 6mL of DMF under nitrogen, 300mg of cesium carbonate was added, stirring was carried out at room temperature for 15min, then 3mL of a DMF solution of 260mg of 3-cyano-benzyl bromide was added dropwise, and after the dropwise addition, the temperature was raised to 85℃and stirring was carried out overnight. Then cooling the reaction liquid to room temperature, pouring the reaction liquid into 100mL of water, extracting the reaction liquid with ethyl acetate for 3 times, combining organic phases, drying, evaporating the organic phases to dryness, recrystallizing the organic phases with ethyl acetate and petroleum ether to obtain 460mg of yellow solid with the yield of 78.5%, 1 HNMR(400MHz，DMSO-d 6 )δ10.24(s,1H,-CHO)，8.05(s,1H,Ar-H)，7.90-7.78(dd,2H,Ar-H)，7.70-7.65(s,1H,Ar-H)，7.65-7.55(m,2H,Ar-H)，7.55-7.30(m,7H,Ar-H)，7.20(s,1H,Ar-H)，5.50-5.35(m,4H,-CH 2 -)。
s5 preparation of N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] serine
340mg of 2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzaldehyde and 120mg of serine are dissolved in ethanol, 150 mu L of acetic acid and 300mg of anhydrous sodium sulfate are added, the mixture is heated and refluxed for 4 hours, cooled to room temperature, 10mL of methanol solution of 300mg of cyano sodium borohydride is added, the mixture is stirred and reacted for 24 hours at room temperature, the solvent is evaporated, the aqueous solution is extracted with ethyl acetate for 3 times, the organic phase is combined, and anhydrous Na is used 2 SO 4 Drying and evaporating the solvent to dryness gave 245mg of the desired product in 61.8% yield, MS:623 (M+1), 1 HNMR(400MHz，DMSO-d 6 ):δ8.03-7.99(s,1H,Ar-H)，7.92-7.87(d,1H,Ar-H),7.84-7.79(d,1H,Ar-H),7.67-7.58(m,2H,Ar-H),7.55-7.35(m,8H,Ar-H),7.08-7.03(s,1H,Ar-H),5.37-5.24(m,4H,-CH 2 -),4.03-3.93(s,2H,-CH 2 -),3.76-3.67(m,1H,-CH-),3.67-3.58(m,1H,-CH-),3.54-3.26(m,1H,-CH-),3.23-3.10(m,1H,-NH-)。
s6, preparation of N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycinoyl glycylglycinoyl (S-t-butylthio) cysteine
By polypeptide solid phase synthesis, 142 mgN-fluorenylmethoxycarbonyl-S-tert-butylsulfanylcysteine is firstly connected to 225mg resin, N protecting group fluorenylmethoxycarbonyl (Fmoc) is removed, then 81 mgN-fluorenylmethoxycarbonyl glycine is connected, N protecting group fluorenylmethoxycarbonyl (Fmoc) is removed, three glycine is connected in turn, 167mgN- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl is connected]Serine, 20mL of 1% trifluoroacetic acid (99 mLCH) was added 2 Cl 2 1mL of trifluoroacetic acid) cutting fluid is added, and N is introduced 2 Bubbling for 1min, and collecting the reaction solution in an eggplant-shaped flask. Repeating the cutting operation for 5 times, collecting all the reaction liquid, and evaporating to dryness by rotation to obtain oily liquid. Proper amount of glacial ethyl ether is added, light yellow solid is separated out, 170mg of product is obtained, the yield is 64.2%, and MS:985 (M+1), 1 HNMR(400MHz，DMSO-d 6 ):8.73-8.67(m,1H,-NH-),8.34-8.28(d,1H,-NH-),8.27-8.20(m,1H,-NH-),8.16-8.10(m,1H,-NH-),7.98-7.94(s,1H,Ar-H),7.84-7.76(m,2H,Ar-H),7.63-7.54(m,3H,Ar-H),7.51-7.31(m,7H,Ar-H),7.07-7.03(s,1H,Ar-H),5.32-5.23(m,4H,-CH 2 -),4.51-4.41(m,1H,-CH-),4.17-4.05(s,2H,-CH 2 -),3.79-3.65(m,8H,-CH 2 -),3.09-3.01(m,1H,-CH 2 -),2.96-2.88(m,1H,-CH 2 -),2.00-1.90(m,1H,-NH-),1.54-1.35(m,1H,-CH-),1.26-1.23(s,9H,-CH 3 )。
s7 preparation of N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycine glycylcysteine (SG 3C-CBM)
10mg of N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycine (S-t-butylthio) cysteine was dissolved in 1mL of ethanol, 1mL of 12.5mg/L of tris (2-carboxyethyl) phosphine (TCEP) was added, and the mixture was left to stand at room temperature for 50min, and was purified by semi-preparative high performance liquid chromatography at a flow rate of 3mL/min with a mobile phase of water/acetonitrile (v/v) =3/2 to give 8mg of the desired N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-serinylglycylglycine cysteine with a yield of 87.91%, MS:897 (M+H), 1HNMR (400 MHz, DMSO-d 6): 8.32-8.20 (s, 1H, -NH-), 8.20-8.12 (M, 2H, -NH-), 8.04-7.92 (s, 1H, ar-H), 7.88-7.77 (M, 2H, ar-H), 7.66-7.59 (M, 2H, ar-H), 7.55-7.34 (M, 8H, ar-H), 7.12-7.01 (s, 1H, ar-H), 5.35-5.25 (s, 4H, -CH 2-), 4.44-4.36 (M, 1H, -CH-), 4.20-4.06 (s, 1H, -CH-), 3.85-3.67 (M, 8H, -CH 2-), 2.90-2.70 (d, 2H, -CH 2-), 2.62-2.57 (s, 1H, -CH 2-), 5.35-5.25 (s, 4H, -CH 2-), 4.44-4.36 (M, 1H, -CH-), and 2.37-2.0.9-H.
Example 2
The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative 99m Tc-SG 3C-CBM) and adopting SG3C bromobenzyl ether derivatives, comprising the following steps:
600 mu g of a labeling precursor (SG 3C bromobenzyl ether derivative, SG 3C-CBM) is dissolved in 200 mu L of ethanol, 120 mu L of 50mg/mL of sodium glucoheptonate, 50 mu L of 20mg/mL of disodium ethylenediamine tetraacetate, 10 mu L of 10mg/mL of stannous chloride and 0.5mL of pertechnetate solution (1 mCi/mL) are added, shaking is carried out, and incubation is carried out at 37 ℃ for 60min, thus obtaining the required product 99m Tc-SG3C-CBM。
99m Detection of Tc-SG3C-CBM labelling Rate
Prepared by the method 99m The labeling rate of Tc-SG3C-CBM was detected by isotope high performance liquid phase, C18 reverse phase column, mobile phase was water/acetonitrile=1/1 (v/v), flow rate was 1mL/min, labeling rate was more than 96%, as shown in FIG. 3. Without labelling precursors, other conditions being the same as for labelling 99m Tc-blank, as shown in FIG. 4. The retention times of the two are about 5min apart and can be completely separated.
99m Stability determination of Tc-SG3C-CBM
To be prepared into 99m The radiochemical purity of Tc-SG3C-CBM was determined after being left at room temperature (25 ℃) for different times (0 h, 1h, 2h, 3h, 4h, 5h, 6 h).
The experimental result shows that the method has the advantages of high yield, 99m after the Tc-SG3C-CBM is left at room temperature for 6 hours, the radiochemical purity is still more than 95%, which indicates 99m The Tc-SG3C-CBM is stable in vitro at room temperature and is suitable for clinical application.
99m Lipid fraction distribution coefficient of Tc-SG3C-CBM
50 μL (50 μCi) 99m Tc-SG3C-CBM was added to a tube containing 1mL of n-octanol and 1mL of phosphate buffer (PBS, pH=7.0), after vortexing for 3min, 100. Mu.L of n-octanol and 100. Mu.L of LPBS were removed, radioactivity was measured on a gamma-counter, 200. Mu.L of n-octanol was added to a tube containing 800. Mu.L of n-octanol and 1mLPBS, and the operation was repeated until the ratio of counts of n-octanol to counts of PBS was constant. Calculation of lipid partition coefficient logp=log [ (count of n-octanol)/(count of PBS)]=0.86, which can reflect the partition of the drug between the aqueous and lipid phases in the organism.
99m Cell uptake assay for Tc-SG3C-CBM
Tumor cell lines (A375-hPD-L1, A375) with different PD-L1 expression levels were plated separately and incubated overnight; the next day add 99m Tc-SG3C-CBM (10. Mu. Ci), cells were incubated for 2h in a37℃cell incubator, the cell culture broth was aspirated, rinsed 2 times with PBS, lysed with NaOH solution for 15min, the cell lysate was collected and radioactivity was measured on a gamma-counter. Cell uptake (AD%) is equal to the percentage ratio of measured cell radioactivity to total radioactivity added to each well. 99m Tc-SG3C-CBM uptake at A375-hPD-L1 (17.51%) was 6.46 times that of A375 cells (2.71%), the two cell lines were expressed differently by PD-L1, to 99m There was a significant difference in Tc-SG3C-CBM uptake.
Example 3
The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative 99m Tc-SG 3C-CBM), the amount of SG3C-CBM was changed to 50-800. Mu.g, and the other components were kept in the same amounts as in example 2, according to the preparation method and the labeling rate measurement method of example 2. Experimental results show that when the dosage of SG3C-CBM reaches 500 mug, the labeling rate is more than 96%.
Example 4
The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative 99m Tc-SG 3C-CBM), the amount of sodium glucoheptonate was changed to 1-10mg, and the other components were kept in the same amounts as in example 2, according to the preparation method and the labeling rate measurement method of example 2. Experimental results show that the marking rate is more than 96% when the dosage of the sodium glucoheptonate is in the range of 2-10 mg.
Example 5
The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative 99m Tc-SG 3C-CBM), the dosage of disodium ethylenediamine tetraacetate is changed to 0.2-10mg, and the content of other components is kept the same as that of the example 2, and the preparation method and the marking rate measurement method of the example 2 are adopted. Experimental results show that the marking rate is more than 96% when the dosage of disodium ethylenediamine tetraacetate is in the range of 1-10 mg.
Example 6
The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative 99m Tc-SG 3C-CBM), the amount of stannous chloride was changed to 5-200. Mu.g, and the other components were kept in the same amounts as in example 2, according to the preparation method and the mark rate determination method of example 2. Experimental results show that the marking rate is more than 96% when the using amount of stannous chloride is in the range of 10-150 mug.
Example 7
The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative 99m Tc-SG 3C-CBM), the incubation time is changed to 45min, 60min, 75min and 90min, and the content of other components is kept the same as the dosage of the example 2, and the preparation method and the marking rate measurement method of the example 2 are adopted. Experimental results show that the heating time is more than 60min, and the marking rate is more than 96%.
The part of the invention which is not specifically described is only required to adopt the prior art, and is not described in detail herein.
The foregoing description is only illustrative of the present invention and is not intended to limit the scope of the invention, and all equivalent structures or equivalent processes or direct or indirect application in other related technical fields are included in the scope of the present invention.
Claims (10)
1. The SG3C bromobenzyl ether derivative is N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl cysteine, and has the following structural formula (I):
2. the preparation method of the SG 3C-type bromobenzyl ether derivative according to claim 1, which is characterized by comprising the following steps:
n- [2- (3-cyanobenzene-1-methoxylidene) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] serine, fmoc-glycine and FMOC-thio-tert-butyl-cysteine are taken and synthesized into N- [2- (3-cyanobenzene-1-methoxylidene) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl (S-tert-butylthio) cysteine by a solid-phase polypeptide synthesis method, tris (2-carboxyethyl) phosphine (TCEP) is added, tert-butylthio is removed, and N- [2- (3-cyanobenzene-1-methoxylidene) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl cysteine is obtained.
3. The method for preparing SG3C bromobenzyl ether derivatives according to claim 2, wherein the solid phase polypeptide synthesis method uses resin as carrier, synthesizes N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl (S-t-butylthio) cysteine, and then cuts N- [2- (3-cyanobenzene-1-methyleneoxy) -4- (2-bromo-3-phenylbenzyloxy) -5-chlorobenzyl ] -N-seryl glycyl (S-t-butylthio) cysteine from the resin by using a cutting solution, wherein the cutting solution is preferably a solution containing trifluoroacetic acid.
4. The use of SG 3C-bromobenzyl ether derivatives as claimed in claim 1 as ligands for forming complexes with nuclide labels for PD-L1 imaging.
5. The use of SG 3C-bromobenzyl ether derivatives as ligands to form complexes with nuclear labels for PD-L1 imaging according to claim 4, wherein the nuclear labels are 99m Tc。
6. The method comprises the following steps of 99m Tc marked SG3C bromobenzyl ether derivative is characterized in that the derivative is prepared by adopting the SG3C bromobenzyl ether derivative in claim 1.
7. A kind of according to claim 6 99m The preparation method of the Tc-marked SG3C bromobenzyl ether derivative is characterized by comprising the following steps:
adding glucoheptonate, edetate, stannous chloride and pertechnetum acid solution into the SG3C bromobenzyl ether derivative solution of claim 1, uniformly mixing, incubating, and taking out to obtain the required product.
8. A kind of according to claim 7 99m The preparation method of the SG3C bromobenzyl ether derivative marked by Tc is characterized in that the SG3C bromobenzyl ether derivative is dissolved in an alcohol solvent to obtain a solution of the SG3C bromobenzyl ether derivative; the incubation temperature is preferably 30-45 ℃, and the incubation time is preferably more than 60 min.
9. A kind of according to claim 6 99m Application of SG3C bromobenzyl ether derivative marked by Tc as imaging agent in detecting PD-L1 expression.
10. An imaging agent, characterized in that said imaging agent is one of the agents of claim 6 99m Tc-labeled SG 3C-bromobenzyl ether derivatives.
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