CN113717169B - N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 - Google Patents
N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 Download PDFInfo
- Publication number
- CN113717169B CN113717169B CN202111030536.4A CN202111030536A CN113717169B CN 113717169 B CN113717169 B CN 113717169B CN 202111030536 A CN202111030536 A CN 202111030536A CN 113717169 B CN113717169 B CN 113717169B
- Authority
- CN
- China
- Prior art keywords
- carboline
- diphenylamino
- compound
- indolium salt
- beta
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- HGQIRDQCVJKSEI-UHFFFAOYSA-N C1=CC=C2NC=CC2=C1.N1=CC=C2C3=CC=CC=C3NC2=C1 Chemical class C1=CC=C2NC=CC2=C1.N1=CC=C2C3=CC=CC=C3NC2=C1 HGQIRDQCVJKSEI-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 43
- -1 diphenylamino modified beta-carboline indolium salt Chemical class 0.000 claims abstract description 36
- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 62
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000006184 cosolvent Substances 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Substances [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 239000012216 imaging agent Substances 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- DNUXGDOJLQYUTO-UHFFFAOYSA-N Eudistomin N Chemical compound N1=CC=C2C3=CC(Br)=CC=C3NC2=C1 DNUXGDOJLQYUTO-UHFFFAOYSA-N 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 238000005576 amination reaction Methods 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- AKQUHUJZRFFZOO-UHFFFAOYSA-N 1,2,3,3-tetramethylindol-1-ium Chemical class C1=CC=C2C(C)(C)C(C)=[N+](C)C2=C1 AKQUHUJZRFFZOO-UHFFFAOYSA-N 0.000 claims 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims 1
- 150000005826 halohydrocarbons Chemical class 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 abstract description 5
- 238000005507 spraying Methods 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical compound N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- 239000007850 fluorescent dye Substances 0.000 description 7
- 238000003384 imaging method Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000002189 fluorescence spectrum Methods 0.000 description 6
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OUYSFMIEGWBQFB-UHFFFAOYSA-N CC1=NC(C2=CC=C(C=O)S2)=CC(C2=C3)=C1N(C)C2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CC1=NC(C2=CC=C(C=O)S2)=CC(C2=C3)=C1N(C)C2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 OUYSFMIEGWBQFB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- OUKRZXHRDFZLNE-UHFFFAOYSA-N CC1=NC(I)=CC(C2=C3)=C1NC2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CC1=NC(I)=CC(C2=C3)=C1NC2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 OUKRZXHRDFZLNE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CWSODDIUFXFFSG-UHFFFAOYSA-N 1,2,3,3-tetramethyl-1,2-dihydroindol-1-ium;bromide Chemical compound [Br-].C1=CC=C2C(C)(C)C(C)[NH+](C)C2=C1 CWSODDIUFXFFSG-UHFFFAOYSA-N 0.000 description 1
- MBGDTSHOGKMEKH-UHFFFAOYSA-N 1h-indole-3-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CNC2=C1 MBGDTSHOGKMEKH-UHFFFAOYSA-N 0.000 description 1
- FAQVDANXTSFXGA-UHFFFAOYSA-N 2,3-dihydro-1h-benzo[g]indole Chemical group C1=CC=CC2=C(NCC3)C3=CC=C21 FAQVDANXTSFXGA-UHFFFAOYSA-N 0.000 description 1
- CVMXEDZZSWLXPB-UHFFFAOYSA-N 4-(2-bromoethyl)morpholine Chemical compound BrCCN1CCOCC1 CVMXEDZZSWLXPB-UHFFFAOYSA-N 0.000 description 1
- QKWYMDSYNLYTMF-UHFFFAOYSA-N CC1=NC(C(O)=O)=CC(C2=C3)=C1N(C)C2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CC1=NC(C(O)=O)=CC(C2=C3)=C1N(C)C2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 QKWYMDSYNLYTMF-UHFFFAOYSA-N 0.000 description 1
- GRWJDPBTIKVMOM-UHFFFAOYSA-N CC1=NC(C=O)=CC(C2=C3)=C1N(C)C2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound CC1=NC(C=O)=CC(C2=C3)=C1N(C)C2=CC=C3N(C1=CC=CC=C1)C1=CC=CC=C1 GRWJDPBTIKVMOM-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 125000004036 acetal group Chemical group 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Chemical group CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 230000006536 aerobic glycolysis Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000003271 compound fluorescence assay Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000007857 hydrazones Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002466 imines Chemical group 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000029219 regulation of pH Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
-
- 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
- C09K2211/1014—Carbocyclic compounds bridged by heteroatoms, e.g. N, P, Si or B
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
- C09K2211/1033—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom with oxygen
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
-
- 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
- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Materials Engineering (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及生物医药领域，涉及一类N,N二苯基氨基修饰的β‑咔啉吲哚鎓盐、制备方法与应用。该β‑咔啉吲哚鎓盐具有通式Ⅰ所示结构，可以利用ICT原理，在肿瘤组织酸性微环境下激活，选择性地在肿瘤部位快速产生pH敏感的近红外荧光，具体实施方法是将本发明β‑咔啉吲哚鎓盐的溶液喷洒或局部注射于肿瘤病灶部位及周围的组织上，利用荧光腔镜或活体成像仪对肿瘤病灶组织进行快速、选择性荧光成像和示踪，具有较高的肿瘤组织荧光成像选择性和较低的背景荧光干扰，能够对肿瘤进行精确检测。
Description
技术领域
本发明涉及生物医药领域，涉及一类N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用，具体涉及一类具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓及其制备方法与应用。
背景技术
癌症是人类面临的最致命的疾病之一，根据世界卫生组织2018年的统计，全球新增癌症病例1810万例，癌症死亡960万例。但是，如果能够对在肿瘤发展的早期对肿瘤进行成像诊断，这将大大改善癌症的死亡率。
临床上常见的成像技术如CT、MRI和PET等因其空间分辨率有限而难以对肿瘤进行精确的诊断指导。相比之下，荧光成像技术因其高灵敏度、高空间分辨率和能够实时成像诊断成等优势而受到越来越多的关注。在肿瘤荧光成像诊断技术中，一个关键就是设计出能够对肿瘤标志物快速准确响应的荧光探针。肿瘤细胞主要依赖于有氧糖酵解提供能量，在此过程中产生的乳酸会外排到细胞外，进而造成肿瘤酸性微环境，已有一些文献报道利用较低的pH来设计低pH响应的肿瘤诊断剂。以往报道的pH响应探针常常基于酸性敏感键来达到“开关”效果，如通过控制酸敏感的腙键、亚胺键或缩醛等断裂来控制荧光。但是该类pH探针具有明显的缺陷，第一，共价键断键过程需要一定的时间，不能够对肿瘤进行喷洒模式的快速、实时诊断；第二，其不具备荧光可逆性，所以不能够动态观察不同pH的肿瘤和正常组织。
与紫外-可见荧光相比，近红外(NIR)荧光探针具有对生物体损伤小、对组织穿透性好、组织自身荧光干扰少等优点而更适合体内成像。因此为了使其能够实时、精确、快速地对肿瘤进行成像诊断，本发明对β-咔啉进行修饰改造。
发明内容
β-咔啉化合物是一大类天然存在的吲哚生物碱，具有类似于咔唑的吡啶[3,4-b]并吲哚的平面三环结构骨架，同时具有较低的毒性。本发明在β-咔啉的6位引入供电子基团NN-二苯基氨基，可快速产生稳定的 pH敏感型荧光，通过在3位引入乙烯基连接不同取代的吲哚鎓盐或不同拼合形式的苯并吲哚鎓盐片段，β- 咔啉6位给电子效应的NN-二苯基氨基可以增强给电子能力，以获得更长的荧光波长和更大的Stokes位移值的荧光化合物，在β-咔啉的N9位引入含有吗啉基、哌嗪基等水溶性侧链，以改善整个分子的脂水分布系数，获得基于“供体-受体”型大Stokes位移的NIR荧光分子。与传统的pH荧光探针通过酸性敏感的腙键或缩醛基团激活的方式不同，该荧光探针可以通过分子内电荷转移(ICT)快速实现pH敏感性荧光，且具有酸性pH调控的荧光可逆性。
本发明化合物具有pH敏感的近红外荧光特性，且荧光随pH变化具有可逆性，能够制备成喷剂，可喷洒或局部注射在肿瘤细胞或组织表面进行快速、实时、选择性的荧光成像。目前临床上尚未有任何荧光显影剂采用喷洒方式对肿瘤组织进行快速、实时、选择性的荧光成像，本发明化合物将为临床这一应用领域进行很好的补充和扩展。
本发明具体技术方案如下：
一类具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐，具有通式Ⅰ所示结构：
其中，R1选自H，C1-C6烷基，C1-C6直链烷基吗啉；R2选自H、F、Cl、Br、I中的一种；Y-代表卤负离子、六氟磷酸根负离子、对甲苯磺酸负离子、或者甲磺酸负离子；n为0或1。
进一步的，一类具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐，所述式I的结构中，R1、R2、Y 及n选自如下组合：
R1＝CH3，R2＝I，Y＝I，n＝0，
或者
R2＝H，Y＝CH3SO3，n＝0，
或者R1＝CH3CH2，R2＝H，Y＝Br，n＝1，
或者R1＝CH3，R2＝I，Y＝PF6，n＝1，
上述通式结构化合物优选结构如表1所示：
表1通式Ⅰ部分化合物代号及其对应的结构
本发明的另一目的在于提供本发明通式Ⅰ所述化合物的如下制备方法：
制备方法路线为：
其中，R1选自H，C1-C6烷基，C1-C6直链烷基吗啉；R2选自H、F、Cl、Br、I中的一种；Y-代表卤负离子、六氟磷酸根负离子、对甲苯磺酸负离子、或者甲磺酸负离子；n为0或1。
制备方法具体包括以下步骤：
S1.制备中间体5：6-溴-β-咔啉1与卤代烃R1Br或R1I经NaH作用反应生成化合物2；
S2.化合物2通过与二苯胺在叔丁醇钠条件下经Pd(dBa)3、P(t-Bu)3催化反应得到胺化产物3；S3.经 LiAlH4还原胺化产物3的羧基变成醇中间体4；醇中间体4经DMP氧化醇获得醛中间体5；
S4.胺化产物3在K3PO4和I2催化下脱羧碘代获得化合物6，再在K2CO3、Pd(PPh)4催化下与甲酰基噻吩硼酸酯进行Suzuki偶联得到中间体7；
S5.醛中间体5或中间体7与吲哚鎓盐或苯并吲哚鎓盐在催化量的哌啶中加热回流，通过Knoevenagel 反应获得化合物I，具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐。
本发明还提供了上述N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐在制备pH响应的荧光显影剂中的应用。
进一步的，所述荧光显影剂为用于体内外肿瘤组织或肿瘤细胞的选择性荧光成像显影剂。
进一步的，所述应用具体为以助溶剂/表面活性剂/溶剂体系溶解所述N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐，得到可喷洒的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐溶液。
进一步的，所述助溶剂/表面活性剂/溶剂体系中，按体积百分比计，所述助溶剂的含量为1～30％，所述表面活性剂的含量为1～30％；所述助溶剂为1,2-丙二醇、DMSO或乙醇；所述溶剂为水；所述表面活性剂为吐温20、吐温40或吐温80。
进一步的，所述肿瘤为肝癌、结肠癌、乳腺癌、肺癌和宫颈癌肿瘤中的一种。
与现有技术相比，本发明具有的应用效果：本发明化合物利用ICT原理，在肿瘤组织酸性微环境下激活，选择性地在肿瘤部位快速产生pH敏感的近红外荧光，具体实施方法是将喷洒或局部注射本发明化合物溶液于术前或术中肿瘤病灶部位及周围的组织上，利用荧光腔镜或活体成像仪对肿瘤病灶组织进行快速、选择性荧光成像和示踪，具有较高的肿瘤组织荧光成像选择性和较低的背景荧光干扰，能够对肿瘤进行精确诊断，以指导手术和/或药物治疗。
附图说明
图1为本发明化合物紫外、荧光光谱，其中A图为I1的紫外吸收谱图，B图为I1的荧光谱图，C图为I4的紫外吸收谱图，D图为I4的荧光谱图；
图2为本发明化合物I1对肝癌细胞选择性荧光成像；
图3位本发明化合物I2对肺癌细胞荧光成像；
图4为本发明化合物I1对离体乳腺癌肿瘤选择性荧光成像；
图5为本发明化合物I1对临床结肠癌肿瘤选择性荧光成像；
图6为本发明化合物I4对临床结肠癌肿瘤选择性荧光成像。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1：(E)-2-(2-(6-(二苯基氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-7-碘-1,1,3-三甲基 -1H-苯并[e]吲哚-3-碘盐(化合物I1)
(1)6-溴-9-甲基-9H-吡啶甲基[3,4-b]吲哚-3-羧酸酯(化合物2)的制备
首先将化合物1(500mg,1.57mmol)溶于无水DMF，冰浴条件下加入NaH(301mg,12.56mmol)搅拌 0.5h后，加入CH3I(1ml,15.7mmol)，继续室温搅拌1h后，经TLC监测反应结束后，将反应液倒入冰水中，用0.1mol盐酸溶液调至pH为7，将滤液抽滤，滤饼干燥，得到化合物2，产率85％。1H NMR(400MHz,DMSO)δ12.21(s,1H,NH),8.84(s,1H,ArH),8.66(d,J＝1.7Hz,1H,ArH),7.70(dd,J＝ 8.7,1.9Hz,1H,ArH),7.61(d,J＝8.7Hz,1H,ArH),3.90(s,3H,OCH3),2.81(s,3H,CH3).
(2)6-(二苯氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-羧酸(化合物3)的制备
首先将化合物2(480mg,1.45mmol)，二苯胺(1.47g,8.7mmol)，Pd(dBa)3(83.375g,0.145mmol)，叔丁醇钠(430mg,5.8mmol)，三叔丁基膦0.1ml加入密封管中，加入4ml甲苯，N2保护，110℃反应12h，待反应结束后，经TLC监测反应结束后，将反应液用浓缩，制砂，过柱得化合物3，产率76％。1H NMR(400MHz,DMSO)δ10.8(s,1H,COOH),8.70(s,1H,ArH),8.19(s,1H,ArH),7.79(d,J＝8.9Hz,1H, ArH),7.42(dd,J＝8.8,1.9Hz,1H,ArH),7.27(t,J＝7.9Hz,4H,4ArH),6.98(dd,J＝10.7,7.7Hz,6H,2CH＝C, 4ArH),4.21(s,3H,CH3),3.08(s,3H,CH3).
(3)6-(二苯氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醇(化合物4)
首先将化合物3(530mg,1.3mmol)用无水THF(10ml)溶解，冰浴10min后，分批加入LiAlH4(74.1 mg,1.95mmol)，加完后搅拌30min后，恢复至室温继续反应约3h，经TLC监测反应结束后，加入10ml 甲醇至无气泡产生后加入1ml水，抽滤，用甲醇清洗滤饼，旋干得化合物4，产率80％。1H NMR(400MHz,DMSO)δ8.70(s,1H,ArH),8.19(s,1H,ArH),7.79(d,J＝8.9Hz,1H,ArH),7.42(dd,J＝ 8.8,1.9Hz,1H,ArH),7.27(t,J＝7.9Hz,4H,4ArH),6.98(dd,J＝10.7,7.7Hz,6H,2CH＝C,4ArH),5.21(m,2H, CH2),4.21(s,3H,CH3),3.89(s,1H,OH),3.08(s,3H,CH3).
(4)6-(二苯氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-甲醛(化合物5)的制备
首先将化合物4(500mg,1.27mmol)用无水DCM(10ml)溶解，加入DMP(1.076g,2.54mmol)，大约反应2h，待反应完毕后，将反应液用滴管加入50ml碳酸氢钠饱和溶液中，抽滤获得产物5，产率67％。1H NMR(400MHz,DMSO)δ9.75(s,1H,CHO),8.70(s,1H,ArH),8.19(s,1H,ArH),7.79(d,J＝8.9Hz,1H, ArH),7.42(dd,J＝8.8,1.9Hz,1H,ArH),7.27(t,J＝7.9Hz,4H,4ArH),6.98(dd,J＝10.7,7.7Hz,6H,2CH＝C, 4ArH),4.21(s,3H,CH3),3.08(s,3H,CH3).
(5)(E)-2-(2-(6-(二苯基氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-7-碘-1,1,3-三甲基-1H-苯并[e]吲哚-3-碘盐(化合物I1)的制备
首先将化合物5(480mg,1.22mmol)用无水乙醇(约2ml)溶解，加入7-碘-1,1,2,3-四甲基-1H-苯并[e] 吲哚-3-碘盐(379mg,1.22mmol)，大约反应0.5h，待反应完毕后，抽滤获得产物I1，产率85％。1H NMR(400MHz,CDCl3)δ8.13(d,J＝8.5Hz,1H,ArH),8.08(d,J＝8.9Hz,2H,2ArH),7.99(d,J＝8.1Hz, 2H,2ArH),7.84(m,1H,CH＝C),7.66(s,2H,2ArH),7.59(d,J＝7.9Hz,2H,2ArH),7.43(dd,J＝10.1,8.4Hz, 3H,3ArH),7.04(d,J＝7.7Hz,5H,5ArH),6.95(t,J＝7.4Hz,3H,2ArH,CH＝C),4.45(s,3H,CH3),4.18(s,3H, CH3),2.06(s,6H,2CH3),1.92(s,3H,CH3).
实施例2(E)-2-(2-(6-(6-(二苯氨基)-1-甲基-9-(2-吗啉代乙基)-9H-吡啶并[3,4-b]吲哚-3-基)乙烯基)-1,1,3-三甲基-1H-苯并[e]吲哚-3-磺酸盐(化合物I2)
参考实施例1中2的制备方法，将化合物碘甲烷替代方法中的溴乙基吗啉，最后得到深红色产物I2，产率 76％。1H NMR(400MHz,DMSO)δ8.67(s,1H,ArH),8.23(d,J＝2.1Hz,1H,ArH),8.23(m,2H,2ArH),8.06 (m,2H,2ArH),7.82(d,J＝8.9Hz,1H,ArH),7.54(m,3H,3ArH)7.44(d,J＝2.1Hz,1H,ArH),7.30(m,4H, 4ArH),6.99(t,J＝8.2Hz,6H,6ArH),4.78(dt,2H,CH2),3.54(m,4H,2CH2),3.11(s,3H,CH3),2.75(m,2H, CH2),2.47(m,4H,2CH2),2.06(s,6H,2CH3),1.9(s,3H,CH3).
实施例3(E)-2-(2-(5-(6-(二苯氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)噻吩-2-基)乙烯基)-1,3,3- 三甲基-3H-吲哚-1-溴盐(化合物I3)
(1)3-碘-1-甲基-N,N-二苯基-9H-吡啶并[3,4-b]吲哚-6-胺(化合物6)的制备
首先将化合物3(200mg,0.508mmol)、I2(280mg,1.103mmol)、K3PO4(186mg,0.876mmol)加入密封管中，用乙腈2ml溶解，N2保护，110℃反应18h，待反应结束后，加入三乙胺约1.2ml继续150℃反应4h，减压浓缩，柱层析分离获得化合物6，产率65％。1H NMR(400MHz,DMSO)δ8.70(s,1H,ArH),8.19(s,1H,ArH),7.79(d,J＝8.9Hz,1H,ArH),7.42(dd,J＝ 8.8,1.9Hz,1H,ArH),7.27(t,J＝7.9Hz,4H,4ArH),6.98(dd,J＝10.7,7.7Hz,6H,2CH＝C,4ArH),4.21(s,3H, CH3),3.08(s,3H,CH3).
(2)5-(6-(二苯氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)噻吩-2-甲醛(化合物7)的制备
首先将化合物6(170mg,0.730mmol)，碳酸钾(202mg,1.46mmol)，Pd(PPh3)4(69.44mg,0.073mmol)，噻吩硼酸酯醛(163mg,1.46mmol)加入密封管中，N2保护，用4ml甲苯溶解，110℃反应3h。待反应结束后，可以点板看见黄色荧光，然后用EA:PE＝1:2过柱，然后约500ml溶剂可以过下来，获得黄色固体化合物7，产率82％。1H NMR(400MHz,DMSO)δ9.84(s,1H,CHO),8.13(s,1H,ArH),8.00(d,1H,CH＝C),7.37-7.20(m,6H, 6ArH),6.81(m,2H,ArH),6.73-6.63(m,4H,4ArH),6.12(m,1H,ArH),3.82(s,3H,CH3),2.89(s,3H,CH3).
(3)(E)-2-(2-(5-(6-(二苯氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)噻吩-2-基)乙烯基)-1,3,3-三甲基 -3H-吲哚-1-溴盐(化合物I3)的制备首先将化合物7(121mg,0.256mmol)用无水乙醇(约2ml)溶解，加入1,2,3,3-四甲基-3H-吲哚溴盐(58.3mg,0.256mmol)，大约反应0.5h，待反应完毕后，将反应液抽滤获得产物I3，产率78％。1H NMR(400MHz,DMSO)δ8.92(d,1H,ArH),8.13(s,1H,ArH),8.02(m,1H,CH＝C),7.73(d,1H,ArH),7.37-7.20(m,9H,8ArH,CH＝C),6.81(m,2H,2ArH),6.65(m,5H,4ArH,CH＝C),6.20(m,1H,ArH),5.67(m, 1H,ArH),3.82(s,3H,CH3),2.89(s,3H,CH3),2.06(s,6H,2CH3),1.92(s,3H,CH3).
实施例4(E)-2-(2-(5-(6-(二苯氨基)-1,9-二甲基-9H-吡啶并[3,4-b]吲哚-3-基)噻吩-2-基)乙烯基)-7-碘-1,1,3-三甲基-1H-苯并[e]吲哚-3-六氟磷酸盐(化合物I4)的制备
参考实施例3中I3的制备方法，将化合物7-碘-1,1,2,3-四甲基-1H-苯并[e]吲哚-3-六氟磷酸盐代替方法中的 1,2,3,3-四甲基-3H-吲哚-1-溴盐，最后得到深红色产物I4，产率78％。1H NMR(400MHz,DMSO)δ8.92(d,1H,ArH),8.13(s,1H,ArH),8.02(m,3H,3ArH),7.73(d,1H,ArH),7.54 (d,2H,2ArH)7.37-7.20(m,9H,9ArH),6.81(m,2H,2ArH),6.65(m,5H,4ArH,CH＝C),6.20(m,1H,ArH),5.67 (m,1H,ArH),3.82(s,3H,CH3),2.89(s,3H,CH3),2.06(s,6H,2CH3),1.92(s,3H,CH3).
实施例5本发明化合物的紫外吸收光谱测试
将本发明荧光化合物溶于含1％DMSO的水溶液中，配制成5-20μM的检测液。采用紫外-可见分光光度计测试其紫外吸收光谱数据，结果显示本发明荧光化合物紫外最大吸收波长在520-650nm范围内。其中化合物I1和I4紫外最大吸收波长分别在592和583nm左右(图1中A和图1中C)；注：图1中A为I1的紫外吸收谱图，图1中B为I1的荧光谱图，图1中C为I4的紫外吸收谱图，图1中D为I4的荧光谱图。
实施例6本发明化合物的pH敏感荧光测试
将本发明荧光化合物溶于含1％DMSO的水溶液中，配制成5-20μM的检测液。采用荧光光谱仪测试其在pH＝3～8的荧光光谱数据，结果如图1所示。结果显示本发明荧光化合物最大发射波长在680-750nm 范围内。本发明化合物I1和I4在pH3.5～6.5之间的最大发射波长分别在740和692nm左右，荧光波长达到近红外区域，而在中性pH下几乎没有荧光，此外本发明化合物的Stokes位移值达到150～200nm，具有良好的荧光特性；
此外，化合物I1在740nm左右的荧光峰值随化合物I1的pH减小而增加，相反其荧光峰值随pH增加而减小，其峰值相差8倍(图1中B)。
实施例7本发明化合物对肿瘤细胞选择性荧光成像测试
通过使用40X物镜的共聚焦激光扫描显微镜(Leica TCS SP8)进行细胞摄取和定位。将人肝癌细胞 HepG2、正常肝细胞LO2和人肺癌细胞A549分别用1mL培养基以1×105细胞的密度在共聚焦培养皿中于37℃培养24h。然后，将HepG2和LO2细胞培养基替换为含有1～100μM的I1的新鲜培养基，将A549 细胞的培养基替换为含有1～100μM的I2的新鲜培养基，并在37℃下孵育10～30min，然后用PBS洗涤细胞3次。最后，使用共聚焦激光扫描显微镜获得细胞荧光成像的图像，结果如图2(化合物I1)和图3(化合物I2)所示。图2和图3中左测图为细胞明场图，右测图为细胞荧光成像图。
图2和图3成像结果显示，本发明化合物I1(10μM)在4h后能够清晰地对肝肿瘤细胞HepG2进行荧光成像，而在正常细胞LO2荧光很弱，根据细胞内荧光的量化，HepG2的荧光强度是LO2细胞的6.5倍，说明本发明化合物能够选择性地对肝肿瘤细胞荧光成像；同时，本发明化合物I2(50μM)在4h后能够清晰地对A549细胞进行荧光成像。这些结果表明本发明化合物的对肿瘤细胞具有选择性荧光成像的能力。
实施例8本发明化合物对离体肿瘤组织进行喷洒模式的荧光成像试验
取人乳腺癌细胞(MDA-MB-231)移植瘤模型裸鼠，将其处死，取出乳腺癌肿瘤及主要脏器进行喷洒成像分析。将配制好的本发明化合物I1溶液(10～100μM)喷洒在组织上3～5次，用PBS清洗并用棉花吸干，采用活体成像仪进行组织荧光成像。结果如图4所示，乳腺癌组织的荧光强度值明显高于其他器官组织，而正常器官组织几乎看不到荧光。由此说明了本发明化合物可选择性、快速对肿瘤组织喷洒成像，以实现对临床肿瘤组织的快速检测。
实施例9本发明化合物对临床肿瘤组织荧光成像试验
在此基础上，进一步研究本发明化合物对临床肿瘤组织的选择性成像能力。选取临床结肠癌组织及癌旁组织进行喷洒成像分析，将本发明化合物I1和I4溶液(10～100μM)均匀喷洒在结肠癌组织及癌旁组织 1～3次，3～10min后再用适当生理盐水洗去表面多余的溶液，利用活体成像仪进行荧光成像，结果如图5 (化合物I1)和图6(化合物I4)所示。
荧光成像结果表明，本发明化合物I1和I4能够在50μM下选择性、快速点亮临床结肠癌组织，而对周围正常组织不显色或显示较弱(图5-6)。由此进一步确认了本发明化合物对临床肝肿瘤组织的选择性成像能力。
以上对本发明的实施例进行了详细说明，但所述内容仅为本发明的较佳实施例，不能被认为用于限定本发明的实施范围。凡依本发明申请范围所作的均等变化与改进等，均应仍归属于本发明的专利涵盖范围之内。
Claims (9)
1.一类具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐，其特征在于，具有通式Ⅰ所示结构：
其中，R1选自H、C1-C6烷基和C1-C6直链烷基吗啉中的一种；R2选自H、F、Cl、Br和I中的一种；Y-代表卤负离子、六氟磷酸根负离子、对甲苯磺酸负离子和甲磺酸负离子中的一种；n为0或1。
2.根据权利要求1所述的一类具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐，其特征在于：R1选自H、甲基、乙基和乙基吗啉中的一种；R2选自H或I；Y-代表卤负离子、六氟磷酸根负离子、对甲苯磺酸负离子或者甲磺酸负离子；n为0或1。
3.根据权利要求1所述的一类具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐，其特征在于，所述通式Ⅰ所示结构中，R1、R2、Y及n选自如下组合：
R1＝CH3，R2＝I，Y＝I，n＝0，
或者
R2＝H，Y＝CH3SO3，n＝0，
或者R1＝CH3CH2，R2＝H，Y＝Br，n＝1，
或者R1＝CH3，R2＝I，Y＝PF6，n＝1，
4.一类具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐的制备方法，其特征在于，所述制备方法的路线如下式所示：
其中，R1选自H、C1-C6烷基和C1-C6直链烷基吗啉中的一种；R2选自H、F、Cl、Br和I中的一种；Y-代表卤负离子、六氟磷酸根负离子、对甲苯磺酸负离子或者甲磺酸负离子；n为0或1；
所述制备方法包括以下步骤：
S1.6-溴-β-咔啉1与卤代烃R1Br或R1I经NaH作用反应生成化合物2；
S2.化合物2通过与二苯胺在叔丁醇钠条件下经Pd(dBa)3、P(t-Bu)3催化反应得到胺化产物3；S3.经LiAlH4还原胺化产物3的羧基变成醇中间体4；醇中间体4经DMP氧化醇获得醛中间体5；
S4.胺化产物3在K3PO4和I2催化下脱羧碘代获得化合物6，再在K2CO3、Pd(PPh)4催化下与甲酰基噻吩硼酸酯进行Suzuki偶联得到中间体7；
S5.醛中间体5或中间体7与1,2,3,3-四甲基-3H-吲哚鎓盐或R2取代的1,2,3,3-四甲基-3H-苯并吲哚鎓盐在催化量的哌啶中加热回流，通过Knoevenagel反应获得化合物I，化合物I为具有pH敏感的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐。
5.权利要求1-3任一项所述N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐或权利要求4制备得到的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐在制备pH响应的荧光显影剂中的应用。
6.根据权利要求5所述的应用，其特征在于，所述荧光显影剂为用于体内外肿瘤组织或肿瘤细胞的选择性荧光成像显影剂。
7.根据权利要求5所述的应用，其特征在于，所述应用具体为以助溶剂/表面活性剂/溶剂体系溶解所述N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐，得到可喷洒的N,N-二苯基氨基修饰的β-咔啉吲哚鎓盐溶液。
8.根据权利要求7所述的应用，其特征在于，所述助溶剂/表面活性剂/溶剂体系中，按体积百分比计，所述助溶剂的含量为1～30％，所述表面活性剂的含量为1～30％；所述助溶剂为1,2-丙二醇、DMSO或乙醇；所述溶剂为水；所述表面活性剂为吐温20、吐温40或吐温80。
9.根据权利要求6所述的应用，其特征在于，所述肿瘤为肝癌、结肠癌、乳腺癌、肺癌和宫颈癌肿瘤中的一种。
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111030536.4A CN113717169B (zh) | 2021-09-03 | 2021-09-03 | N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 |
| PCT/CN2022/097845 WO2023029638A1 (zh) | 2021-09-03 | 2022-06-09 | N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 |
| AU2022338581A AU2022338581B2 (en) | 2021-09-03 | 2022-06-09 | N,N-DIPHENYLAMINO-MODIFIED β-CARBOLINE INDOLIUM SALT, PREPARATION METHOD AND USE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111030536.4A CN113717169B (zh) | 2021-09-03 | 2021-09-03 | N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113717169A CN113717169A (zh) | 2021-11-30 |
| CN113717169B true CN113717169B (zh) | 2022-05-17 |
Family
ID=78681323
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111030536.4A Active CN113717169B (zh) | 2021-09-03 | 2021-09-03 | N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN113717169B (zh) |
| AU (1) | AU2022338581B2 (zh) |
| WO (1) | WO2023029638A1 (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113717169B (zh) * | 2021-09-03 | 2022-05-17 | 南通大学 | N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 |
| CN114539232B (zh) * | 2022-01-26 | 2023-04-28 | 深圳大学 | 一种pH可逆激活近红外二区聚集诱导发光I型光敏剂及其应用 |
| CN115028572B (zh) * | 2022-04-27 | 2024-02-20 | 南通大学 | 一类咔唑苯并[e]吲哚杂合物及其制备方法与应用 |
| CN115385935B (zh) * | 2022-09-15 | 2023-06-27 | 南方医科大学 | 一种有机染料化合物及其制备方法和应用 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981870A (zh) * | 2019-12-09 | 2020-04-10 | 南通大学 | 基于pH和GSH双重响应的β-咔啉-环烯酮衍生物及其用途 |
| CN111196922A (zh) * | 2018-11-16 | 2020-05-26 | 南通大学 | pH敏感型β-咔啉衍生物荧光探针在肿瘤荧光成像中的应用 |
| CN111875603A (zh) * | 2020-08-03 | 2020-11-03 | 南通大学 | 一种β-咔啉吡啶鎓盐荧光探针及其制备方法与应用 |
| CN111925369A (zh) * | 2020-08-18 | 2020-11-13 | 南通大学 | 一类β-咔啉氰基呋喃衍生物及其制备方法与应用 |
| CN111943948A (zh) * | 2020-08-03 | 2020-11-17 | 南通大学 | β-咔啉吲哚鎓盐及其制备方法与应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113717169B (zh) * | 2021-09-03 | 2022-05-17 | 南通大学 | N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 |
-
2021
- 2021-09-03 CN CN202111030536.4A patent/CN113717169B/zh active Active
-
2022
- 2022-06-09 WO PCT/CN2022/097845 patent/WO2023029638A1/zh active Application Filing
- 2022-06-09 AU AU2022338581A patent/AU2022338581B2/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111196922A (zh) * | 2018-11-16 | 2020-05-26 | 南通大学 | pH敏感型β-咔啉衍生物荧光探针在肿瘤荧光成像中的应用 |
| CN110981870A (zh) * | 2019-12-09 | 2020-04-10 | 南通大学 | 基于pH和GSH双重响应的β-咔啉-环烯酮衍生物及其用途 |
| CN111875603A (zh) * | 2020-08-03 | 2020-11-03 | 南通大学 | 一种β-咔啉吡啶鎓盐荧光探针及其制备方法与应用 |
| CN111943948A (zh) * | 2020-08-03 | 2020-11-17 | 南通大学 | β-咔啉吲哚鎓盐及其制备方法与应用 |
| CN111925369A (zh) * | 2020-08-18 | 2020-11-13 | 南通大学 | 一类β-咔啉氰基呋喃衍生物及其制备方法与应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113717169A (zh) | 2021-11-30 |
| AU2022338581B2 (en) | 2023-06-29 |
| WO2023029638A1 (zh) | 2023-03-09 |
| AU2022338581A1 (en) | 2023-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113717169B (zh) | N,N二苯基氨基修饰的β-咔啉吲哚鎓盐、制备方法与应用 | |
| Niu et al. | Highly photostable two-photon NIR AIEgens with tunable organelle specificity and deep tissue penetration | |
| JP6606487B2 (ja) | ｉｎｖｉｔｒｏおよびｉｎｖｉｖｏイメージングおよび検出のための置換シラキサンテニウム赤色〜近赤外蛍光色素 | |
| JP5823413B2 (ja) | 新規なポルフィリン誘導体の製造方法、ならびにｐｄｔ剤および蛍光プローブとしてのそれらの使用 | |
| ES2670852T3 (es) | Colorantes con policiclo y uso de los mismos | |
| Goswami et al. | Synthesis of tumor-avid photosensitizer− Gd (III) DTPA conjugates: impact of the number of gadolinium units in T1/T2 relaxivity, intracellular localization, and photosensitizing efficacy | |
| CN105884748B (zh) | 一种马来酰亚胺丙酰哌嗪七甲川菁盐荧光载体及其制备方法和应用 | |
| Zou et al. | A multi-functional fluorescent probe with aggregation-induced emission characteristics: Mitochondrial imaging, photodynamic therapy and visualizing therapeutic process in zebrafish model | |
| WO2018206126A1 (en) | Imaging agents and methods | |
| CN103820104B (zh) | 一类以尼罗蓝为母体的近红外荧光探针、其制法及应用 | |
| AU2005275220B2 (en) | Adduct of fluorescent dye and tumor avid tetrapyrrole | |
| Huang et al. | NIR aza-pentamethine dyes as photosensitizers for photodynamic therapy | |
| CA2803876C (en) | Metallation enhancements in tumor-imaging and pdt therapy | |
| Li et al. | A live cell tracking NIR bioprobe for lung cancer cell metastasis monitoring | |
| Patel et al. | Impact of Substituents in Tumor Uptake and Fluorescence Imaging Ability of Near‐Infrared Cyanine‐like Dyes | |
| Yu et al. | Fluorescence enhancement of near infrared cell membrane probe by β-cyclodextrin supramolecular interaction | |
| CN113735839B (zh) | 二氢呫吨/苯并[cd]吲哚杂合物荧光探针及其制备方法与应用 | |
| Hu et al. | An advanced multifunctional prodrug combining photodynamic therapy with chemotherapy for highly efficient and precise tumor ablation | |
| CN113754642B (zh) | pH响应的半花菁吲哚类化合物及其制备方法与应用 | |
| CN109678888B (zh) | 噁嗪类化合物及其用途 | |
| IL148405A (en) | Apply dye-antibody to link to target structures of blood vessel formation in order to mark while linking the tumor boundaries | |
| CN114835629B (zh) | 一类咔唑苯并[cd]吲哚鎓盐及其制备方法与应用 | |
| CN115028572B (zh) | 一类咔唑苯并[e]吲哚杂合物及其制备方法与应用 | |
| CN115028625B (zh) | 一类β-咔啉喹啉杂合物、制备方法与应用 | |
| KR101842633B1 (ko) | 카텝신 b에 의해 활성화되는 암의 진단 또는 치료용 조성물, 이를 이용한 암의 근적외선 형광 이미징 및 광선 치료 |
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 |