CN113683605A - 一种基于聚集诱导发光的高效靶向高尔基体的化合物及生物应用 - Google Patents
一种基于聚集诱导发光的高效靶向高尔基体的化合物及生物应用 Download PDFInfo
- Publication number
- CN113683605A CN113683605A CN202110826693.XA CN202110826693A CN113683605A CN 113683605 A CN113683605 A CN 113683605A CN 202110826693 A CN202110826693 A CN 202110826693A CN 113683605 A CN113683605 A CN 113683605A
- Authority
- CN
- China
- Prior art keywords
- compound
- pyt
- cps
- tpe
- golgi
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 162
- 230000002776 aggregation Effects 0.000 title claims abstract description 15
- 238000004220 aggregation Methods 0.000 title claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 46
- 230000008685 targeting Effects 0.000 claims abstract description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000003384 imaging method Methods 0.000 claims abstract description 7
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims abstract description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 238000002428 photodynamic therapy Methods 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000003389 potentiating effect Effects 0.000 claims 4
- 210000004027 cell Anatomy 0.000 abstract description 52
- 210000002288 golgi apparatus Anatomy 0.000 abstract description 25
- 210000001519 tissue Anatomy 0.000 abstract description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 230000000694 effects Effects 0.000 description 28
- 238000011282 treatment Methods 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 239000000523 sample Substances 0.000 description 26
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 241000699670 Mus sp. Species 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000005286 illumination Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000014509 gene expression Effects 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 17
- 210000003470 mitochondria Anatomy 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 16
- 102000004169 proteins and genes Human genes 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 230000008045 co-localization Effects 0.000 description 13
- 230000008859 change Effects 0.000 description 12
- 238000004896 high resolution mass spectrometry Methods 0.000 description 12
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 12
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 210000003712 lysosome Anatomy 0.000 description 10
- 230000001868 lysosomic effect Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 101100377855 Artemia franciscana ABDA gene Proteins 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000013256 coordination polymer Substances 0.000 description 9
- 230000005284 excitation Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- AZJPTIGZZTZIDR-UHFFFAOYSA-L rose bengal Chemical compound [K+].[K+].[O-]C(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 AZJPTIGZZTZIDR-UHFFFAOYSA-L 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 230000001678 irradiating effect Effects 0.000 description 8
- 230000002438 mitochondrial effect Effects 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229930187593 rose bengal Natural products 0.000 description 8
- 229940081623 rose bengal Drugs 0.000 description 8
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 206010034972 Photosensitivity reaction Diseases 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000002189 fluorescence spectrum Methods 0.000 description 6
- 208000007578 phototoxic dermatitis Diseases 0.000 description 6
- 231100000018 phototoxicity Toxicity 0.000 description 6
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 210000001700 mitochondrial membrane Anatomy 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 210000003463 organelle Anatomy 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000010226 confocal imaging Methods 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 231100000263 cytotoxicity test Toxicity 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000006862 quantum yield reaction Methods 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- BMVSAKPRNWZCPG-UHFFFAOYSA-N 2-pyridin-4-ylacetonitrile Chemical compound N#CCC1=CC=NC=C1 BMVSAKPRNWZCPG-UHFFFAOYSA-N 0.000 description 3
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 3
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 3
- 238000002073 fluorescence micrograph Methods 0.000 description 3
- 230000005283 ground state Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 description 3
- JRCJYPMNBNNCFE-UHFFFAOYSA-N 1,6-dibromopyrene Chemical compound C1=C2C(Br)=CC=C(C=C3)C2=C2C3=C(Br)C=CC2=C1 JRCJYPMNBNNCFE-UHFFFAOYSA-N 0.000 description 2
- -1 4- (1, 2-bis (4-methoxyphenyl) -2-phenylethenyl) phenyl Chemical group 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 102100021181 Golgi phosphoprotein 3 Human genes 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 101001040734 Homo sapiens Golgi phosphoprotein 3 Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000005281 excited state Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- OIXUJRCCNNHWFI-UHFFFAOYSA-N 1,2-dioxane Chemical compound C1CCOOC1 OIXUJRCCNNHWFI-UHFFFAOYSA-N 0.000 description 1
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- FTCUDNKNMYYVKS-UHFFFAOYSA-N 1-methoxy-2-(1,2,2-triphenylethenyl)benzene Chemical group COC1=CC=CC=C1C(C=1C=CC=CC=1)=C(C=1C=CC=CC=1)C1=CC=CC=C1 FTCUDNKNMYYVKS-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102000006404 Mitochondrial Proteins Human genes 0.000 description 1
- 108010058682 Mitochondrial Proteins Proteins 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 239000008358 core component Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004424 polypyridyl Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1011—Condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—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
- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials Engineering (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Optics & Photonics (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明属于肿瘤治疗和生物分析检测领域,涉及一种基于聚集诱导发光的化合物,特别涉及一种高效靶向高尔基体的化合物及生物应用。
背景技术
迄今为止,癌症被认为是威胁人类健康的第二大杀手。联合国癌症署日前指出,至2030年,每年死于癌症的患者将超过1300万人。目前,治疗癌症的手段主要有手术、放疗、化疗和分子靶向药物。其中手术和放疗为局部治疗,化疗和分子靶向药物治疗为全身治疗。化疗药物中,铂类药物的临床使用率超过50%。但是,铂类抗肿瘤药物在临床使用中出现了严重的副作用,例如肾毒性、神经毒性、嗜中性白血球减少症等。为了减少治疗中的副作用,新的肿瘤治疗方法成为目前研究的热点。
光动力治疗(PDT)因具有超高时空分辨率、非侵入性和毒副作用低、能够克服传统治疗方法中存在的耐药性等优点,被认为是肿瘤治疗和各种非恶性疾病的有效方法之一。光动力治疗的核心组成部分为化合物、氧气和特定波长的光。其基本原理为:局部使用化合物(photosensitizer,PS),理想条件下PS会聚集在病变肿瘤细胞。PS接收特定波长的光后,由基态跃迁至激发态,处于激发态的PS能量较高,通过隙间穿越的方式达到激发三重态。PS从三重态衰变会基态的过程中会将其能量转移给周围的基态氧(II型PDT),从而生成一种高效的活性氧物质即单线态氧1O2,它可以造成细胞凋亡、坏死等。研究表明,单线态氧在生物系统中的寿命很短(半衰期:0.03to 0.18ms),这导致了它扩散聚集有限(扩散半径:0.02μm)。因此,为了提高光动力治疗的效果,人们开发出靶向亚细胞器的化合物。目前,已经报道的基于聚集诱导发光(aggregation induced emission,AIE)的化合物,它们靶向的亚细胞器包括线粒体、溶酶体、内质网、细胞膜等(Lv,W.;Zhang,Z.;Zhang,K.Y.;Yang,H.;Liu,S.;Xu,A.;Guo,S.;Zhao,Q.;Huang,W.,A Mitochondria-Targeted PhotosensitizerShowing Improved Photodynamic Therapy Effects Under Hypoxia.Angew Chem Int EdEngl 2016,55(34),9947-51;Li,W.;Yang,J.;Luo,L.;Jiang,M.;Qin,B.;Yin,H.;Zhu,C.;Yuan,X.;Zhang,J.;Luo,Z.;Du,Y.;Li,Q.;Lou,Y.;Qiu,Y.;You,J.,Targetingphotodynamic and photothermal therapy to the endoplasmic reticulum enhancesimmunogenic cancer cell death.Nat Commun 2019,10(1),3349;Huang,H.;Yu,B.;Zhang,P.;Huang,J.;Chen,Y.;Gasser,G.;Ji,L.;Chao,H.,Highly Charged Ruthenium(II)Polypyridyl Complexes as Lysosome-Localized Photosensitizers for Two-Photon Photodynamic Therapy.Angew Chem Int Ed Engl 2015,54(47),14049-52;Bu,Y.;Xu,T.;Zhu,X.;Zhang,J.;Wang,L.;Yu,Z.;Yu,J.;Wang,A.;Tian,Y.;Zhou,H.;Xie,Y.,ANIR-I light-responsive superoxide radical generator with cancer cell membranetargeting ability for enhanced imaging-guided photodynamic therapy.ChemicalScience 2020,11(37),10279-10286)。但是,目前能够靶向高尔基体的化合物鲜有报道,尤其是基于AIE的能够靶向高尔基体的化合物。
发明内容
针对现有化合物的不足,本发明提供了一种能基于AIE的能够高效靶向高尔基体的化合物及生物应用。在对肿瘤的光动力学治疗中,本发明所述的化合物具有较高的单线态氧产率,对肿瘤细胞的高尔基体实现了精确靶向。细胞实验表明,在光照下该化合物不仅具有更高的光毒性,在黑暗条件下具有较低的暗毒性。同时,在活体小鼠上对其肿瘤生长起到了显著的抑制作用且毒副作用较小,实现了良好的PDT效果。
本发明具体技术方案如下:
一种基于聚集诱导发光的高效靶向高尔基体的化合物及生物应用,具有如下通式结构:R1代表R2代表一个或多个苯环上任意位被一个或多个H或R3取代的R3代表C1-C12的烷基、C1-C12的烷氧基或C1-C12的卤代烷氧基,且被多个R3取代时,各取代基相同或不同。
R1分子结构中的氰基对于靶向高尔基体起到关键作用且能够提高化合物ROS产生效率。
优选的,R3代表C原子数为1、6、8或12的烷基、烷氧基或氟代烷氧基。
所述R1为带有正电荷的基团时,与阴离子成盐。优选的,阴离子选自Cl-,Br-,I-,NO3 -、或PF6 -。
本发明一种具体的高效靶向高尔基体的基于AIE的化合物,它们的化学结构式如下图所示:
本发明另一目的在于提供本发明所述的基于聚集诱导发光的高效靶向高尔基体的化合物在光动力治疗中的应用。
本发明所述的高效靶向高尔基体的化合物TPE-PyT-CPS能有效靶向高尔基体,其Pearson共定位系数0.98且能有效成像活细胞的高尔基体。本发明所述的化合物,具有较高的单线态氧量子产率(77.8%),能有效的在肿瘤细胞内产生单线态氧,其对宫颈癌细胞(HeLa Cells)IC50值为0.17μM;能对小鼠肿瘤部位进行成像,且能有效抑制肿瘤的生长。
有益效果
(1)本发明所述的高效靶向高尔基体的化合物TPE-PyT-CPS对高尔基体具有显著靶向效果,其与高尔基体的共定位系数为0.98,而在其他亚细胞器分布较少比如在线粒体的共定位系数为0.36。该化合物的荧光发射波长位于近红外区域(680nm),能有效成像小鼠肿瘤区域,因此在医学中具有广阔的应用前景。
(2)本发明所述的高效靶向高尔基体的化合物在黑暗条件下对细胞毒性很小;在532nm激光照射下能够显著的产生单线态氧,从而导致出现显著细胞凋亡。活体实验中该化合物能够显著的抑制小鼠肿瘤生长,且对其他器官没有明显损伤。
附图说明
图1.为本发明所述化合物TPE-PyT-CPS在水/乙腈混合溶剂中的荧光谱图。(A)为化合物TPE-PyT-CPS不同水组分的乙腈/水混溶剂中的荧光发射光谱图;(B)为不同含水量下TPE-PyT-CPS的相对荧光强度(黑点)和最大发射波长(红点)的曲线图,I0表示乙腈中的发射强度。
图2.为本发明所述化合物在乙腈(A)或水(B)中在光照下引起ABDA在371nm处紫外吸收光谱图变化。
图3.为本发明所述化合物TPE-PyT-CP分别与线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像。
图4.为本发明所述化合物TPE-PyT-CPS分别与线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像。
图5.为本发明所述化合物TPE-PyT-PS分别与线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像。
图6.为本发明所述化合物TPE-T-CPS分别与线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像。
图7.为本发明所述化合物HTPA-PyT-CPS分别与线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像。
图8.为本发明所述化合物TPA-PyT-CPS分别与线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像。
图9.为本发明所述化合物TPE-PyT-CPS进入HeLa细胞后在黑暗或光照条件下在的单线态氧激光共聚焦图像。
图10.为本发明所述化合物TPE-PyT-CPS在光照(A)或黑暗(B)条件下对HeLa细胞的体外细胞毒活实验。
图11.为本发明所述化合物TPE-T-CPS在光照(A)或黑暗(B)条件下对HeLa细胞的体外细胞毒活实验。
图12.为本发明所述化合物HTPA-PyT-CPS在光照(A)或黑暗(B)条件下对HeLa细胞的体外细胞毒活实验。
图13.为本发明所述化合物TPA-PyT-CPS在光照(A)或黑暗(B)条件下对HeLa细胞的体外细胞毒活实验。
图14.为本发明所述化合物TPE-PyT-CPS在不同处理条件下对HeLa细胞的高尔基体形貌的影响。
图15.为本发明所述化合物TPE-PyT-CPS在不同处理条件下对HeLa细胞中高尔基体相关蛋白表达的影响。(A)在不同光照条件下TPE-PyT-CPS引起HeLa细胞中高尔基体相关蛋白表达变化;(B)归一化后,不同照射时间下高尔基体相关蛋白表达,以黑暗中的蛋白质表达为1。
图16.为本发明所述化合物TPE-PyT-CPS在不同处理条件下对HeLa细胞中线粒体相关蛋白表达的影响。(A)在不同光照条件下TPE-PyT-CPS引起HeLa细胞中线粒体相关蛋白表达变化;(B)归一化后,不同照射时间下线粒体相关蛋白表达,以黑暗中的蛋白质表达为1。
图17.为本发明所述化合物TPE-PyT-CPS在不同光照条件下对HeLa细胞中线粒体膜电位的影响。
图18.为本发明所述化合物TPE-PyT-CPS经小鼠瘤内注射后经不同时间在小鼠体内荧光图像生物分布。(A)为瘤内注射TPE-PyT-CPS后在荷瘤小鼠体内的荧光分布;(B)为不同的时间小鼠TPE-PyT-CPS荧光强度的时间依赖性变化。
图19.为经本发明所述化合物TPE-PyT-CPS治疗后,肿瘤组织体积、重量以及小鼠体重的变化。(A)为小鼠肿瘤实物图;(B)为小鼠肿瘤体积变化;(C)为小鼠肿瘤重量变化;(D)为小鼠体重变化。
图20.不同处理后小鼠的各器官H&E染色切片图像。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实例。
实施例1:化合物TPE-PyT-PS的制备(吸电子基团中不含氰基)
化合物1的合成:在N2氛围中,向250ml三口烧瓶中分别加入1,6-二溴芘(5.0g,13.90mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)噻吩-2-氨基甲醛(3.33g,14.0mmol)和无水碳酸钾(4.14g),并向该体系中加入90ml甲苯和15ml水并进行脱氧处理,最后再加入四(三苯基膦)钯催化剂(0.81g,0.70mmol)。将该反应混合溶液在85℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:1),从而得到浅黄色的产物1(2.3g,42.3%)。1H NMR(400MHz,Chloroform-d)δ10.02(s,1H),8.49(d,J=9.2Hz,1H),8.42(d,J=9.2Hz,1H),8.27(d,J=8.2Hz,1H),8.24(d,J=7.9Hz,1H),8.17(d,J=9.3Hz,1H),8.11(d,J=7.9Hz,1H),8.06(d,J=9.3Hz,1H),8.03(d,J=8.2Hz,1H),7.92(d,J=3.8Hz,1H),7.47(d,J=3.8Hz,1H).13CNMR(101MHz,Chloroform-d)δ182.90,152.61,144.21,136.68,131.68,130.65,130.20,129.88,129.30,128.97,128.88,128.80,128.68,128.35,127.06,125.99,125.77,125.20,124.49,124.35,120.87,29.70.HR-MS(ESI,positive mode,m/z):calcd for C21H11BrOS[M+H]+:390.9787,found:390.9779。
化合物2的合成:在N2氛围中,向100ml三口烧瓶中分别加入化合物1(0.942g,2.0mmol)、2-(4-(1,2-双(4-甲氧基苯基)-2-苯基乙烯基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊烷(1.10g,2.1mmol)和无水碳酸钾(0.55g),并向该体系中加入15ml甲苯和3ml水并进行脱氧处理,最后再加入四(三苯基膦)钯催化剂(0.115g,0.095mmol)。将该反应混合溶液在85℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:1),从而得到浅黄色的产物2(0.38g,27.1%)。1H NMR(400MHz,Chloroform-d)δ10.02(s,1H),8.44(d,J=9.2Hz,1H),8.24(d,J=7.9Hz,1H),8.21(d,J=4.5Hz,1H),8.19(d,J=3.2Hz,1H),8.14(d,J=9.3Hz,1H),8.10(d,J=7.9Hz,1H),8.02(t,J=8.7Hz,2H),7.93(d,J=3.9Hz,1H),7.51(d,J=3.8Hz,1H),7.38(d,J=8.1Hz,2H),7.24–7.13(m,7H),7.07(d,J=8.7Hz,2H),7.01(d,J=8.7Hz,2H),6.74(d,J=8.7Hz,2H),6.68(d,J=8.7Hz,2H),3.81(s,3H),3.77(s,3H).13C NMR(101MHz,Chloroform-d)δ182.92,171.99,158.15,156.79,153.26,144.18,143.96,143.56,140.65,136.75,136.44,132.77,132.64,131.80,131.50,131.41,130.06,129.95,129.14,128.74,128.21,128.13,127.82,127.14,126.58,126.25,125.19,124.45,124.05,113.08,113.05,55.20,55.12.HR-MS(ESI,positive mode,m/z):calcd for C49H34O3S[M+H]+:703.2301,found:703.2296。
化合物TPE-PyT-PS的合成:在氮气保护下,将化合物2(120mg,0.17mmol)和1,4-二甲基吡啶-1-溴化铵(300mg,2.12mmol)的混合物添加到50ml双口烧瓶中,然后添加20ml乙醇和6滴哌啶。将混合物加热至80℃并搅拌24小时。冷却至室温后,加入Et2O(20ml)形成固体。过滤固体并在真空下干燥,然后将所得固体溶解在丙酮(10ml)中,并且添加在2ml H2O中的KPF6(915mg,5mmol)溶液。将混合物在室温下搅拌6小时。在减压下去除丙酮,并通过硅胶层析使用CH2Cl2/MeOH(40:1,Rf=0.5)作为洗脱液纯化残余物,得到棕色固体(80mg,50.2%)的TPE-PyT-PS。1H NMR(400MHz,DMSO-d6)δ8.85(d,J=6.4Hz,2H),8.55(d,J=9.2Hz,1H),8.45–8.37(m,2H),8.34(dd,J=12.7,2.9Hz,2H),8.28–8.15(m,4H),8.07(dd,J=14.3,8.5Hz,2H),7.72(d,J=3.5Hz,1H),7.63(d,J=3.5Hz,1H),7.43(d,J=7.9Hz,2H),7.31(d,J=16.0Hz,1H),7.20(dq,J=14.9,7.1Hz,5H),7.11(d,J=7.2Hz,2H),7.00(d,J=8.5Hz,2H),6.94(d,J=8.4Hz,2H),6.81(d,J=8.5Hz,2H),6.73(d,J=8.5Hz,2H),4.25(s,3H),3.75(s,3H),3.71(s,3H).13C NMR(101MHz,DMSO-d6)δ157.83,157.70,152.04,145.11,144.88,143.57,143.07,141.34,140.32,138.27,137.73,137.55,135.57,135.44,133.42,132.61,132.10,131.97,130.87,130.74,129.97,129.72,129.53,128.61,128.31,128.23,128.02,127.91,127.46,126.29,125.30,124.92,124.42,124.13,123.85,123.08,122.07,113.16,54.83,46.74,28.92.HR-MS(ESI,positive mode,m/z):calcd for C56H42NO2S+[M]+:792.2931,found:792.2903。
实施例2:化合物TPE-PyT-CPS的制备
化合物TPE-PyT-CP的合成:在氮气保护下,将化合物2(147mg,0.228mmol)和2-(吡啶-4-基)乙腈(34mg,0.228mmol)加入50ml的双口烧瓶中,然后加入15ml乙醇和4滴哌啶。将混合物加热至80℃并搅拌24小时。反应后,用二氯甲烷和水萃取,然后用无水硫酸镁干燥。用DCM进行柱分离(Rf=0.4)粗产物,得到120mg红色固体,收率65.3%。1H NMR(400MHz,Chloroform-d)δ8.72(d,J=5.5Hz,2H),8.48(d,J=9.2Hz,1H),8.27–8.18(m,3H),8.18–8.12(m,2H),8.07–7.99(m,3H),7.94(d,J=3.8Hz,1H),7.76(d,J=5.0Hz,2H),7.55(d,J=3.8Hz,1H),7.38(d,J=8.1Hz,2H),7.25–7.13(m,7H),7.07(d,J=8.8Hz,2H),7.01(d,J=8.6Hz,2H),6.75(d,J=8.8Hz,2H),6.68(d,J=8.7Hz,2H),3.81(s,3H),3.77(s,3H).13CNMR(101MHz,Chloroform-d)δ158.27,158.15,148.72,148.71,144.17,143.57,140.66,138.88,138.71,138.46,137.85,137.52,136.44,136.26,136.05,132.76,132.64,131.80,131.80,131.50,131.42,130.07,129.95,129.31,129.25,128.82,128.73,128.34,128.16,127.84,127.82,128.73,127.17,126.61,126.25,125.32,125.21,124.98,124.51,124.04,119.97,117.05,113.09,113.05,55.20,55.12.HR-MS(ESI,positive mode,m/z):calcdfor C56H38N2O2S[M+H]+:803.2727,found:803.2757。
化合物TPE-PyT-CPS的合成:在氮气保护下,将TPE-PyT-CP(105mg,0.13mmol、CH3I(300mg,2.12mmol)和CH3CN(10ml)加入到50ml双口烧瓶中,并将混合物在90℃回流4h。冷却至室温后,加入Et2O(15ml)形成固体。过滤固体并在真空下干燥,然后将所得固体溶解在丙酮(10ml)中,并且添加在2mL H2O中的KPF6(915mg,5mmol)溶液。然后,将混合物在室温下搅拌6小时,后减压去除丙酮,以DCM/MeOH(30:1,Rf=0.5)为洗脱液,通过硅胶层析纯化粗产物,得到深红色固体TPE-PyT-CPS(103mg,82.2%)。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),9.01(d,J=6.9Hz,2H),8.51(d,J=9.3Hz,1H),8.42(dd,J=8.2,2.6Hz,2H),8.40–8.33(m,3H),8.27(dd,J=14.1,8.7Hz,2H),8.20(d,J=4.0Hz,1H),8.09(dd,J=17.9,8.6Hz,2H),7.87(d,J=3.9Hz,1H),7.44(d,J=8.1Hz,2H),7.20(dq,J=16.0,7.4Hz,5H),7.11(d,J=7.0Hz,2H),7.00(d,J=8.7Hz,2H),6.94(d,J=8.6Hz,2H),6.81(d,J=8.7Hz,2H),6.73(d,J=8.7Hz,2H),4.33(s,3H),3.75(s,3H),3.70(s,3H).13C NMR(101MHz,DMSO-d6)δ157.94,157.80,151.99,148.77,145.61,143.81,143.67,143.20,140.51,140.50,140.43,138.35,137.90,137.75,137.36,135.66,135.54,132.22,132.09,131.37,130.98,130.85,130.41,129.85,129.69,129.61,129.15,128.48,128.42,128.24,128.02,127.90,127.56,127.50,126.40,125.85,125.66,125.11,124.48,124.14,123.85,122.39,116.50,113.26,113.21,100.78,55.04,54.94,47.19,29.04.HR-MS(ESI,positive mode,m/z):calcd forC57H41N2O2S+[M-PF6 -]+:817.2883,found:817.2894。
实施例3:化合物HTPA-PyT-CPS的制备
化合物4的合成:在N2氛围中,向250ml三口烧瓶中分别加入1-溴辛烷(1.93g,10.0mmol)、4,4′-((4-溴苯基)氮炔基)二苯酚(1.89g,5.07mmol)和无水碳酸钾(2.1g,15mmol),并向该体系中加入90ml DMF并进行脱氧处理,将该反应混合溶液在140℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:6),从而得到产物4(2.52g,87.1%)。1H NMR(400MHz,Chloroform-d)δ7.22(d,J=8.9Hz,2H),7.00(d,J=8.6Hz,4H),6.90–6.68(m,6H),3.92(t,J=6.5Hz,4H),1.77(dt,J=14.5,6.6Hz,4H),1.45(dt,J=14.9,6.3Hz,4H),1.32(dd,J=13.4,7.8Hz,16H),0.97–0.82(m,6H)。
化合物5的合成:在N2氛围中,向100ml三口烧瓶中分别加入化合物4(1.5g,2.60mmol)、联硼酸频那醇酯(2.5g,10.0mmol)和乙酸钾(2g,20mmol),无水碳酸钾(4.14g),并向该体系中加入90ml DMSO并进行脱氧处理,最后再加入催化剂Pd(dppf)Cl2(1g)。将该反应混合溶液在90℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:1),从而得到浅黄色液体5(1.29g,79.3%)。1H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.2Hz,2H),7.04(d,J=8.4Hz,4H),6.91–6.74(m,6H),3.92(t,J=6.5Hz,4H),1.82–1.71(m,4H),1.49–1.41(m,4H),1.37–1.26(m,28H),0.92–0.86(m,6H)。
化合物HTPA-PyT-CHO的合成:在N2氛围中,向50ml三口烧瓶中分别加入1(0.2g,0.5mmol)、化合物5(0.8g,1.27mmol)和无水碳酸钾(1.3g,1mmol),并向该体系中加入45ml四氢呋喃和5ml水并进行脱氧处理,最后再加入四(三苯基膦)钯催化剂(0.3g,0.31mmol)。将该反应混合溶液在85℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:1),从而得到浅黄色的产物HTPA-PyT-CHO(0.326g,80.5%)。1H NMR(400MHz,Chloroform-d)δ10.01(s,1H),8.42(d,J=9.2Hz,1H),8.37(d,J=9.2Hz,1H),8.23(d,J=7.9Hz,1H),8.17(d,J=8.0Hz,1H),8.13(d,J=9.3Hz,1H),8.08(d,J=7.9Hz,1H),8.04(d,J=3.6Hz,1H),8.02(d,J=2.1Hz,1H),7.91(d,J=3.8Hz,1H),7.50(d,J=3.8Hz,1H),7.44(d,J=8.0Hz,2H),7.23–6.99(m,6H),6.95–6.82(m,4H),3.96(t,J=6.5Hz,4H),1.84–1.73(m,4H),1.51–1.44(m,4H),1.35–1.27(m,16H),0.90–0.87(m,6H).13C NMR(101MHz,Chloroform-d)δ182.88,153.34,143.91,136.71,131.87,131.12,129.78,129.33,129.09,128.74,128.25,128.15,127.94,126.96,126.80,125.33,125.26,125.04,124.31,123.82,115.32,68.30,31.83,29.39,29.26,26.11,22.67,14.11。
化合物HTPA-PyT-CP的合成:在氮气保护下,将化合物HTPA-PyT-CHO(500mg,0.615mmol)和2-(吡啶-4-基)乙腈(154mg,1.0mmol)加入50ml的双口烧瓶中,然后加入15ml乙醇和4滴哌啶。将混合物加热至80℃并搅拌24小时。反应后,用二氯甲烷和水萃取,然后用无水硫酸镁干燥。用DCM进行柱分离粗产物,得到384mg,收率68.6%。1H NMR(400MHz,Chloroform-d)δ8.69(d,J=5.6Hz,2H),8.46(d,J=9.2Hz,1H),8.37(d,J=9.2Hz,1H),8.22(d,J=8.0Hz,1H),8.19–8.08(m,3H),8.03(dd,J=8.5,2.8Hz,2H),7.93(s,1H),7.86(d,J=3.9Hz,1H),7.64–7.55(m,2H),7.50(d,J=3.8Hz,1H),7.46–7.38(m,2H),7.22–7.13(m,4H),7.13–7.05(m,2H),6.93–6.82(m,4H),3.96(t,J=6.5Hz,4H),1.85–1.72(m,4H),1.53–1.41(m,4H),1.39–1.26(m,16H),0.89(d,J=13.5Hz,6H).13C NMR(101MHz,Chloroform-d)δ155.68,150.80,149.77,148.29,142.27,140.59,138.81,137.55,137.22,135.52,132.30,131.80,131.71,131.15,129.80,129.33,129.09,128.76,128.73,128.28,128.22,127.79,126.99,126.92,126.77,125.40,125.24,125.08,124.35,123.86,119.75,117.19,115.37,104.55,68.30,31.83,29.39,29.26,26.11,22.67,14.11。
化合物HTPA-PyT-CPS的合成:在氮气保护下,将HTPA-PyT-CP(180mg,0.197mmol、CH3I(1g,7.04mmol)和CH3CN(10ml)加入到50ml双口烧瓶中,并将混合物在90℃回流4h。冷却至室温后,加入Et2O(15ml)形成固体。过滤固体并在真空下干燥,然后将所得固体溶解在丙酮(10mL)中,并且添加在2mL H2O中的KPF6(915mg,5mmol)溶液。然后,将混合物在室温下搅拌6小时,后减压去除丙酮,以DCM和MeOH为洗脱液,通过硅胶层析纯化粗产物,得到深红色固体HTPA-PyT-CPS(182mg,86.2%)。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),9.00(d,J=6.5Hz,2H),8.48(d,J=9.3Hz,1H),8.34(ddd,J=19.1,15.6,9.0Hz,6H),8.26–8.13(m,3H),8.06(d,J=7.8Hz,1H),7.84(d,J=3.9Hz,1H),7.46(d,J=8.1Hz,2H),7.13(d,J=8.4Hz,4H),6.95(dd,J=8.6,5.8Hz,6H),4.33(s,3H),3.93(t,J=6.4Hz,4H),1.69(p,J=6.6Hz,4H),1.39(q,J=7.1Hz,4H),1.31–1.21(m,16H),0.85(t,J=6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ155.98,152.60,149.26,148.51,146.07,144.25,140.94,140.16,138.73,137.76,131.94,131.60,131.46,130.78,130.07,129.77,129.61,128.95,128.86,128.78,128.31,127.78,127.72,127.63,126.71,126.15,125.32,125.06,124.73,124.34,123.85,122.84,118.96,116.95,116.03,101.19,68.10,47.65,31.71,29.22,29.15,26.02,22.56,14.42。
实施例4:化合物TPA-PyT-CPS的制备
化合物6的合成:在N2氛围中,向250ml三口烧瓶中分别加入1,6-二溴芘(5.0g,13.90mmol)、N,N-二苯基-4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺(5.2g,14.0mmol)和无水碳酸钾(4.14g),并向该体系中加入90ml甲苯和15ml水并进行脱氧处理,最后再加入四(三苯基膦)钯催化剂(0.803g,0.70mmol)。将该反应混合溶液在90℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:10),从而得到浅黄色的产物6(4.64g,63.7%)。1H NMR(400MHz,Chloroform-d)δ8.40(d,J=9.1Hz,1H),8.28(d,J=9.3Hz,1H),8.20(dd,J=8.0,4.1Hz,2H),8.13(d,J=9.2Hz,1H),8.00(d,J=7.9Hz,1H),7.97–7.90(m,2H),7.50–7.43(m,2H),7.34–7.28(m,4H),7.26–7.20(m,6H),7.06(tt,J=7.2,1.3Hz,2H).13C NMR(101MHz,Chloroform-d)δ147.73,147.26,138.26,134.64,131.39,130.48,130.16,129.96,129.41,129.02,128.51,128.27,127.00,126.18,125.77,125.26,125.22,124.71,124.46,123.18,119.87.HR-MS(ESI,positive mode,m/z):calcd for 523.0936,found:523.0839。
化合物TPA-PyT-CHO的合成:在N2氛围中,向250ml三口烧瓶中分别加入化合物6(2.0g,3.82mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)噻吩-2-氨基甲醛(1.67g,7.0mmol)和无水碳酸钾(1.38g,10mmol),并向该体系中加入60ml甲苯和5ml水并进行脱氧处理,最后再加入四(三苯基膦)钯催化剂(0.22g,0.191mmol)。将该反应混合溶液在90℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:5),从而得到浅黄色的产物TPA-PyT-CHO(1.51g,71.3%)。1H NMR(400MHz,Chloroform-d)δ9.99(s,1H),8.41(d,J=9.2Hz,1H),8.34(d,J=9.2Hz,1H),8.22(d,J=7.9Hz,1H),8.15(d,J=8.0Hz,1H),8.11(d,J=9.3Hz,1H),8.06(d,J=7.9Hz,1H),8.05–7.98(m,2H),7.88(d,J=3.8Hz,1H),7.54–7.44(m,3H),7.37–7.28(m,4H),7.28–7.20(m,6H),7.07(t,J=7.4Hz,2H).13C NMR(101MHz,Chloroform-d)δ182.83,153.20,147.68,147.26,143.93,138.42,136.66,134.61,131.79,131.37,129.94,129.37,129.28,129.08,128.70,128.17,128.04,127.11,126.59,125.27,125.24,124.99,124.68,124.39,123.95,123.15.HR-MS(ESI,positive mode,m/z):calcd for 555.1657,found:556.1714。
化合物TPA-PyT-CP的合成:在氮气保护下,将化合物TPA-PyT-CHO(138mg,0.248mmol)和2-(吡啶-4-基)乙腈(40mg,0.259mmol)加入25ml的双口烧瓶中,然后加入15ml乙醇和4滴哌啶。将混合物加热至80℃并搅拌24小时。反应后,用二氯甲烷和水萃取,然后用无水硫酸镁干燥。用DCM进行柱分离粗产物,得到79.2mg,收率48.7%。1HNMR(400MHz,Chloroform-d)δ8.74–8.66(m,2H),8.48(d,J=9.2Hz,1H),8.37(d,J=9.2Hz,1H),8.25(d,J=8.0Hz,1H),8.22–8.11(m,3H),8.06(dd,J=8.6,4.8Hz,2H),7.97(s,1H),7.90(d,J=3.9Hz,1H),7.69–7.62(m,2H),7.55–7.48(m,3H),7.37–7.29(m,4H),7.28(d,J=2.0Hz,1H),7.26–7.21(m,5H),7.08(tt,J=7.2,1.3Hz,2H).13C NMR(101MHz,Chloroform-d)δ151.10,149.15,147.70,147.29,142.94,138.50,137.59,137.56,135.81,134.62,131.81,131.39,130.00,129.39,129.34,129.19,128.79,128.76,128.34,128.22,127.88,127.17,126.64,125.38,125.27,125.07,124.71,124.48,124.01,123.17,119.86,117.10,104.35,53.42.HR-MS(ESI,positive mode,m/z):calcd for 655.2082,found:656.2160。
化合物TPA-PyT-CPS的合成:在氮气保护下,将TPA-PyT-CP(100mg,0.152mmol、CH3I(0.5g,3.52mmol)和CH3CN(10ml)加入到50ml双口烧瓶中,并将混合物在90℃回流4h。冷却至室温后,加入Et2O(15ml)形成固体。过滤固体并在真空下干燥,然后将所得固体溶解在丙酮(10mL)中,并且添加在2mL H2O中的KPF6(915mg,5mmol)溶液。然后,将混合物在室温下搅拌6小时,后减压去除丙酮,以DCM和MeOH为洗脱液,通过硅胶层析纯化粗产物,得到深红色固体TPA-PyT-CPS(109mg,88.5%)。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),9.01(d,J=6.5Hz,2H),8.51(d,J=9.2Hz,1H),8.48–8.35(m,5H),8.35–8.24(m,3H),8.20(d,J=3.7Hz,1H),8.11(s,1H),7.87(d,J=3.7Hz,1H),7.59(d,J=8.3Hz,2H),7.39(t,J=7.7Hz,4H),7.19(t,J=6.6Hz,6H),7.13(t,J=7.3Hz,2H),4.33(s,3H).13C NMR(101MHz,DMSO-d6)δ152.05,148.75,147.03,145.58,140.52,137.89,137.31,133.65,131.47,131.42,130.36,129.73,129.51,129.14,128.44,128.36,127.87,127.52,127.38,126.12,125.71,124.98,124.53,124.50,124.21,123.56,123.51,122.50,122.36,116.48,100.71,47.18.HR-MS(ESI,positive mode,m/z):calcd for 670.2312,found:670.2325。
实施例5:化合物TP-PyT-CPS的制备
化合物TPE-T-CHO的合成:在N2氛围中,向250ml三口烧瓶中分别加入4,4′-(2-(4-溴苯基)-2-苯基乙烯-1,1-二基)双(甲氧基苯)(4.71g,10.00mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)噻吩-2-氨基甲醛(3.33g,14.0mmol)和无水碳酸钾(4.14g),并向该体系中加入90ml甲苯和15ml水并进行脱氧处理,最后再加入四(三苯基膦)钯催化剂(0.803g,0.70mmol)。将该反应混合溶液在90℃反应18h,并用TLC板跟踪反应进程。待反应结束后,将反应液冷却至室温,得到的粗产物用水和二氯甲烷体系萃取,然后把溶剂减压蒸馏除去。粗产物使用二氯甲烷和石油醚进行层析柱分离(DCM:petroleum ether=1:1),从而得到浅黄色的产物TPE-T-CHO(3.80g,75.6%)。1H NMR(400MHz,Chloroform-d)δ9.86(s,1H),7.70(d,J=3.9Hz,1H),7.42(d,J=8.4Hz,2H),7.34(d,J=3.9Hz,1H),7.16–7.09(m,3H),7.07(d,J=8.4Hz,2H),7.03(dd,J=7.6,1.9Hz,2H),6.97(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),3.75(s,3H),3.74(s,3H).13CNMR(101MHz,Chloroform-d)δ182.71,158.36,158.23,154.37,145.95,143.83,141.96,141.20,138.16,137.46,135.99,132.62,132.59,132.16,131.39,130.46,127.86,126.35,125.63,123.72,113.22,113.02,55.12,55.09.HR-MS(ESI,positive mode,m/z):calcdfor C33H26O3S+[M]+:503.1675,found:503.1665。
化合物TPE-T-CP的合成:在氮气保护下,将化合物TPE-T-CHO(251mg,0.50mmol)和2-(吡啶-4-基)乙腈(88mg,0.60mmol)加入25ml的双口烧瓶中,然后加入15ml乙醇和4滴哌啶。将混合物加热至80℃并搅拌24小时。反应后,用二氯甲烷和水萃取,然后用无水硫酸镁干燥。用DCM进行柱分离粗产物,得到210mg,收率69.7%。1H NMR(400MHz,Chloroform-d)δ8.66(d,J=5.3Hz,2H),7.84(s,1H),7.65(d,J=4.0Hz,1H),7.58(d,J=6.1Hz,2H),7.44(d,J=8.4Hz,2H),7.34(d,J=4.0Hz,1H),7.13(d,J=7.2Hz,3H),7.06(dd,J=10.5,8.1Hz,4H),6.98(d,J=8.7Hz,2H),6.94(d,J=8.7Hz,2H),6.68(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),3.76(s,3H),3.74(s,3H).13C NMR(101MHz,Chloroform-d)δ158.40,158.25,152.07,149.41,145.83,143.84,142.66,141.25,138.20,137.43,136.62,136.02,135.81,132.62,132.60,132.20,131.42,130.36,127.86,126.37,125.57,123.78,119.68,117.18,113.25,113.03,103.72,55.13,55.10.HR-MS(ESI,positive mode,m/z):calcd forC40H30N2O2S+[M+H]+:603.2101,found:603.2082。
化合物TPE-T-CPS的合成:在氮气保护下,将TPE-T-CP(200mg,0.33mmol、CH3I(0.3g,2.12mmol)和CH3CN(15ml)加入到50ml双口烧瓶中,并将混合物在90℃回流4h。冷却至室温后,加入Et2O(15ml)形成固体。过滤固体并在真空下干燥,然后将所得固体溶解在丙酮(10mL)中,并且添加在2mL H2O中的KPF6(915mg,5mmol)溶液。然后,将混合物在室温下搅拌6小时,后减压去除丙酮,以DCM和MeOH为洗脱液,通过硅胶层析纯化粗产物,得到深红色固体TPE-T-CPS(150mg,59.6%)。1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.96(s,2H),8.30(d,J=6.9Hz,2H),7.98(d,J=4.1Hz,1H),7.80(d,J=4.0Hz,1H),7.63(d,J=8.3Hz,2H),7.15(dq,J=14.2,7.0Hz,3H),7.07(d,J=8.3Hz,2H),7.00(d,J=6.8Hz,2H),6.93(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),6.75(d,J=8.7Hz,2H),6.70(d,J=8.7Hz,2H),4.30(s,3H),3.69(d,J=2.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ157.92,157.78,153.18,148.78,145.69,145.40,143.58,143.30,141.27,140.88,137.71,135.42,135.28,132.03,131.96,131.79,130.74,129.70,129.50,127.91,126.40,125.66,125.44,122.14,116.38,113.30,113.09,99.92,54.84,47.02.HR-MS(ESI,positive mode,m/z):calcd for C41H33N2O2S+[M]+:617.2257,found:617.2243。
实施例6:化合物TPE-PyT-CPS在水/乙腈混合溶剂中的荧光谱图
(1)配制化合物TPE-PyT-CPS的乙腈溶液,浓度为1mM;(2)配制不同含水量的水/乙腈混合溶剂,其含水量由0-99%;(3)向上述混合溶剂中加入相同体积的浓度为10μM的TPE-PyT-CPS并测试其荧光发射光谱。
由化合物在水/乙腈混合溶剂中的荧光发射光谱(图1)可知,当含水量的增加到99%时,TPE-PyT-CPS的荧光发射光谱显著增强,这表明TPE-PyT-CPS具有显著的AIE性质。
实施例7:化合物TPE-PyT-CPS单线态氧产率的测定
(1)配制ABDA的DMSO溶液,浓度为5mM作为母液避光保存;(2)配制探针TPE-PyT-CPS的乙腈溶液,浓度为1mM。参照标准物:孟加拉玫瑰红(Rose Bengal,RB)用甲醇作为溶剂配制相同的浓度;(3)取一定体积的RB溶液加入到盛有3ml水或乙腈的比色皿中,使其紫外吸收强度最大值位于0.2-0.3之间;(4)取一定体积的ABDA溶液加入到上述比色皿中,并使其最大吸收强度位于0.7-1之间;根据RB的紫外吸收波长选择波长为530nm的激光器,测定特定时间(共150S)的紫外吸收即可测出ABDA随参比化合物RB的衰减曲线;(5)测试化合物TPE-PyT-CPS的单线态氧时,维持上述ABDA的浓度和体积以及激光器的功率不变。将上述参比RB换成TPE-PyT-CPS并维持其他条件不变,即可测试不同光照时间内ABDA随化合物TPE-PyT-CPS的衰减曲线,即可测出化合物单线态氧量子产率。
根据以下所述公式可以得到单线态氧效率:
ΦPS=ΦRB .(KPS .ARB)/(KRB ·APS)
式中,KPS和KRB分别为TPE-PyT-CPS和RB对ABDA的分解速率常数,其数值为ABDA在不同化合物作用的衰减拟合曲线的斜率。APS和ARB分别代表TPE-PyT-CPS和RB最大吸收值。ΦRB为RB的1O2量子产率,其数值在水中为0.75。
在光照下TPE-PyT-CPS分别在乙腈(图2A)或水(B)中引起ABDA的紫外可见光谱变化如图2所示。通过公式计算得出TPE-PyT-CPS在水中单线态氧产生效率为77.8%,而在乙腈中的单线态氧产率明显降低,表明该化合物在聚集条件下能够显著产生单线态氧的优势。此外,TPE-PyT-CPS具有较高的单线态氧量子产率,这可能与芘和噻吩的的引入能够降实现分子内有效的电荷分离,从而降低激发单重态(S1)和激发三重态(T1)的能级差ΔEST,实现较高的单线态氧产生效率。
实施例8:化合物TPE-PyT-CPS及其衍生物分别于线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像
(1)以TPE-PyT-CPS或TPE-PyT-PS为例进行共定位实验,其他化合物按照下面实验方法进行。在黑暗条件下先将HeLa细胞与10μM化合物TPE-PyT-CPS或TPE-PyT-PS进行共孵育6h;(2)弃去含化合物的细胞培养液并分别加入相应工作浓度的商业探针(Mito-Green、ER-Blue、Gogli-Green、Lyso-Green),然后各个商业探针的实验要求孵育30min左右;(3)弃去不同商业探针的培养液并用冷的PBS洗两遍,然后进行共定位激光共聚焦成像实验。
共聚焦成像实验:(1)对于化合物(TPE-PyT-CPS或TPE-PyT-PS)通道,采用488nm激发,600nm-750nm通道收集;(2)对于线粒体染料通道,采用488nm激发,495nm-535nm通道收集;(3)对于内质网染料通道,采用405nm激发,455nm-520nm通道收集;(4)对于高尔基体染料通道,采用488nm激发,495nm-535nm通道收集;(5)对于溶酶体染料通道,采用488nm激发,495nm-535nm通道收集。
由化合物TPE-PyT-CPS(图4)和TPE-PyT-PS(图5)分别与线粒体、溶酶体、高尔基体和内质网的共定位激光共聚焦图像可知,绿色通道内的商业探针表现出分布的显著不同,由此说明各个商业探针对各自靶向的亚细胞器的有效性。将绿色通道不同商业探针和红色通道的化合物(TPE-PyT-CPS)进行叠加(Merge),发现化合物与高尔基体探针的共定位系数为0.98,而它与其他亚细胞器的共定位系数显著降低,表明化合物TPE-PyT-CPS确实能够实现对高尔基体的高效靶向。值得注意的是,将化合物TPE-PyT-PS与高尔基体的共定位系数只有0.68(图5),说明吸该分子体系中的氰基对于高效靶向高尔基体起到关键作用。此外,由化合物HTPA-PyT-CPS的共定位图片(图7所示)可知,改变给电子基团部分后该类型化合物对高尔基体的靶向能力并未出现明显降低。由图8的TPA-PyT-CPS可知,将甲氧基四苯基乙烯换成三苯胺时它与高尔基体的共定位系数为0.97,而与线粒体、内质网、溶酶体的共定位系数均低于0.8,这说明供电子基团的改变并未对该类分子靶向高尔基体产生明显影响。
实施例9:化合物TPE-PyT-CPS在黑暗和光照条件下进入HeLa细胞后的单线态氧激光共聚焦图像
(1)在黑暗条件下先将HeLa细胞与0.20μM化合物TPE-PyT-CPS进行共孵育6h;(2)弃去含化合物的细胞培养液并分别加入相应工作浓度的商业探针SOSG(Singlet OxygenSensor Green),然后该商业探针的实验要求孵育30min左右;(3)弃去不同商业探针的培养液并用冷的PBS洗两遍,然后进行共定位激光共聚焦成像实验。
共聚焦成像实验:(1)对照组1只加入SOSG,并用532nm激光进行照射2min;(2)对照组2加入化合物TPE-PyT-CPS和单线态氧检测探针SOSG,不用激光照射预处理;(3)对实验组加入化合物TPE-PyT-CPS(0.2μM)和单线态氧检测探针SOSG,并用532nm激光照射2min预处理;(4)对于商业探针SOSG,采用488nm激发,498-535nm通道收集。
化合物TPE-PyT-CPS进入HeLa细胞后在黑暗或光照条件下在的单线态氧激光共聚焦图像如图9所示。由单线态氧探针SOSG的激光共聚焦图像可知,在黑暗条件下化合物并未被激发,因此在图片中的SOSG基本没有荧光出现。然后,在原位用532nm激光进行照射发现SOSG的荧光强度显著增强,这表明该化合物在细胞内能够显著产生单线态氧。
实施例10:化合物TPE-PyT-CPS对HeLa细胞的体外细胞毒活实验
对化合物TPE-PyT-CPS在体外细胞中光照和非光照条件下的细胞毒活性进行了研究。该研究采用标准MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide]法,选择人宫颈癌细胞系HeLa细胞进行测试。将细胞分别种在96孔板中(每孔约5000个细胞)在37℃,5%CO2条件下培养24h,待细胞贴壁后,换成含有不同浓度的TPE-PyT-CPS的DMEM培养液培养24h。其中,光照条件下TPE-PyT-CPS的毒活性是在化合物与细胞共孵育6h后使用532nm激光器光照(65mW cm-2,2min),继续孵育20小时结束。
化合物TPE-PyT-CPS在光照(10A)或黑暗(10B)条件下对HeLa细胞的体外细胞毒活实验结果如图10所示,图10A为化合物TPE-PyT-CPS对HeLa细胞的体外细胞光毒活性,图10B为,化合物TPE-PyT-CPS对HeLa细胞的体外细胞暗毒性。结果显示在暗毒性测试中,HeLa细胞与化合物TPE-PyT-CPS共孵育24h进行活性测试,当浓度超过256μM细胞仍然保持较高活性,说明TPE-PyT-CPS在黑暗条件下具有较好的生物相容性。光毒性实验中,细胞与不同浓度TPE-PyT-CPS共孵育6h后接受532nm激光光照(65mW cm-2,2min),黑暗处继续孵育至24h,HeLa细胞的IC50值降低到0.17μM,这表明了化合物TPE-PyT-CPS对肿瘤细胞均表现了良好的光动力治疗活性。化合物TPA-PyT-CPS也表现出较高的光毒性(13A)和较低的暗毒性(13B)。
相比之下如图11所示,TPE-PyT-CPS将芘去掉后由于分子内电荷分离的效果降低,其光毒性也出现升高(11A),光毒性IC50值为0.4μM。由图12A中HTPA-PyT-CPS的毒活数值可知,长烷基链的引入更加显著的降低了化合物的光毒性,其IC50值甚至超过64μM。但是,这两个化合物的的暗毒性(11B,12B)也都很低。
实施例11:化合物TPE-PyT-CPS光照后对HeLa细胞的高尔基体形貌的影响
(1)在黑暗条件下先将HeLa细胞与0.2μM化合物TPE-PyT-CPS进行共孵育6h;(2)弃去含化合物的细胞培养液并分别加入相应工作浓度的高尔基体商业探针Gogli-Green,然后实验要求孵育在4℃孵育30min左右;(3)弃去探针的培养液并用冷的PBS洗两遍,然后进行共定位激光共聚焦成像实验。
共聚焦成像实验:(1)对于对照组1只加入Gogli-Green,并用532nm激光进行照射2min;(2)对照组2加入化合物TPE-PyT-CPS和高尔基体探针Gogli-Green,不用激光照射预处理;(3)对实验组加入化合物TPE-PyT-CPS(0.2μM)和高尔基体探针Gogli-Green,并用532nm激光照射2min预处理;(4)对于高尔基体商业探针Gogli-Green,采用488nm激发,495-535nm通道收集。
化合物TPE-PyT-CPS在不同处理条件下引起HeLa细胞的高尔基体相貌变化结果如图14所示。由高尔基体商业探针Gogli-Green的激光共聚焦图像可知,在未加化合物的光照组中和加入化合物但保持黑暗条件的对照组中,图片中Gogli-Green荧光保持棒状且紧密排列,表明高尔基体并未收到损伤。在加入化合物且光照条件下,用532nm激光进行照射发现Gogli-Green的出现碎片化的点状分布,这表明该化合物在细胞内的高尔基体能够显著产生单线态氧并造成高尔基的形态发生显著变化,从而导致高尔基体的氧化应激。此外,相同处理条件下TEM图像中也说明了高尔基体发生了碎片化。
实施例12:化合物TPE-PyT-CPS光照后对HeLa细胞的高尔基体和线粒体相关蛋白表达的影响
(1)在黑暗条件下先将HeLa细胞与0.20μM配合物TPE-PyT-CPS进行共孵育6h;(2)对于黑暗组,加入化合物但不进行光照;(3)对于对照组不加化合物,但是用532nm(65mWcm-2)激光进行照射20min;(4)对于实验组加入化合物后,照射不同时间分别为4min,6min,8min,10min,20min;(5)用Western Blot检测高尔基体和线粒体相关蛋白表达。
化合物TPE-PyT-CPS在不同处理条件下对HeLa细胞中高尔基体相关蛋白表达的影响如图15所示,图15A为不同光照条件下TPE-PyT-CPS引起HeLa细胞中高尔基体相关蛋白表达变化;图15B为归一化后,不同照射时间下高尔基体相关蛋白表达,以黑暗中的蛋白质表达为1。
化合物TPE-PyT-CPS在不同处理条件下对HeLa细胞中线粒体相关蛋白表达的影响如图16所示,图16A为不同光照条件下TPE-PyT-CPS引起HeLa细胞中线粒体相关蛋白表达变化;图16B为归一化后,不同照射时间下线粒体相关蛋白表达,以黑暗中的蛋白质表达为1。
由Western Blot图像(图15)可知,在黑暗条件下高尔基体蛋白p115表达显著下降且被切割为30kDa和90kDa的片段。同时,另一个高尔基体结构蛋白GM130表达显著下降,以上结果表明高尔基体经化合物损伤后造成了高尔基体氧化应激,改变了高尔基体相关蛋白表达。同时,高尔基体氧化应激后会造成抑癌基因p53促表达,这与细胞凋亡密切相关。此外,p53的过表达还上调了位于线粒体上的PUMA(p53上调凋亡调控因子)和Bax(图16),同时下调了线粒体蛋白Bcl-2,从而启动caspase-3导致细胞凋亡。
实施例13:化合物TPE-PyT-CPS光照后对HeLa细胞中线粒体膜电位的影响
(1)在黑暗条件下先将HeLa细胞与0.2μM配合物TPE-PyT-CPS进行共孵育6h;(2)弃去含化合物的细胞培养液并分别加入相应工作浓度的线粒体商业探针JC-1,然后实验要求孵育在37℃孵育30min左右;(3)弃去探针的培养液并用冷的PBS洗两遍,然后进行共定位激光共聚焦成像实验。
共聚焦成像实验:(1)对于对照组1只加JC-1探针,并用532nm激光进行照射2min;(2)对照组2加入化合物TPE-PyT-CPS和JC-1探针,不用激光照射预处理;(3)对实验组加入化合物TPE-PyT-CPS(0.2μM)和JC-1探针,并用532nm激光照射2min预处理;(4)对于线粒体商业探针JC-1,绿色通道采用490nm激发,510-550nm通道收集,红色通道,采用525激发,570-630通道收集。
化合物TPE-PyT-CPS在不同光照条件下对HeLa细胞中线粒体膜电位的影响如图17所示。由线粒体商业探针JC-1的激光共聚焦图像可知,在未加化合物的光照组中和加入化合物但保持黑暗条件的对照组中,图片中JC-A荧光相对JC-M强度较高,表明线粒体膜电位正常。在加入化合物且光照条件下,用532nm激光进行照射发现图片中JC-A荧光显著下降而JC-M的荧光强度显著提高,表明线粒体膜电位正常发生显著下降,从而启动线粒体相关凋亡通路导致细胞凋亡。
实施例14:小鼠瘤内注射化合物TPE-PyT-CPS经照射后经不同时间在小鼠体内荧光图像生物分布
所有动物实验按照动物保护和使用委员会的指导方针进行并使用PerkinElmerIVIS Lumina K Series III活体成像仪检测,激发光源530nm,收集690nm波段的荧光信号。
小鼠肿瘤成像:化合物TPE-PyT-CPS溶液(100μM,120μL)经肿瘤内(I.T.)注射到小鼠测试部位,分别在0h,3h,6h,12h,18h和30h收集一次荧光信号,化合物TPE-PyT-CPS经小鼠瘤内注射后经不同时间在小鼠体内荧光图像生物分布结果如图18所示。注射化合物TPE-PyT-CPS的肿瘤部位在3h左右出现明显的荧光信号,3-18h内荧光信号逐渐增强且时间达到30h时荧光强度出现衰减。同时,在小鼠的其他器官(心、肝、脾、肺、肾)分布较少甚至非常微弱。这表明化合物TPE-PyT-CPS能成像活体小鼠肿瘤区域且在经过一段时间可以代谢出体外。
实施例15:小鼠瘤内注射化合物TPE-PyT-CPS经照射后肿瘤组织和重量变化以及小鼠体重变化
小鼠肿瘤治疗:通过皮下注射癌细胞的方法建立肿瘤模型,小鼠采用BALB/c雌性裸鼠,待肿瘤生长到一定体积时,开始给与药物进行治疗,给药方式为瘤内注射。分别于1,4,7,10,13,16,19,22天给药后18h进行激光照射治疗(35mW cm-2,5min)
实验鼠分为4组每组5只小鼠,分别为生理盐水组(生理盐水+light-)、生理盐水组激光照射组(生理盐水光+Light+)、化合物黑暗组组(AIEgen+light-)、化合物激光照射组(AIEgen+light+)。肿瘤的重量和体积以及小鼠体重在接下来的治疗过程中每两天记录一次。TPE-PyT-CPS治疗后,小鼠肿瘤体积(A、B)、重量(C)以及体重(D)变化结果如图19所示。结果显示,经过22天的治疗(图19A),生理盐水黑暗组、生理盐水光照组以及单纯激光组(AIEgen+light-)的肿瘤生长迅速,肿瘤体积大小分别约为1543mm3,1509mm3和1437mm3(图19B)。然而,化合物加光照组(AIEgen+light+)组的体积为94mm3,抗肿瘤效率为93.5%。同时肿瘤的重量在化合物加光照组(AIEgen+light+)相比于其他对照组显著降低(图19C),说明该化合物展现出显著的的抗肿瘤效果。同等条件下,单纯激光组并没有展现明显的肿瘤损伤效果,排除了激光本身的因素对肿瘤组织的抑制作用。另外,不同组的小鼠体重没有明显差异(图19D),表明TPE-PyT-CPS对小鼠的毒副作用微弱、可忽略的系统毒性。以上实验结果证实,合成的基于AIE的具有高效高尔基体靶向的化合物TPE-PyT-CPS在体内抗肿瘤中展现良好的肿瘤抑制作用。
实施例16:小鼠肿瘤区域经不同处理(包括本发明所述化合物)后小鼠的各种H&E染色的器官切片图像
通过Hematoxylin&Eosin(H&E)染色对光动力治疗实验中小鼠的肿瘤和主要器官(心、肝、脾、肺、肾)进行增殖和组织形态学研究。4组小鼠的主要器官都没有出现明显的损伤,说明光动力治疗的过程对小鼠的正常生理过程几乎没有影响。肿瘤切片结果如图20所示,在saline(生理盐水组)和存在化合物但不施加光照组(AIEgen+light-)中,没有发现明显的肿瘤细胞坏死且在其它未光照的对照组中依然存在大量的肿瘤细胞。而在PS&Irradiation光照组中,观察到少量的肿瘤细胞坏死,而在PS&dark组中,肿瘤细胞数量明显较少。因此,可以认为TPE-PyT-CPS在小鼠中确实具有较好的光动力治疗效果,且对小鼠的主要器官没有明显影响。
Claims (8)
3.根据权利要求1所述的基于聚集诱导发光的高效靶向高尔基体的化合物,其特征在于R1为带有正电荷的基团时,与阴离子成盐,阴离子选自Cl-、Br-,I-,NO3 -或PF6 -。
4.根据权利要求1所述的基于聚集诱导发光的高效靶向高尔基体的化合物,其特征在于R3代表C原子数为1、6、8或12的烷基、烷氧基或氟代烷氧基。
6.根据权利要求1-5任一项所述的基于聚集诱导发光的高效靶向高尔基体的化合物在光动力治疗中的应用。
7.根据权利要求6任一项所述的应用,其特征在于所述靶向高尔基体的化合物为肿瘤光动力治疗药物。
8.根据权利要求6所述的应用,其特征在于所述靶向高尔基体的化合物用于细胞成像或肿瘤治疗。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110826693.XA CN113683605B (zh) | 2021-07-21 | 2021-07-21 | 一种基于聚集诱导发光的高效靶向高尔基体的化合物及生物应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110826693.XA CN113683605B (zh) | 2021-07-21 | 2021-07-21 | 一种基于聚集诱导发光的高效靶向高尔基体的化合物及生物应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113683605A true CN113683605A (zh) | 2021-11-23 |
CN113683605B CN113683605B (zh) | 2023-04-07 |
Family
ID=78577631
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110826693.XA Active CN113683605B (zh) | 2021-07-21 | 2021-07-21 | 一种基于聚集诱导发光的高效靶向高尔基体的化合物及生物应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113683605B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114163427A (zh) * | 2021-12-16 | 2022-03-11 | 深圳大学 | 两亲性聚集诱导发光材料、近红外聚集诱导发光有机硅纳米粒子及其制备方法、应用 |
CN116239584A (zh) * | 2023-02-15 | 2023-06-09 | 东南大学 | 一种单体m1、二聚体d1及其制备方法和应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101439191A (zh) * | 2008-12-31 | 2009-05-27 | 南京大学 | 一类可在细胞/组织/活体中应用的可见光激发的锌离子荧光造影试剂及其合成方法和应用 |
-
2021
- 2021-07-21 CN CN202110826693.XA patent/CN113683605B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101439191A (zh) * | 2008-12-31 | 2009-05-27 | 南京大学 | 一类可在细胞/组织/活体中应用的可见光激发的锌离子荧光造影试剂及其合成方法和应用 |
Non-Patent Citations (1)
Title |
---|
GANG YUAN: "Molecular Engineering of Efficient Singlet Oxygen Generators with Near-Infrared AIE Features for Mitochondrial Targeted Photodynamic Therapy", 《ADVANCED FUNCTIONAL MATERIALS》 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114163427A (zh) * | 2021-12-16 | 2022-03-11 | 深圳大学 | 两亲性聚集诱导发光材料、近红外聚集诱导发光有机硅纳米粒子及其制备方法、应用 |
CN114163427B (zh) * | 2021-12-16 | 2023-09-26 | 深圳大学 | 两亲性聚集诱导发光材料、近红外聚集诱导发光有机硅纳米粒子及其制备方法、应用 |
CN116239584A (zh) * | 2023-02-15 | 2023-06-09 | 东南大学 | 一种单体m1、二聚体d1及其制备方法和应用 |
CN116239584B (zh) * | 2023-02-15 | 2024-06-11 | 东南大学 | 一种单体m1、二聚体d1及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN113683605B (zh) | 2023-04-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Gao et al. | A dual‐functional photosensitizer for ultraefficient photodynamic therapy and synchronous anticancer efficacy monitoring | |
Xu et al. | A supramolecular photosensitizer derived from an Arene-Ru (II) complex self-assembly for NIR activated photodynamic and photothermal therapy | |
CN113683605B (zh) | 一种基于聚集诱导发光的高效靶向高尔基体的化合物及生物应用 | |
Gottumukkala et al. | Synthesis, cellular uptake and animal toxicity of a tetra (carboranylphenyl)-tetrabenzoporphyrin | |
Serra et al. | New porphyrin amino acid conjugates: Synthesis and photodynamic effect in human epithelial cells | |
Yang et al. | Mitochondria-targeting Pt/Mn porphyrins as efficient photosensitizers for magnetic resonance imaging and photodynamic therapy | |
Zhu et al. | Comparison between porphin, chlorin and bacteriochlorin derivatives for photodynamic therapy: Synthesis, photophysical properties, and biological activity | |
CN108727256B (zh) | 一种基于三苯胺多吡啶盐的光敏剂及其制备方法与应用 | |
Sun et al. | Cationic telluroviologen derivatives as type‐I photosensitizers for tumor photodynamic theranostics | |
CN113336743B (zh) | 一种具有“主动”与“被动”双重靶向的化合物及其药物组合物和应用 | |
Gao et al. | The photodynamic activities of dimethyl 131-[2-(guanidinyl) ethylamino] chlorin e6 photosensitizers in A549 tumor | |
CN113956190A (zh) | 可激活肿瘤细胞焦亡的细胞器靶向光敏剂及其制备方法和应用 | |
Gurram et al. | NIR-excited superoxide radical procreators to eradicate tumors by targeting the lyso-membrane | |
Li et al. | Sono-ReCORMs for synergetic sonodynamic-gas therapy of hypoxic tumor | |
Srdanović et al. | The photodynamic activity of 131-[2′-(2-pyridyl) ethylamine] chlorin e6 photosensitizer in human esophageal cancer | |
CN113321644B (zh) | 一种具有刺激响应性的超分子光热剂化合物及其组合物和应用 | |
CN115385851A (zh) | 具有不对称二乙腈基结构的近红外聚集诱导发光型超高效光敏剂、制备方法及应用 | |
Sun et al. | Phototheranostics for NIR fluorescence image guided PDT/PTT with extended conjugation and enhanced TICT | |
Hasrat et al. | A viscosity-sensitive and mitochondria-targeted AIEgen effectuated fatty liver imaging and cancer photodynamic therapy | |
Singh et al. | Mitochondria-targeted photoactivatable real-time monitoring of a controlled drug delivery platform | |
Yang et al. | A promising strategy for synergistic cancer therapy by integrating a photosensitizer into a hypoxia-activated prodrug | |
CN110857310B (zh) | 一种具有光活性的多联吡啶钌配合物及其应用 | |
Suvorov et al. | Synthesis of PSMA-targeted 131-and 152-substituted chlorin e6 derivatives and their biological properties | |
WO2016161903A1 (zh) | 锇杂稠环化合物及其制备方法、含有该化合物的组合物以及应用 | |
CN114045045A (zh) | 一类单光子上转换五甲川菁类光敏染料、其制备方法和应用 |
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 |