CN107286186A - 硫化氢荧光探针及其制备方法和应用 - Google Patents
硫化氢荧光探针及其制备方法和应用 Download PDFInfo
- Publication number
- CN107286186A CN107286186A CN201610223412.0A CN201610223412A CN107286186A CN 107286186 A CN107286186 A CN 107286186A CN 201610223412 A CN201610223412 A CN 201610223412A CN 107286186 A CN107286186 A CN 107286186A
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- Prior art keywords
- compound
- hydrogen sulfide
- alkyl
- reaction
- aryl
- Prior art date
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- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 38
- 239000000523 sample Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 230000003834 intracellular effect Effects 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 9
- -1 BODIPY Chemical compound 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229940125890 compound Ia Drugs 0.000 claims description 4
- 229960000789 guanidine hydrochloride Drugs 0.000 claims description 4
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims description 4
- VEMGMDZKKZMAIQ-UHFFFAOYSA-N 7,9-dihydro-3H-purine-2,6,8-trione 2,2,2-trichloroacetonitrile Chemical compound N1C(=O)NC=2NC(=O)NC2C1=O.ClC(C#N)(Cl)Cl VEMGMDZKKZMAIQ-UHFFFAOYSA-N 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 claims description 3
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-UHFFFAOYSA-N 0.000 claims description 3
- 229930014669 anthocyanidin Natural products 0.000 claims description 3
- 150000001452 anthocyanidin derivatives Chemical class 0.000 claims description 3
- 235000008758 anthocyanidins Nutrition 0.000 claims description 3
- 229910052796 boron Inorganic materials 0.000 claims description 3
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 claims description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 3
- 238000006703 hydration reaction Methods 0.000 claims description 3
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- TZMFJUDUGYTVRY-UHFFFAOYSA-N ethyl methyl diketone Natural products CCC(=O)C(C)=O TZMFJUDUGYTVRY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000007850 fluorescent dye Substances 0.000 abstract description 15
- 238000003384 imaging method Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000004073 vulcanization Methods 0.000 description 3
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- HHRFWSALGNYPHA-UHFFFAOYSA-N [N].C1CNCCN1 Chemical compound [N].C1CNCCN1 HHRFWSALGNYPHA-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 235000021050 feed intake Nutrition 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical group OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 235000004237 Crocus Nutrition 0.000 description 1
- 241000596148 Crocus Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- AHTCKORKOBUGMZ-UHFFFAOYSA-N N1C(=O)NC(=O)NC1=O.ClC=C Chemical compound N1C(=O)NC(=O)NC1=O.ClC=C AHTCKORKOBUGMZ-UHFFFAOYSA-N 0.000 description 1
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- BDKZHNJTLHOSDW-UHFFFAOYSA-N [Na].CC(O)=O Chemical compound [Na].CC(O)=O BDKZHNJTLHOSDW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Natural products CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- TUEYHEWXYWCDHA-UHFFFAOYSA-N ethyl 5-methylthiadiazole-4-carboxylate Chemical compound CCOC(=O)C=1N=NSC=1C TUEYHEWXYWCDHA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical class CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- LPSWFOCTMJQJIS-UHFFFAOYSA-N sulfanium;hydroxide Chemical compound [OH-].[SH3+] LPSWFOCTMJQJIS-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- 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"
-
- 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
- G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
-
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Abstract
本发明提供一系列硫化氢荧光探针化合物及其制备方法。所述荧光探针可以用于检测硫化氢,对硫化氢有很好的选择性,将其配在水溶液或缓冲溶液中,可用于检测体外硫化氢。此类荧光探针化合物可自主渗透细胞膜进入到细胞中,并可用于细胞内硫化氢成像。
Description
技术领域
本发明涉及一系列硫化氢荧光探针以及该类荧光探针化合物的制备方法及其在硫化氢检测中的应用。
背景技术
生物巯基化合物在细胞中是至关重要的分子,在损伤和氧化应激中作为抗氧化剂扮演着重要的角色,与金属相互作用作为螯合剂和信号制剂。硫化氢(H2S)是最简单的生物硫醇,在人体内通过酶催化和非酶催化产生。硫化氢气体以臭鸡蛋气味的存在或者溶解在水中形成HS-阴离子。硫化氢和其他活性硫物种(RSS)会引起一系列生理反应来维持细胞健康。活性硫物种在多种组织中可以作为抗氧化剂和信号制剂,包括肝脏,胃肠系统、胰腺、大脑和循环系统。
作为最小的硫醇,硫化氢可以作为一个简单的还原剂同时也是很好的亲核试剂用于各种有机反应中,同时硫化氢作为很好的还原剂用于有机合成中,此外分析化学家已经采用了几个世纪用硫化氢分析例如铜等金属的重量分布。在分析化学和有机化学方面的这些特性是设计对这种RSS具有很好选择性和灵敏性的荧光探针的基本出发点。现在已经发现的反应型荧光探针检测硫化氢主要有以下三个方法:叠氮还原为胺,亲核反应和硫化铜沉淀。
发明内容
本发明的目的在于提供一类硫化氢荧光探针化合物。
本发明的另一目的在于提供上述荧光探针化合物的制备方法。
本发明的又一目的在于提供上述荧光探针化合物在硫化氢检测中的应用。
本发明提供了一类荧光探针化合物,其结构为如下通式(I)所示:
其中R1为烷基、氨基、烷氧基、-(OC1-3亚烷基)n-OC1-6烷基、烯基、炔基、环烷基、芳基、芳氧基、芳烷基、杂芳基、杂环基,上述取代基可进一步被取代基取代,取代基为烷基、氨基、烷氧基、烯基、炔基、环烷基、芳基、芳氧基、芳烷基、杂芳基、杂环基、卤素等;R2为荧光基团。
所述的烷基代表碳原子数为1-8的直链或支链烷基,优选碳原子数为1-6,例如,甲基、乙基、丙基、丁基、异丁基、叔丁基等。
所述烯基代表碳原子数为2-6的直链或支链烯基,例如,乙烯、丙烯、丁烯等。
所述炔基代表碳原子数为2-6的直链或支链炔基,例如,乙炔、丙炔、丁炔等。
所述环烷基代表具有碳原子数为3-6个的碳环,例如环己烷基等。
所述的芳基指具有6-20个碳原子的单环、多环芳族基团,代表性的芳基包括:苯基、萘基等。
所述杂芳基代表具有1-20个碳原子、1-4个选自N、S、O杂原子的单环或多环杂芳基,例如吡咯基、吡啶基、嘧啶基等。
所述杂环基代表具有1-20个碳原子、1-4个选自N、S、O杂原子的饱和或不饱和的单环或多环杂环基。例如四氢吡咯基、哌嗪基等。
所述氨基代表基团-NX2,其中X代表氢、烷基、烷氧基等。
所述的荧光染料代表在吸收某一波长的光波后能发射出另一波长大于吸收光的光波的物质,例如,荧光素、罗丹明、BODIPY、香豆素、花青素、三芳基硼等。
根据本发明,所述R1优选为烷基、氨基、烷氧基、-(OC1-3亚烷基)n-OC1-6烷基、芳基、芳氧基、芳烷基,更优选为C1-6烷基、-(OCH2CH2)n-OC1-6烷基。
根据本发明,所述荧光染料优选为荧光素、罗丹明、BODIPY、香豆素、花青素、三芳基硼等。
根据本发明,所述式I化合物可为如下具体化合物Ia和Ib
本发明还提供了一种上述通式I化合物的制备方法,合成途径如下:
其中R1、R2如前述所定义;
本发明通式(I)化合物的具体合成方法如下:
(a)盐酸胍与水合肼反应得到化合物1;
(b)将步骤(a)中得到的化合物1与2,4-戊二酮过氧化物反应得到化合物2;
(c)将步骤(b)中得到的化合物2经过还原得到化合物3;
(d)将步骤(c)中得到的化合物3在溶剂中与水合肼反应生成化合物4;
(e)将步骤(d)中得到的化合物4与三氯乙氰尿酸反应生成化合物5;
(f)将步骤(e)中得到的化合物5与R1H反应生成化合物6;
(g)将步骤(f)中得到的化合物6与荧光基团发生取代反应得到化合物I。
根据本发明,所述步骤(a)中盐酸胍与水合肼按1:1.3摩尔比投料,1,4-二氧六环作溶剂,反应温度为回流温度,反应时间为2-3h。
根据本发明,所述步骤(b)中化合物1与2,4戊二酮过氧化物按1:2摩尔比投料,水作溶剂,反应温度为25℃-70℃,反应时间为4.5-5h。
根据本发明,所述步骤(c)中化合物2与亚硝酸钠和醋酸按1:2.8:2.8摩尔比投料,水和二氯甲烷作溶剂,反应温度为0℃,反应时间为0.5-2h。
根据本发明,所述步骤(d)中化合物3与水合肼按1:2摩尔比投料,乙腈作为溶剂,反应温度为室温,反应时间为0.5h。
根据本发明,所述步骤(e)中化合物4与三氯乙氰尿酸取代基按1:2摩尔比投料,乙腈作为溶剂,反应温度为0℃-室温,反应时间为0.5-1h。
根据本发明,所述步骤(f)中化合物5与R1H按1:1摩尔比投料,二氯甲烷作为溶剂,反应温度为室温,反应时间为3-5h。
根据本发明,所述步骤(g)中化合物6与荧光基团按3:1摩尔比投料,二氯甲烷作为溶剂,反应温度为室温,反应时间为3-5h。
本发明所述的硫化氢荧光探针化合物,可以检测硫化氢,在一定硫化氢浓度下,其发光能力随着时间的变化而逐渐增强。其原因是所述化合物中含有四氮嗪结构,其拉电子效应淬灭了荧光基团,加入硫化氢后硫化氢还原四氮嗪,形成具有给电子效应的基团,从而使其荧光基团荧光恢复。
进一步的,本发明还提供一种所述荧光探针化合物的用途,其用于检测硫化氢。
本发明所述的硫化氢荧光探针化合物,对硫化氢的选择具有专一性,其他生物硫醇或者金属离子等对所述化合物的发光能力几乎无影响。
本发明所述的硫化氢荧光探针化合物,对于硫化氢的检测可以在水溶液中,也可以在缓冲溶液中进行,如HEPES缓冲溶液。所述化合物对于硫化氢检测所适用的pH范围为7.0-9.0。
本发明所述的荧光探针化合物,可自主进入到小鼠成纤维细胞中,并用于细胞内荧光成像检测硫化氢。所述荧光探针化合物进入细胞后,在荧光显微镜下通过荧光探针可以观察到所述化合物被硫化氢还原的过程。
本发明所述的硫化氢荧光探针优点在于:首次使用四氮嗪结构基团检测硫化氢;对硫化氢具有高效的选择性;所述化合物具有亲水亲油两性基团,可自主渗透细胞膜进入到细胞内可检测细胞内外源性硫化氢。
附图说明
图1a、1b为实施例7制备的Ia和Ib在HEPES缓冲溶液中,加入硫化氢后随时间变化的荧光光谱图。
图2a、2b为实施例7制备的Ia和Ib在HEPES缓冲溶液中,加入其它生物硫醇以及金属离子等其他物质后,荧光探针在一定时间内的荧光强度比值。
具体实施方式
为了进一步说明本发明的指导思想,给出下列系列具体实施例,但本发明并不受这些具体实施例的限制,任何了解该领域的技术人员对本发明的些许改动将可以达到类似的结果,这些改动也包含在本发明之中。
实施例1
制备化合物1
将盐酸胍(19.1g,0.20mol)溶于100mL1,4-二氧六环中,然后加入3.4当量的水合肼,搅拌回流2小时,反应完成后降至室温,过滤,1,4-二氧六环洗,干燥得到化合物1(27.7g,98%),直接用于下一步反应。
实施例2
制备化合物2
将7.03g化合物2(0.05mol)溶于50mL水中,在室温条件下滴加2,4-二戊酮(10.26ml,0.1mol),滴加完毕后室温下搅拌0.5小时,然后加热至70℃搅拌4小时。反应完全后降至室温,过滤,水洗,得白色黄色固体(5.7g,85%),直接用于下一步反应。
实施例3
制备化合物3
将26.2g亚硝酸钠溶于588ml水中,加入60ml二氯甲烷,降温至0℃,然后加入(37g,0.136mol)化合物2,滴加加入(18.67ml,0.326mol)醋酸。当停止放出气体时,二氯甲烷萃取,有机相用碳酸钾溶液水洗,硫酸镁干燥,旋出有机溶剂,乙醚重结晶得到化合物3(33.45g,91%)。1H-NMR(400MHz,CDCl3),δ:2.398(s,6H),2.719(s,6H),6.203(s,6H).
实施例4
制备化合物4
将化合物3(23.8g,0.09mol)溶于150ml乙腈溶液中,在室温搅拌下逐滴加入水合肼(9.4ml,0.19mol)。滴加完毕后搅拌回流20分钟,然后冷却至室温过滤,乙腈多次冲洗,得到化合物4,直接用于下一步。
实施例5
制备化合物5
将化合物4(12.5g,0.09mol)在0℃下溶于350ml乙腈溶液中,逐滴加入三氯乙氰尿酸(40.8g,0.18mol)的乙腈溶液。滴加完毕后升至室温搅拌20分钟,然后过滤,旋出挥发物,快速过硅胶柱得到橘黄色固体化合物5。ESI-MS:[M]+150.
实施例6
制备化合物6a和6b
化合物5(1.5g,1mmol)溶于20ml甲醇溶液中,在室温下搅拌1小时,旋出有机溶剂,过硅胶柱得到化合物6a(1.24g,85%).1HNMR(400MHz,CDCl3)δ4.33(s,3H).LR-MS分析值C3H3N4OCl(M+Na)169.1;标准值146.0.
化合物5(1.5g,1mol)和四乙二醇单甲醚(3.16ml,1.5mol)溶于50ml二氯甲烷中,然后加入三乙胺(2.96ml,1.5mol)。室温下搅拌3小时,加水淬灭反应,二氯甲烷萃取,干燥,过硅胶柱,得到化合物6b(2.8g,87%).1HNMR(400MHz,CDCl3)δ4.833-4.810(t,2H),4.003-3.980(t,2H),3.680-3.657(t,2H),3.646-3.632(m,8H),3.559-3.546(t,2H),3.389(s,3H).LR-MS分析值C11H19N4O5Cl(M+Na)345.1;标准值322.1.
实施例7
制备化合物Ia和Ib
荧光基团BODIPY化合物(2.02g,3.8mol)和化合物6a(1.12g,7.6mol)溶于60ml乙腈溶剂中,然后加入三乙胺(1.52ml,11.4mol)。搅拌回流10小时,反应后冷却至室温,水淬灭反应,乙酸乙酯萃取,干燥,过硅胶柱得到化合物Ia(2.1g,74%)。1HNMR(400MHz,(CD3)2SO)δ7.76-7.69(m,6H),7.63-7.56(m,4H),7.47-7.44(m,7H),7.02(s,2H),4.20(s,6H),1.44(s,6H).13CNMR(100MHz,(CD3)2SO)δ166.82,166.79,153.92,152.35,142.43,139.77,136.28,134.41,134.20,133.17,129.71,129.61,128.57,121.55,118.93,118.70,57.06,14.57.HR-MALDI-TOF分析值C39H31BF2N10O4(M+Na)775.248980;标准值775.248239.元素分析(%)分析值:C 61.97,H 4.34,N 18.17;标准值:C 62.25,H 4.15,N 18.61.
荧光基团BODIPY化合物(0.798g,1.5mol)和化合物6(1g,3mol)溶于60ml乙腈溶剂中,然后加入三乙胺(0.6ml,4.5mol)。搅拌回流10小时,反应后冷却至室温,水淬灭反应,乙酸乙酯萃取,干燥,过硅胶柱得到化合物Ib(1.4g,85%)。1HNMR(400MHz,(CD3)2SO)δ7.76-7.73(m,4H),7.69-7.57(m,6H),7.51-7.44(m,7H),7.01(s,2H),4.67-4.64(t,2H),3.89-3.86(t,2H),3.64-3.61(m,4H),3.57-3.54(m,4H),3.51-3.48(m,12H),3.44-3.40(m,4H)3.32(s,6H),1.43(s,6H).13CNMR(100MHz,(CD3)2SO)δ165.89,165.60,15.02,151.46,141.52,138.86,135.40,133.52,133.30,132.27,128.82,128.72,128.31,127.67,120.69,118.04,117.77,70.73,69.36,69.28,69.23,69.04,68.33,67.61,57.50,13.69.HR-MALDI-TOF分析值C55H63BF2N10O12(M+Na)1127.458944;标准值1127.458898.元素分析(%)分析值:C 58.75,H 5.78,N 12.66;标准值:C 59.78,H 5.75,N 12.68.
实施例8
将实施例7中的Ia和Ib用于硫化氢检测:将Ia和Ib溶于10mmol HEPES缓冲溶液与甲醇溶液(v/v=4/6)中,得到Ia和Ib的浓度为10-5M。向该溶液中加入浓度为10-3M的硫化氢水溶液,最终硫化氢的浓度为10-5M。最后测得荧光探针Ia和Ib在0-30分钟内随时间变化的荧光光谱(见附图1),随着时间增加,溶液荧光增强。相同条件加入生物硫醇、金属离子等其他物质,检测荧光探针在30分钟内荧光强度比值,结果如附图2所示。在图2中,1为空白试验、2为半胱氨酸、3为谷胱甘肽、4为硫酸钾、5为碳酸氢钠、6为氯化钠、7为碘化钾、8为硫代硫酸钠、9为亚硝酸钠、10为硫酸氢钠、11为溴化钾、12为醋酸钠、13为高氯酸钠、14为次氯酸钠、15为过硫酸钠、16为双氧水、17为硫化氢,从图中可以看出,荧光探针溶液荧光强度受其他物质的影响很小。
实施例9
将实施例7中的Ia和Ib用于细胞内荧光成像:取两组小鼠成纤维细胞,加入荧光探针Ia和Ib(最终浓度为10-5M)培养60min。向其中实验组培养液中加入硫化氢水溶液(最终浓度为10-4M),另一组对照组培养液中不加入硫化氢水溶液。在荧光显微镜下成像,对照组细胞内荧光很弱,而实验组细胞内荧光很强,这是由于荧光探针在细胞内被硫化氢还原使得荧光基团荧光恢复。
Claims (9)
1.通式(I)的化合物,
其中R1为烷基、氨基、烷氧基、-(OC1-3亚烷基)n-OC1-6烷基、烯基、炔基、环烷基、芳基、芳氧基、芳烷基、杂芳基、杂环基,上述取代基可进一步被取代基取代,取代基为烷基、氨基、烷氧基、烯基、炔基、环烷基、芳基、芳氧基、芳烷基、杂芳基、杂环基、卤素等;R2为荧光基团。
2.如权利要求1所述的化合物,其中,R1为烷基、氨基、烷氧基、-(OC1-3亚烷基)n-OC1-6烷基、芳基、芳氧基、芳烷基。
3.如权利要求1或2所述的化合物,其中,R2为荧光素、罗丹明、BODIPY、香豆素、花青素、三芳基硼等。
4.如权利要求1所述的化合物,其中,所述化合物为如下具体化合物Ia和Ib
(Ia)R1=OMe
。
5.权利要求1-4任一项所述的化合物的制备方法,包括以下步骤:
其中R1,R2如权利要求1-4任一项所定义,
(a)将盐酸胍与水合肼溶于溶剂中,得到化合物1;
(b)将步骤(a)中得到的化合物1与2,4戊二酮过氧化物反应得到化合物2;
(c)将步骤(b)中得到的化合物2经过还原得到化合物3;
(d)将步骤(c)中得到的化合物3在溶剂中与水合肼反应生成化合物4;
(e)将步骤(d)中得到的化合物4与三氯乙氰尿酸反应生成化合物5;
(f)将步骤(e)中得到的化合物5与R1H发生取代反应生成化合物6;
(g)将步骤(f)中得到的化合物6与荧光基团发生取代反应得到化合物I。
6.权利要求1-4任一项所述的化合物的用途,其用作硫化氢荧光探针。
7.根据权利要求6所述的用途,在水溶液或缓冲溶液中检测硫化氢,适用pH范围优选为7.0-9.0。
8.根据权利要求6所述的用途,其中,所述通式(I)化合物在无任何载体携带下,可自主渗透细胞膜进入到细胞中。
9.根据权利要求6所述的用途,其中,所述通式(I)化合物可用于细胞内硫化氢成像。
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