CN110698449A - 一类新型光敏剂的制备方法及应用 - Google Patents
一类新型光敏剂的制备方法及应用 Download PDFInfo
- Publication number
- CN110698449A CN110698449A CN201910508273.XA CN201910508273A CN110698449A CN 110698449 A CN110698449 A CN 110698449A CN 201910508273 A CN201910508273 A CN 201910508273A CN 110698449 A CN110698449 A CN 110698449A
- Authority
- CN
- China
- Prior art keywords
- photosensitizer
- hydroxybenzaldehyde
- compound
- reaction
- nmr
- 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
- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 9
- 238000010521 absorption reaction Methods 0.000 claims abstract description 8
- SXRHGLQCOLNZPT-UHFFFAOYSA-N 3,5-dibromo-4-hydroxybenzaldehyde Chemical compound OC1=C(Br)C=C(C=O)C=C1Br SXRHGLQCOLNZPT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000524 functional group Chemical group 0.000 claims abstract description 5
- WHLUEIMENHLCMY-UHFFFAOYSA-N 4-hydroxy-3,5-diiodobenzaldehyde Chemical compound OC1=C(I)C=C(C=O)C=C1I WHLUEIMENHLCMY-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 3
- 206010034972 Photosensitivity reaction Diseases 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000005286 illumination Methods 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000036211 photosensitivity Effects 0.000 claims description 2
- 229910052724 xenon Inorganic materials 0.000 claims description 2
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 238000010998 test method Methods 0.000 claims 1
- 230000009466 transformation Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 238000002390 rotary evaporation Methods 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000003480 eluent Substances 0.000 description 12
- 239000011669 selenium Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 238000002428 photodynamic therapy Methods 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical class [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- JECYUBVRTQDVAT-UHFFFAOYSA-N 2-acetylphenol Chemical compound CC(=O)C1=CC=CC=C1O JECYUBVRTQDVAT-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- NZCKTGCKFJDGFD-UHFFFAOYSA-N 2-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Br NZCKTGCKFJDGFD-UHFFFAOYSA-N 0.000 description 1
- QHPQWRBYOIRBIT-UHFFFAOYSA-N 4-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C=C1 QHPQWRBYOIRBIT-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XGZVNVFLUGNOJQ-UHFFFAOYSA-N n,n-dimethylformamide;ethyl acetate Chemical compound CN(C)C=O.CCOC(C)=O XGZVNVFLUGNOJQ-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
-
- 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
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D345/00—Heterocyclic compounds containing rings having selenium or tellurium atoms as the only ring hetero atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明涉及光动力治疗技术领域,具体涉及一类新型光敏剂、制备方法及其应用。
背景技术
光动力治疗(PDT)是以非手术的形式治疗癌症的一种手段。1975年,Dougherty等人首次对其进行论证,并进行了广泛的研究。目前,PDT已成为一种癌症治疗的特殊方式。光动力疗法在光照条件下利用光敏剂吸收光子,达到激发态,通过隙间穿越,将能量传递给三线态氧,并将三线态氧转化为具有细胞毒性的单线态氧(1O2),进而不可逆地杀伤癌细胞,达到治疗癌症的目的。相比于化疗和放疗,光动力疗法无创伤、无毒副作用、可重复治疗。
近年来,光动力疗法虽然已经引起人们的广泛关注,但是在实际应用中,治疗效果并不理想,因此设计一种性能优良的光敏剂对于光动力疗法而言尤为重要。
发明内容
本发明提供了一类新型光敏剂的制备方法及其应用,解决了现有光敏剂吸收范围窄、可见光范围内治疗效果差、使用光源功率过大、无法引入官能团的技术问题。
本发明提供了一类新型光敏剂,具有如式(I)所示的结构式:
式(I)和(II)中Q为O或S或Se。
式(II)中X为H或Br或I。
本发明以式(I)中的结构式为母核,创造性地进行改造母核,将中心原子O更换为S和Se,并在R1和R2位置预留官能团,得到其衍生物,具体结构见附图1,合成步骤见附图3。
本发明提供了所述光敏剂的制备方法,将式(I)中的母核分别与对羟基苯甲醛、3,5- 二溴-4-羟基苯甲醛和3,5-二碘-4-羟基苯甲醛进行Knoevenagel反应,得到一类新型光敏剂,具体结构见附图2,具体合成步骤见附图4。
作为优选,Knoevenagel反应的溶剂为乙腈,温度为85℃。
作为优选,Knoevenagel反应中的哌啶和乙酸的体积比为2∶1。
作为优选,引入卤(Br、I)原子,一方面可有效降低光敏剂酚羟基的pKa,使其更加适应生理pH值(Se代光敏剂为例,见附图5),另一方面促进光敏剂隙间穿越,提高光敏性。
作为优选,相同浓度下该类光敏剂与传统的光敏剂(MB)相比较,在可见光区有较大的吸收面积,见附图6。
作为优选,中心原子Q(O、S、Se)所对应的光敏剂,其波长依次红移(X为Br, O<S<Se;X为I,O<S<Se,见附图7),该类光敏剂具有较大的斯托克位移,有效避免了光敏剂的自吸收,减少能量损失。
此外,本发明还提供了一种光动力测试方法,将光敏剂很好地分散在PBS溶液中,测试方法如下:
1)DMA(60μM)、F127(0.3%)和光敏剂(2.5μM)溶于DMF,混合均匀,分散到PBS溶液中。
2)氙灯光源(490-700nm),5mW/cm2,每光照一分钟,使用紫外分光光度计依次扫描,扫描范围350-800nm,共计光照10min。
本发明实施例中引入硒元素的光敏剂,可以发挥重原子效应,有效促进隙间穿越,并且硒为人体重要的组成元素,因此,硒元素的引入可以降低光敏剂的生物毒性,并进一步提高光动力治疗的效果。
附图说明
图1所述光敏剂重要中间体的结构式。
图2所述光敏剂的结构式。
图3所述光敏剂主要中间体的合成路线。
图4所述光敏剂的合成路线。
图5以Se代光敏剂为例,在不同的pH条件下的紫外吸收。
图6相同浓度下部分光敏剂与传统光敏剂(MB)的紫外吸收。
图7所述光敏剂的紫外吸收。
图8所述光敏剂重要中间体及光敏剂结构通式。
具体实施方式
下面结合附图和具体实施例对本发明做出进一步的解释和说明,基于本发明中的实施例,本领域的技术人员,在没有做出创造性的劳动成果下所获得的其他实施例,都属于本发明的保护范围。
实施例一:合成EWGO、alkyneEWGO、azideEWGO,合成路线见附图3
1)邻羟基苯乙酮(10g,73.45mmol)溶于乙酸乙酯中,加入钠(7g,0.3mol),然后85℃搅拌4h。反应结束后,加入水(10mL),浓盐酸调节pH至3,乙酸乙酯萃取,无水硫酸钠干燥,旋蒸除去溶剂,得粗品化合物2。将粗品化合物2直接溶于乙醇(100mL),升温至80℃,逐滴滴加浓硫酸(4mL),继续反应5h。反应结束后,加入10%氢氧化钠水溶液调节pH至12,乙酸乙酯萃取,无水硫酸钠干燥,旋蒸除去溶剂,以石油醚和二氯甲烷作为洗脱剂进行柱层析提纯得纯品化合物3(4.3g,36.6%)。将化合物3(4.3g,26.8mmol)溶于乙酸酐(30mL),加入丙二腈(2.7g,40.87mmol),140℃搅拌过夜。反应结束后,旋蒸除去溶剂,以二氯甲烷作为洗脱剂进行柱层析得亮黄色固体EWGO(2.3g,41.2%)。
2)使用与EWGO相同的合成方法合成化合物7,化合物7(3.0g,8.1mmol)以乙酸乙酯(50mL)作为溶剂,加入钯炭(0.3g),使用氩气将反应瓶内的空气置换3次,插上氢气囊,反应12h。反应结束后,过滤,旋蒸除去溶剂,以石油醚和乙酸乙酯进行柱层析得到黄色固体化合物8(2.17g,95.6%)。化合物8(2.17g,7.74mmol)溶于乙腈(20mL),加入碳酸钾(2.14g,15.48mmol),升温至80℃,逐滴滴加炔丙溴(1.38g,11.6mmol),滴加完毕后,继续反应8h。反应结束后,过滤,旋蒸除去溶剂,以石油醚和二氯甲烷进行柱层析得黄色固体alkyneEWGO(2.2g,89.6%)。1H NMR(400MHz,CDCl3)δ(ppm)8.83(s,1H),6.95(s,1H),6.65(d,J=0.9Hz,1H),4.85(d,J=2.4Hz,2H),2.59(t,J=2.4Hz,1H),2.40(d,J=0.8Hz,3H),1.43(s,9H).13C NMR(100MHz,CDCl3)δ(ppm)161.37,160.92,153.37,153.20,138.68,124.10,117.26,116.16,110.93,105.28,100.91,76.92,76.81,59.75,56.09,36.00,29.67,20.34.
使用与alkyneEWGO相同合成方法得到azideEWGO。1H NMR(400MHz,CDCl3)δ(ppm) 8.82(s,1H),6.82(s,1H),6.63(d,J=0.4Hz,1H),4.21(t,J=5.2Hz,2H),3.81(t,J=5.2 Hz,2H),2.40(d,J=0.4Hz,3H),1.45(s,9H).13C NMR(100MHz,CDCl3)δ(ppm)162.21,160.82,153.32,138.36,124.12,117.23,116.11,110.76,105.27,100.18,99.98,66.79,59.78,50.25,36.02,29.64,20.29.
实施例二:合成EWGS、alkyneEWGS,合成路线见附图3
1)将磷酸(22.5g,229.6mmol)和五氧化二磷(40.7g,287.0mmol)在90℃搅拌一小时,对叔丁基苯硫酚(4.5mL,26.1mmol)和乙酰乙酸乙酯(3.3mL,26.1mmol)的混合物被逐滴滴加,继续反应2h。反应结束后,将反应液直接倒入冰水中,10%氢氧化钠水溶液调节pH至9,乙酸乙酯萃取,无水硫酸钠干燥,旋蒸除去溶剂,以石油醚和二氯甲烷为洗脱剂进行柱层析得到纯品黄色油状化合物10(3.09g,51.0%)。将化合物10(2g,8.6mmol)溶解在15mL乙酸酐中,加入丙二腈(0.68g,10.3mmol),140℃反应过夜,反应结束后,旋蒸除去溶剂,以石油醚和二氯甲烷为洗脱剂进行柱层析,得黄色固体EWGS(1.12g,46.4%)。1H NMR(400MHz,CDCl3)δ8.96(d,J=2.0Hz,1H),7.69(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.4Hz,1H), 7.41(d,J=0.8Hz,1H),2.52(d,J=0.4Hz,3H),1.41(s,9H).13C NMR(100MHz,CDCl3) δ156.53,152.27,148.81,132.94,129.98,126.68,125.21,124.62,120.58,117.38,116.08, 67.36,35.70,31.09,23.51.
2)使用与化合物10相同的合成方法合成化合物12,化合物12(4.5g,21.8mmol)溶于二氯甲烷中,三溴化硼(6mL,63.5mmol)在0℃下被逐滴滴加,逐渐升至室温,搅拌过夜。反应结束后,加入冰水淬灭多余的三溴化硼,除去二氯甲烷,用乙酸乙酯萃取,无水硫酸钠干燥,旋蒸除去溶剂,以石油醚和二氯甲烷作为洗脱剂进行柱层析得白色固体化合物13(3.4g, 81.0%)。化合物13(4.4g,22.9mmol),碳酸钾(7.9g,57.2mmol)加入丙酮(50mL)中,升温至 80℃,逐滴滴加炔丙溴(2.7mL),反应8h。过滤,旋蒸除去丙酮,以石油醚和二氯甲烷为洗脱剂进行柱层析得白色固体化合物14(4.59g,87%)。化合物14(3.4g,14.78mmol)和丙二腈 (1.3g,19.7mmol)溶于乙酸酐(20mL),140℃搅拌过夜,旋蒸除去溶剂,以石油醚和二氯甲烷为洗脱剂进行柱层析得得alkyneEWGS(1.75g,42.5%)。1H NMR(400MHz,DMSO-d6)δ(ppm) 8.38(d,J=2.4Hz,1H),8.00(d,J=8.8Hz,1H),7.56(dd,J=8.8,2.4Hz,1H),7.38(s,1H), 4.93(d,J=2.0Hz,2H),3.69(t,J=2.Hz,1H),2.60(s,3H).13C NMR(100MHz,DMSO-d6) δ(ppm)157.21,155.58,151.89,129.65,129.00,125.64,121.86,119.83,117.91,116.53, 112.42,79.72,78.55,65.19,56.69,23.49.
实施例三:合成EWGSe、alkyneEWGSe、azideEWGSe,合成路线见附图3
1)将邻溴苯甲酰氯(25g,0.114mol)溶于干燥的四氢呋喃(100mL)和三乙胺(100mL) 的混合溶液,除去反应液中的空气,加入二氯二(三苯基磷)钯(0.8g,11.4mmol)和碘化亚铜 (259.7mg,1.36mmol),氩气保护,冰水浴下逐滴滴加丙炔(0.114mol,1M的四氢呋喃溶液)。滴加完毕后,撤掉冰水浴,慢慢恢复至室温,继续反应17h。加入甲醇(10mL)淬灭反应,旋蒸除去溶剂,乙酸乙酯溶解粗品,5%硫酸水溶液、碳酸氢钠水溶液、饱和氯化钠水溶液分别洗涤2次,无水硫酸钠干燥,旋蒸除去溶剂,以石油醚和乙酸乙酯为洗脱剂进行柱层析,纯化得淡黄色油状化合物17(7.27g,28.6%)。硒粉(1.54g,19.5mmol)和硼氢化钠(0.54g, 14.27mmol)溶于DMF(60mL),100℃反应1h,氩气保护下缓慢滴加化合物18(2.03g,9.1mmol)的乙醇溶液,滴加完毕后,继续反应5h,反应结束后,旋蒸除去DMF,溶于乙酸乙酯,饱和食盐水洗涤3次,干燥,旋蒸除去溶剂,以石油醚和乙酸乙酯进行柱层析纯化得白色固体化合物18(1.32g,65.0%)。1H NMR(400MHz,CDCl3)δ(ppm)8.56(d,J=7.2Hz, 1H),7.63-7.54(d,J=6.8Hz,1H),7.53-7.41(m,2H),6.97(s,1H),2.51(s,3H).13C NMR (100MHz,CDCl3)δ(ppm)182.48,152.40,136.56,131.57,131.41,129.99,128.15,127.56, 127.03,25.04.
将化合物18(2.23g,10.4mmol)和丙二腈(0.79g,12mmol)溶于乙酸酐(15mL)中,140℃反应过夜。旋蒸除去溶剂,以石油醚和二氯甲烷为洗脱剂进行柱层析得黄色固体EWGSe(1.21g,42.9%)。1H NMR(400MHz,CDCl3)δ(ppm)8.73(d,J=4.8Hz,1H),7.71(d,J= 4.4Hz,1H),7.52(m,3H),2.60(s,3H).13C NMR(100MHz,CDCl3)δ(ppm)158.83,151.34,135.45,131.61,129.77,129.15,128.19,125.97,122.37,116.63,115.31,72.36,25.32.
2)使用与化合物18相同的方法合成化合物21,化合物21(2.5g,9.88mmol)以二氯甲烷(20mL)为溶剂,0℃下逐滴滴加三溴化硼(2.75mL,29.09mmol),逐渐升至室温,搅拌过夜,反应结束后,加入冰水淬灭多余的三溴化硼,用乙酸乙酯萃取,无水硫酸钠干燥,旋蒸除去溶剂,以乙酸乙酯和二氯甲烷为洗脱剂进行柱层析得白色固体化合物22(1.96g,83.0%)。化合物22(3.7g,15.47mmol),溶于乙腈(50mL),加入碳酸钾(4.27g,30.90mmol)升温至80℃,逐滴滴加炔丙溴(2.7g,22.7mmol),滴加完毕,继续反应8h。反应结束后,过滤,旋蒸除去溶剂,以石油醚和二氯甲烷进行柱层析得白色固体化合物23(3.3g,77.0%)。使用与化合物23 相同的合成方法得到白色固体化合物24。将化合物23(2g,7.2mmol)溶于20(mL)乙酸酐中,加入丙二腈(0.57g,8.6mmol),140℃搅拌过夜,反应结束后,旋蒸除去溶剂,以石油醚和二氯甲烷为洗脱剂进行柱层析,得黄色固体化合物alkynePSSe(0.99g,42.0%)。1H NMR(400MHz, DMSO-d6)δ(ppm)8.26(d,J=2.8Hz,1H),8.07(d,J=8.8Hz,1H),7.53-7.40(m,2H), 4.91(d,J=2.0Hz,2H),3.67(t,J=2.0Hz,1H),2.65(t,J=6.4Hz,3H).13C NMR(101MHz, DMSO-d6)δ(ppm)158.29,157.09,155.18,131.50,128.42,126.54,121.74,121.10,117.54, 116.14,114.42,79.62,78.70,69.90,56.70,25.39.
使用与alkynePSSe相同的合成方法合成黄色固体化合物azidePSSe。1H NMR(400MHz,CDCl3)δ(ppm)8.21(d,J=2.8Hz,1H),8.04(d,J=8.8Hz,1H),7.47(d,J=0.8Hz,1H), 7.39(dd,J=8.8,2.8Hz,1H),4.28(t,J=4.8Hz,2H),3.75(t,J=5.2Hz,2H),2.65(s,3H). 13CNMR(100MHz,CDCl3)δ(ppm)158.45,157.77,155.08,131.51,128.23,126.57,121.71,121.57,117.69,116.16,113.32,69.89,67.82,49.80,25.35.
实例四:合成PSO-Br、PSO-I、alkynePSO-I,合成路线见附图4
1)3,5-二溴-4-苯甲醛(0.8g,2.9mmol)溶于乙腈(20mL),分别加入哌啶(1.6mL)和乙酸(0.8mL),再加入适量的分子筛,搅拌,升温至85℃,加入EWGO(0.5g,2.4mmol),继续反应8h。反应结束后,过滤除掉分子筛,加入乙酸乙酯(50mL),1M的盐酸水溶液洗涤,过滤得粗品,以二氯甲烷为洗脱剂通过柱层析的方式进行纯化,得黄色固体化合物PSO-Br(0.42g,37.4%)。1H NMR(400MHz,DMSO-d6)δ(ppm)10.57(s,1H),8.73(d,J=8.4Hz,1H),8.02 (s,2H),7.94(m,1H),7.72(d,J=8.4Hz,1H),7.63(m,2H),7.49(d,J=15.6Hz,1H),6.98 (s,1H).
2)使用和PSO-Br相同的合成方法合成PSO-I。1H NMR(400MHz,DMSO-d6)δ(ppm) 10.10(s,1H),8.72(d,J=8.4Hz,1H),8.18(s,2H),7.93(m,1H),7.72(d,J=8.4Hz,1H),7.64-7.56(m,2H),7.44(d,J=16.0Hz,1H),6.98(s,1H).13C NMR(101MHz,DMSO-d6) δ(ppm)158.60,157.95,153.30,152.44,139.40,136.18,135.90,131.37,126.60,125.12,119.39,119.03,117.68,117.57,116.32,107.04,87.85,60.44.HRMS(ESI):m/z[M+H]+calcd for C20H11I2N2O2 564.8905;found 564.8819.
3)使用和PSO-Br相同的合成方法合成alkynePSO-I。1H NMR(400MHz,DMSO-d6)δ (ppm)10.05(s,1H),8.66(s,1H),8.16(s,2H),7.52(d,J=16.0Hz,1H),7.42(d,J=16.0 Hz,1H),7.33(s,1H),6.90(s,1H),5.10(d,J=2.Hz,2H),3.73(s,1H),1.40(s,9H).13C NMR(101MHz,DMSO-d6)δ(ppm)161.75,157.94,157.44,153.14,152.85,139.21,137.75, 135.10,131.67,123.25,119.41,118.09,116.64,110.69,106.86,102.22,87.59,79.70,78.44,58.28,56.92,55.37,36.00.
实例五:合成PSS-Br、PSS-I,合成路线见附图4
1)使用和PSO-Br相同的合成方法合成PSS-Br。1H NMR(400MHz,DMSO-d6)δ(ppm)10.49(s,1H),8.80(s,1H),8.05(s,2H),7.91(m,2H),7.76(d,J=16.0Hz,1H),7.63(s,1H),7.34-7.25(d,J=16.8Hz,1H),1.36(d,J=2.2Hz,9H).13C NMR(101MHz,DMSO- d6)δ(ppm)156.23,152.45,151.80,148.31,134.37,132.23,131.95,131.09,130.24,128.14,126.27,124.63,124.56,121.78,118.11,116.43,112.66,66.76,35.80,31.11.
2)使用和PSO-Br相同的合成方法合成PSS-I。1H NMR(400MHz,DMSO-d6)δ(ppm) 10.01(s,1H),8.80(d,J=1.2Hz,1H),8.22(s,2H),7.94-7.86(m,2H),7.71(d,J=16.4Hz, 1H),7.64(s,1H),7.27(d,J=16.0Hz,1H),1.36(s,9H).13C NMR(101MHz,DMSO-d6)δ (ppm)157.20,156.13,155.96,151.67,148.32,139.07,134.00,131.90,131.69,130.94,130.85,128.03,125.74,124.53,121.56,118.09,116.41,87.51,66.51,35.75,31.13.HRMS(ESI):m/z[M+H]+ calcd for C24H19I2N2OS 636.9302;found 636.9291.
实例五:合成PSSe、PSSe-Br、PSSe-I、azidePSSe-I,合成路线见附图4
1)使用和PSO-Br相同的合成方法合成PSSe。1H NMR(400MHz,DMSO-d6)δ(ppm) 10.06(s,1H),8.61(d,J=7.6Hz,1H),8.09(d,J=6.8Hz,1H),7.80-7.50(m,6H),7.31- 7.16(d,J=16.0Hz,1H),6.83(d,J=6.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ(ppm) 160.07,159.07,151.84,139.03,134.12,132.58,130.56,130.47,129.58,128.59,126.85, 126.51,125.04,122.45,117.64,116.38,116.17,70.49.HRMS(ESI):m/z[M+H]+ calcd forC20H13N2OSe 377.0188;found 377.0181.
2)使用和PSO-Br相同的合成方法合成PSSe-Br。1H NMR(400MHz,DMSO-d6,Figure S23)δ(ppm)10.48(s,1H),8.60(d,J=8.0Hz,1H),8.13-8.01(m,3H),7.83-7.61(m,4H), 7.19(d,J=16.0Hz,1H).13C NMR(100MHz,DMSO-d6,Figure S24)δ(ppm)159.04,152.37,150.70,135.53,134.10,132.69,132.26,130.60,130.52,129.68,128.70,128.31,126.39,123.83,117.43,115.92,112.72,71.80.HRMS(ESI):m/z[M]calcd for C20H10Br2N2OSe533.0810;found 533.0991.
3)使用和PSO-Br相同的合成方法合成PSSe-I。1H NMR(400MHz,DMSO-d6)δ(ppm)10.01(s,1H),8.59(dd,J=8.0,1.2Hz,1H),8.22(s,2H),8.10(dd,J=7.6,1.2Hz,1H),7.81-7.59(m,4H),7.16(d,J=16.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ(ppm)159.10,157.16,150.95,139.13,135.37,134.12,132.66,132.08,130.59,129.68,128.68,127.88,126.42,123.65,117.47,115.95,87.65,71.65.HRMS(ESI):m/z[M+H]+ calcd forC20H11I2N2OSe 628.8121;found 628.8042.
4)使用和PSO-Br相同的合成方法合成azidePSSe-I。1H NMR(400MHz,DMSO-d6)δ (ppm)9.69(s,1H),8.17(m,3H),8.01(d,J=8.8Hz,1H),7.68(m,2H),7.36(dd,J=8.4, 1.6Hz,1H),7.11(d,J=15.6Hz,1H),4.27(t,J=4.4Hz,2H),3.75(t,J=3.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ(ppm)158.44,157.78,151.71,139.17,135.36,131.79,131.31,127.39,127.23,125.89,122.99,121.56,117.92,116.27,113.43,88.01,70.25,67.80,49.78.
以上所述仅是本发明的优选实施方式,应当指出,对于使用本技术领域的研究人员,在不脱离本发明技术原理的前提下,对这些实施例进行的多种修改,这些修改应该视为本发明的保护范围。
Claims (10)
4.根据权力要求3所述光敏剂的制备方法,其特征在于,Knoevenagel反应的溶剂为乙腈,温度为85℃。
5.根据权力要求3所述光敏剂的制备方法,其特征在于,Knoevenagel反应中的哌啶和乙酸的体积比为2∶1。
6.根据权力要求1所述光敏剂,其特征在于,引入卤(Br、I)原子,一方面可有效降低光敏剂酚羟基的pKa,使其更加适应生理pH值,另一方面促进隙间穿越,提高光敏性。
7.根据权力要求1所述光敏剂,其特征在于,相同浓度下该类光敏剂与传统的光敏剂(MB)相比较,在可见光区有较大的吸收面积。
8.根据权力要求1所述光敏剂,其特征在于,中心原子Q(O、S、Se)所对应的光敏剂,其波长依次红移(X为Br,O<S<Se;X为I,O<S<Se)。
9.根据权力要求1所述光敏剂,提供了一种光动力测试方法:1)DMA(60μM)、F127(0.3%)和光敏剂(2.5μM)溶于DMF,混合均匀,分散到PBS溶液中。2)氙灯光源(490-700nm),5mW/cm2,每光照一分钟,使用紫外分光光度计依次扫描,扫描范围350-800nm,共计光照10min。
10.根据权力要求2所述的中间体的制备方法,凡依照本策略做出的等同于替代或变换所制得的中间体,均在本发明的保护范围之内。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910508273.XA CN110698449B (zh) | 2019-06-12 | 2019-06-12 | 一类光敏剂的制备方法及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910508273.XA CN110698449B (zh) | 2019-06-12 | 2019-06-12 | 一类光敏剂的制备方法及应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110698449A true CN110698449A (zh) | 2020-01-17 |
CN110698449B CN110698449B (zh) | 2022-12-02 |
Family
ID=69193075
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910508273.XA Expired - Fee Related CN110698449B (zh) | 2019-06-12 | 2019-06-12 | 一类光敏剂的制备方法及应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110698449B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112679486A (zh) * | 2021-01-18 | 2021-04-20 | 南开大学 | 基于硝基还原酶响应的光敏剂的制备及应用 |
CN112876445A (zh) * | 2021-01-18 | 2021-06-01 | 南开大学 | 一类谷胱甘肽激活的光敏剂的制备及应用 |
CN113603682A (zh) * | 2021-08-04 | 2021-11-05 | 华东理工大学 | 具有aie效应的二氰基亚甲基-4h-吡喃分子、构建方法及应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016183315A1 (en) * | 2015-05-12 | 2016-11-17 | Georgetown University | Glutathione-cleavable prodrug and methods of use thereof |
-
2019
- 2019-06-12 CN CN201910508273.XA patent/CN110698449B/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016183315A1 (en) * | 2015-05-12 | 2016-11-17 | Georgetown University | Glutathione-cleavable prodrug and methods of use thereof |
Non-Patent Citations (3)
Title |
---|
WENHAO ZHAI, ET AL.: "Universal Scaffold for an Activatable Photosensitizer with Completely Inhibited Photosensitivity", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 * |
XIAODONG ZENG, ET AL.: "A novel near-infrared fluorescent light-up probe for tumor imaging and drug-induced liver injury detection", 《CHEMICAL COMMUNICATIONS》 * |
YIPENG LI, ET AL.: "Highly efficient organic photosensitizer with aggregation-induced emission for imaging-guided photodynamic ablation of cancer cells", 《TETRAHEDRON LETTERS》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112679486A (zh) * | 2021-01-18 | 2021-04-20 | 南开大学 | 基于硝基还原酶响应的光敏剂的制备及应用 |
CN112876445A (zh) * | 2021-01-18 | 2021-06-01 | 南开大学 | 一类谷胱甘肽激活的光敏剂的制备及应用 |
CN113603682A (zh) * | 2021-08-04 | 2021-11-05 | 华东理工大学 | 具有aie效应的二氰基亚甲基-4h-吡喃分子、构建方法及应用 |
Also Published As
Publication number | Publication date |
---|---|
CN110698449B (zh) | 2022-12-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103626781B (zh) | 一种靶向抗癌分子吉非替尼酞菁轭合物及其制备和应用 | |
JP6910551B2 (ja) | 光増感剤、その誘導体および用途 | |
CN107501313A (zh) | 一种基于氮杂氟硼烷的近红外光热染料及制备和应用 | |
CN110698449B (zh) | 一类光敏剂的制备方法及应用 | |
WO2020118116A1 (en) | Heterocyclyl polymethine ir chromophores | |
CN103242260A (zh) | 一种制备苯并吩硒嗪光敏剂的方法 | |
CN109575061A (zh) | 一种水溶性的抗癌光敏剂及其制备和应用 | |
CN104311566A (zh) | 水溶性阳离子型酞菁锌光敏剂的制备和应用 | |
CN113527319B (zh) | 一种新型二氢卟吩e4衍生物及其药学上可接受的盐和制备方法与应用 | |
CN109081852B (zh) | 一种双重靶向酞菁类抗癌光敏剂及其制备方法 | |
CN113831351A (zh) | 一类新型四吡咯衍生物及其应用 | |
Cyza et al. | Iodinated zinc phthalocyanine–The novel visible-light activated photosensitizer for efficient generation of singlet oxygen | |
CN113384695A (zh) | 具有长激发态寿命的五甲川菁染料类光敏染料、其制备方法和应用 | |
CN103073553B (zh) | 水溶性萘菁基化合物、制备方法及作为光敏剂的应用 | |
CN110615755A (zh) | 一种控释单线态氧的近红外荧光分子及其制备方法 | |
CN113754672B (zh) | 一类新型四吡咯化合物及其应用 | |
CN105837583B (zh) | 卟烯‑铱金属配合物及其制备方法和应用 | |
CN113278036B (zh) | 一种含吩噻嗪铱配合物及其制备方法和应用 | |
CN106083872B (zh) | 紫红素-18醚类衍生物及其制备方法和用途 | |
CN101456880B (zh) | 磷胺两亲性酞菁衍生物、其制备方法和其在制备光疗药物中的应用 | |
CN114516879B (zh) | 一类新型中介四苯基萘并卟吩衍生物及其在医药领域的应用 | |
CN111778016A (zh) | 一种近红外荧光探针及其制备方法和应用 | |
EP1472259A1 (en) | Tetrapyrrolic macrocycles as photodynamic agents | |
RU2725641C1 (ru) | Тетра(пирен-1-ил)тетрацианопорфиразин как мультифункциональный агент терапии злокачественных новообразований | |
CN113717037A (zh) | 一种2,5-二甲氧基苯甲醛的绿色合成方法 |
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 | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20221202 |