JP5795963B2 - がん診断薬 - Google Patents
がん診断薬 Download PDFInfo
- Publication number
- JP5795963B2 JP5795963B2 JP2011549976A JP2011549976A JP5795963B2 JP 5795963 B2 JP5795963 B2 JP 5795963B2 JP 2011549976 A JP2011549976 A JP 2011549976A JP 2011549976 A JP2011549976 A JP 2011549976A JP 5795963 B2 JP5795963 B2 JP 5795963B2
- Authority
- JP
- Japan
- Prior art keywords
- cancer
- group
- diagnostic agent
- fluorescence
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 90
- 201000011510 cancer Diseases 0.000 title claims description 87
- 150000001875 compounds Chemical class 0.000 claims description 44
- 229940039227 diagnostic agent Drugs 0.000 claims description 28
- 239000000032 diagnostic agent Substances 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 238000001356 surgical procedure Methods 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 238000003745 diagnosis Methods 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000007689 inspection Methods 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 238000002674 endoscopic surgery Methods 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 description 46
- 125000000217 alkyl group Chemical group 0.000 description 14
- -1 di-substituted amino group Chemical group 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 108020004206 Gamma-glutamyltransferase Proteins 0.000 description 8
- 238000003384 imaging method Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 6
- 230000005284 excitation Effects 0.000 description 6
- 239000007850 fluorescent dye Substances 0.000 description 6
- 238000002350 laparotomy Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 210000000683 abdominal cavity Anatomy 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005507 spraying Methods 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001839 endoscopy Methods 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002405 diagnostic procedure Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 239000012064 sodium phosphate buffer Substances 0.000 description 3
- JNGRENQDBKMCCR-UHFFFAOYSA-N 2-(3-amino-6-iminoxanthen-9-yl)benzoic acid;hydrochloride Chemical compound [Cl-].C=12C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C2C=1C1=CC=CC=C1C(O)=O JNGRENQDBKMCCR-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000007428 craniotomy Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 2
- 238000010859 live-cell imaging Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YMOYURYWGUWMFM-VIFPVBQESA-N (4s)-5-[(2-methylpropan-2-yl)oxy]-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CCC(O)=O)C(=O)OC(C)(C)C YMOYURYWGUWMFM-VIFPVBQESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WRCZSYNKKSWEFM-UHFFFAOYSA-N 9h-xanthene-3,6-diamine Chemical class C1=C(N)C=C2OC3=CC(N)=CC=C3CC2=C1 WRCZSYNKKSWEFM-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- ASXATXRFWSDLQU-UHFFFAOYSA-N [K].O.O.O.O.C(C(O)C(O)C(=O)O)(=O)O Chemical compound [K].O.O.O.O.C(C(O)C(O)C(=O)O)(=O)O ASXATXRFWSDLQU-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 125000002642 gamma-glutamyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000000713 mesentery Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- MYFATKRONKHHQL-UHFFFAOYSA-N rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C2C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C21 MYFATKRONKHHQL-UHFFFAOYSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
- A61K49/0043—Fluorescein, used in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B11/00—Diaryl- or thriarylmethane dyes
- C09B11/04—Diaryl- or thriarylmethane dyes derived from triarylmethanes, i.e. central C-atom is substituted by amino, cyano, alkyl
- C09B11/10—Amino derivatives of triarylmethanes
- C09B11/24—Phthaleins containing amino groups ; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
より具体的には、がん組織の存在が疑われる部位に適用すると短時間にがん組織において特異的に蛍光を発するがん診断薬を提供すること、及び手術や内視鏡検査などにおいて迅速ながん組織の特定を可能にするがん診断薬を提供することが本発明の課題である。
さらに、上記のがん診断薬の製造のための上記一般式(I)で表される化合物又はその塩の使用も本発明により提供される。
(1) 上記一般式(I)で表される化合物又はその塩をがん組織を含む生体部位に適用する工程;及び
(2) がん組織において生成する下記一般式(II):
を含む方法が提供される。
例1
以下のスキームで化合物(2)を製造した。
ローダミン110 285 mg (0.8 mmol 1eq.) をメタノール 10 mLに溶かし硫酸を加えてアルゴン雰囲気下に80℃で10時間攪拌した。反応溶媒を減圧除去し、残渣を飽和重曹水および水で洗浄した。得られた固体をテトラヒドロフラン(THF) 10 mL に溶解させ、アルゴン雰囲気下に0℃で5 M ナトリウムメトキシド溶液(メタノール中) 400μL (0.8 mmol 1eq.)を加えて10分間攪拌した。続いてリチウムアルミニウムハイドライド 333 mg (8 mmol, 10eq.) を加えて3時間攪拌した。飽和塩化アンモニウム水溶液 を5 mL加え、溶媒を減圧除去し、得られた固体をジクロルメタン及び酒石酸4水和物カリウム・ナトリウム塩の飽和水溶液で抽出した。有機層に硫酸ナトリウムを加えてろ過した後、溶媒を除去し、固体を得た。得られた固体をジクロルメタンに溶解し、クロラニル 196 mg (1mmol 1eq.) を加えて30分間室温で攪拌した。溶媒を減圧下で除去し、残渣をシリカゲルクロマトグラフィーで精製して(ジクロルメタン/メタノール=10 : 1)目的化合物 (104 mg, 41%) を得た。
13C NMR (400 MHz, CD3OD): δ 161.5, 159.9, 159.6, 141.0, 133.4, 132.2, 131.3, 130.3, 129.5, 128.8, 118.0, 115.0, 98.4, 62.8
HRMS (ESI+) Calcd for [M+H]+, 317.12900, Found, 317.12862 ( - 0.38 mmu)
化合物(1)(0.05 mmol 1eq.)、HATU (0.11 mmol 2eq.)、及びN,N-ジイソプロピルエチルアミン (0.11 mmol 2eq.) をジメチルホルムアミド(DMF) 2 mLに溶解し、アルゴン雰囲気下に0℃で10分間攪拌した。続いてBoc-Glu-OtBu (0.05 mmol 1eq.) を溶解したDMF 0.5 mLを加え15時間攪拌した。反応溶媒を減圧除去した後に得られた固体をジクロルメタン 2 mL とトリフルオロ酢酸(TFA) 2 mLに溶かし、30分間攪拌した。溶媒を除去しHPLCを用いて精製を行い(eluent A: H2O 0.1% TFA及びeluent B: CH3CN 80%, H2O 20% 0.1% TFA; A / B = 80 / 20 to 0 / 100 for 40 min.)、目的化合物を得た。
1H NMR (400 MHz, CD3OD): δ 8.39 (s, 1H), 7.62-7.61 (m, 2H), 7.50-7.47 (m, 1H), 7.39 (d, 1H, J = 7.8 Hz), 7.24 -7.22 (m, 3H), 6.94 (d, 1H, J = 8.3 Hz), 6.86 (s, 1H), 4.25 (s, 2H), 3.96 (t, 1H, J = 6.3 Hz), 2.71-2.69 (m, 2H), 2.30-2.27 (m, 2H)
13C NMR (400 MHz,CD3OD): δ173.4, 171.8, 164.5, 163.1, 160.7, 157.1, 148.7, 141.2, 134.9, 131.9, 131.7, 130.5, 129.8, 129.0, 121.4, 119.4, 118.5, 106.9, 98.5, 63.1, 53.5, 33.4, 26.6
HRMS (ESI+) Calcd for [M+H]+, 446.17160, Found, 446.17195 ( + 0.36 mmu).
グルタミン酸由来のアシル残基を化合物(1)(RhoHM)の一方のアミノ基に結合させた化合物(2)(γGlu-RhoHM)を中性リン酸バッファーに溶解して、γ-グルタミルトランスペプチダーゼ(GGT, equine kidney, SIGMA G9270-100UN)を作用させた。化合物の5 μM ジメチルスルホキシド(DMSO)溶液 3 μLを3 mL の0.1 M リン酸ナトリウムバッファー(pH 7.4) に最終濃度 5 μMとなるように溶解し、GGT (1.1 U) を加えて37℃で酵素反応を行った。励起波長は501 nmとした。この結果、アシル基の加水分解により開環体を与え即時に吸収及び蛍光強度の顕著な上昇が認められた(図1)。
化合物(2)の酵素特異性を検討した。DMSO溶液 (5 mM) のうち3 μLを3 mL の0.1 M リン酸ナトリウムバッファー(pH 7.4) に最終濃度 5 μMとなるように溶解し、LAP(0.4 U)を加えて 37℃で酵素反応を行った。この結果、化合物(2)(γGlu-RhoHM)とLAPとを反応させた場合には蛍光強度の増強が認められなかった。一方、化合物(2)はGGTと反応して顕著な蛍光強度を与えたことから(例2)、γGlu-RhoHMはGGTを特異的に検出するものと考えられた。
散在性腹膜転移は卵巣がんにおいて一般的に起こる致死的な合併症として知られている。このような腹膜転移は卵巣がんの比較的早い段階で起こり始め、腫瘍が漿膜を浸し、腹腔内に落ち込む結果、腹腔内の他の臓器に種を播くように転移する(播種転移)。この現象を実験的に再現すべく、卵巣がん由来のSHIN3細胞を胸腺欠損マウスに腹腔内投与し、腹膜播種モデルを作製した(Neoplasia, 8, pp.607-612, 2006)。
イソフルラン麻酔下、腹膜播種モデルマウスの腹部に小さな穴をあけて蛍光内視鏡を腹腔内に挿入し、300 μLの化合物(2)(γGlu-RhoHM)のPBS溶液(50 μM)を内視鏡の先端から霧状に散布した。その後、450-480 nmの励起光を照射し、516 nm-556 nmの蛍光を経時的に観測して蛍光内視鏡動画及び画像を得た。図4に結果を示す。図中、噴霧直後(0 sec)、30秒後、60秒後、90秒後の各結果において左側は白色光画像、右側は蛍光画像を示し、「白色画像」は比較のため蛍光モードではなく通常の内視鏡モードで撮影した画像である。蛍光像において噴霧直後から90秒後までにがん組織増が鮮明化してくる様子が確認できる。また、10分後においても明確にがん組織がイメージングされていた(同様に「白色画像」は比較のため蛍光モードではなく通常の内視鏡モードで撮影した画像である)。この結果、本発明のがん診断薬を用いることにより数分以内にがん部位が選択的に蛍光を発するようになることが確認できた。
Claims (5)
- 下記の一般式(I):
- R1、R2、R3、R4、R5、R6、R7、R8、及びR9が水素原子である上記の化合物又はその塩を含む請求項1に記載のがん診断薬。
- がん外科治療又はがん検査に用いる請求項1又は2に記載のがん診断薬。
- がん外科治療又はがん検査が開創手術、鏡視下手術、又は内視鏡検査である請求項3に記載のがん診断薬。
- 術中迅速診断に用いる請求項4に記載のがん診断薬。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011549976A JP5795963B2 (ja) | 2010-01-13 | 2011-01-12 | がん診断薬 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010004797 | 2010-01-13 | ||
JP2010004797 | 2010-01-13 | ||
PCT/JP2011/050299 WO2011087000A1 (ja) | 2010-01-13 | 2011-01-12 | がん診断薬 |
JP2011549976A JP5795963B2 (ja) | 2010-01-13 | 2011-01-12 | がん診断薬 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2011087000A1 JPWO2011087000A1 (ja) | 2013-05-20 |
JP5795963B2 true JP5795963B2 (ja) | 2015-10-14 |
Family
ID=44304274
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011549976A Active JP5795963B2 (ja) | 2010-01-13 | 2011-01-12 | がん診断薬 |
Country Status (5)
Country | Link |
---|---|
US (2) | US20130023675A1 (ja) |
EP (2) | EP2524702B1 (ja) |
JP (1) | JP5795963B2 (ja) |
ES (1) | ES2661712T3 (ja) |
WO (1) | WO2011087000A1 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2399920B1 (en) * | 2009-02-20 | 2015-03-25 | The University of Tokyo | Fluorescent probe for use in measurement of protease |
JP5501538B1 (ja) * | 2012-05-30 | 2014-05-21 | 国立大学法人 東京大学 | 高感度膵液検出用蛍光プローブ、及び膵液検出方法 |
US20150276751A1 (en) | 2012-10-11 | 2015-10-01 | Japan Science And Technology Agency | Reagent for imaging intracellular acetylation |
US9714260B2 (en) | 2013-01-07 | 2017-07-25 | The University Of Tokyo | Asymmetrical Si rhodamine and rhodol synthesis |
JP6311111B2 (ja) * | 2014-01-29 | 2018-04-18 | パナソニックIpマネジメント株式会社 | 放熱構造 |
JP6635555B2 (ja) * | 2014-05-14 | 2020-01-29 | 国立大学法人 東京大学 | 酵素特異的な細胞内滞留性蛍光化合物 |
EP3954697B1 (en) * | 2015-02-27 | 2024-01-03 | The University of Tokyo | Fluorescent probe for detecting calpain activity |
JP7008339B2 (ja) * | 2017-02-17 | 2022-01-25 | 国立大学法人 東京大学 | ペプチダーゼ活性検出用赤色蛍光プローブ |
US20240201189A1 (en) * | 2021-04-12 | 2024-06-20 | The University Of Tokyo | Fluorescent probe for use in detection of pancreatic cancer |
CN113416230B (zh) * | 2021-06-18 | 2022-09-13 | 华东理工大学 | 谷氨酰胺荧光探针及其制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003099780A2 (en) * | 2002-05-24 | 2003-12-04 | Molecular Devices Corporation | Luminogenic protease substrates |
JP2004527299A (ja) * | 2001-04-09 | 2004-09-09 | フルオロ プローブ インコーポレイテッド | 体腔内に位置する腫瘍組織を観察するための方法 |
JP2004535371A (ja) * | 2001-03-16 | 2004-11-25 | ユニバーシティ・オブ・ユタ・リサーチ・ファウンデーション | 蛍光コバラミンおよびその使用 |
JP5588962B2 (ja) * | 2009-02-20 | 2014-09-10 | 国立大学法人 東京大学 | プロテアーゼ測定用蛍光プローブ |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4640893A (en) * | 1983-10-28 | 1987-02-03 | University Of Illinois | Novel rhodamine derivatives as fluorogenic substrates for proteinases |
US6299860B1 (en) | 1998-10-15 | 2001-10-09 | Fluoro Probe, Inc. | Method for viewing diseased tissue located within a body cavity |
US6284223B1 (en) | 1998-10-15 | 2001-09-04 | Fluoroprobe, Inc. | Method for viewing tumor tissue located within a body cavity |
US6797521B2 (en) | 1999-10-26 | 2004-09-28 | University Of Utah Research Foundation | Fluorescent cobalamins and uses thereof |
US20040082863A1 (en) | 2002-03-15 | 2004-04-29 | Mcgreevy James | Device and method for the photodynamic diagnosis of tumor tissue |
-
2011
- 2011-01-12 JP JP2011549976A patent/JP5795963B2/ja active Active
- 2011-01-12 WO PCT/JP2011/050299 patent/WO2011087000A1/ja active Application Filing
- 2011-01-12 US US13/521,326 patent/US20130023675A1/en not_active Abandoned
- 2011-01-12 ES ES11732870.8T patent/ES2661712T3/es active Active
- 2011-01-12 EP EP11732870.8A patent/EP2524702B1/en active Active
- 2011-01-12 EP EP17206929.6A patent/EP3323431B1/en active Active
-
2014
- 2014-01-24 US US14/163,422 patent/US9610366B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004535371A (ja) * | 2001-03-16 | 2004-11-25 | ユニバーシティ・オブ・ユタ・リサーチ・ファウンデーション | 蛍光コバラミンおよびその使用 |
JP2004527299A (ja) * | 2001-04-09 | 2004-09-09 | フルオロ プローブ インコーポレイテッド | 体腔内に位置する腫瘍組織を観察するための方法 |
WO2003099780A2 (en) * | 2002-05-24 | 2003-12-04 | Molecular Devices Corporation | Luminogenic protease substrates |
JP5588962B2 (ja) * | 2009-02-20 | 2014-09-10 | 国立大学法人 東京大学 | プロテアーゼ測定用蛍光プローブ |
Non-Patent Citations (3)
Title |
---|
JPN6011011076; 坂部雅世: '閉環・開環を蛍光制御原理に用いた新規酵素活性検出蛍光プローブの開発' 平成21年3月修士課程修了予定者 修士論文発表要旨集(平成21年3月2,3,4,5日) , 200903, p.171-172, 東京大学大学院薬学系研究科 * |
JPN6011011077; URANO, Y., et al.1: 'Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes' nature medicine Vol.15, No.1, 200901, p.104-109 * |
JPN6014053215; Biochemical Pharmacology Vol.71, 2006, p.231-238 * |
Also Published As
Publication number | Publication date |
---|---|
US9610366B2 (en) | 2017-04-04 |
EP2524702B1 (en) | 2017-12-20 |
EP2524702A4 (en) | 2013-06-26 |
EP3323431A1 (en) | 2018-05-23 |
EP2524702A1 (en) | 2012-11-21 |
JPWO2011087000A1 (ja) | 2013-05-20 |
ES2661712T3 (es) | 2018-04-03 |
EP3323431B1 (en) | 2021-10-13 |
US20140206992A1 (en) | 2014-07-24 |
US20130023675A1 (en) | 2013-01-24 |
WO2011087000A1 (ja) | 2011-07-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5795963B2 (ja) | がん診断薬 | |
JP5526124B2 (ja) | 近赤外蛍光化合物 | |
WO2017078623A9 (en) | Background-free fluorescent probes for live cell imaging | |
JP6731669B2 (ja) | ジペプチジルペプチダーゼiv検出用蛍光プローブ | |
WO2018003686A1 (ja) | 酵素特異的な細胞内滞留性赤色蛍光プローブ。 | |
CN109748896A (zh) | 一种psma抑制剂、化合物与应用 | |
WO2018159631A1 (ja) | ペプチダーゼ活性検出用近赤外蛍光プローブ | |
JP2015203015A (ja) | 蛍光プローブ | |
JP7140398B2 (ja) | ニトロベンゼン誘導体またはその塩およびそれらの用途 | |
JP2019528080A (ja) | 組織サンプルにおける癌細胞を検出するための組成物および方法 | |
JP2018145126A (ja) | カルボキシペプチダーゼ活性検出用蛍光プローブ | |
US10890588B2 (en) | Compositions and methods for detecting cancer cells in a tissue sample | |
JP7157438B2 (ja) | アクロレインとの反応薬、その利用及び新規化合物 | |
EP3974438A1 (en) | Fluorescent probe for use in detection of brain tumor | |
KR102324334B1 (ko) | 황화수소 검출용 형광 프로브 및 이의 제조방법 | |
JP7008339B2 (ja) | ペプチダーゼ活性検出用赤色蛍光プローブ | |
WO2020175688A1 (ja) | 癌検出蛍光プローブ | |
JP2009275006A (ja) | 低酸素環境測定用試薬 | |
JP2018145122A (ja) | Activatable型光音響プローブ | |
JP2013245290A (ja) | 蛍光色素、蛍光試薬、生体患部の診断方法、標的細胞の特定方法及び標的物質の検出方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20131225 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20141216 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150213 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150728 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150817 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5795963 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |