KR20240031282A - Compound based cyanine, labeling dye, kit and contrast medium composition for biomolecule comprising the same - Google Patents
Compound based cyanine, labeling dye, kit and contrast medium composition for biomolecule comprising the same Download PDFInfo
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- KR20240031282A KR20240031282A KR1020240027001A KR20240027001A KR20240031282A KR 20240031282 A KR20240031282 A KR 20240031282A KR 1020240027001 A KR1020240027001 A KR 1020240027001A KR 20240027001 A KR20240027001 A KR 20240027001A KR 20240031282 A KR20240031282 A KR 20240031282A
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- unsubstituted
- substituent
- aryl
- ester
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- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title claims abstract description 62
- 150000001875 compounds Chemical class 0.000 title claims abstract description 58
- 238000002372 labelling Methods 0.000 title claims abstract description 44
- 239000000203 mixture Substances 0.000 title claims abstract description 10
- 239000002872 contrast media Substances 0.000 title claims abstract description 9
- -1 cyano, hydroxy, amino Chemical group 0.000 claims description 71
- 150000007523 nucleic acids Chemical class 0.000 claims description 46
- 108020004707 nucleic acids Proteins 0.000 claims description 45
- 102000039446 nucleic acids Human genes 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000000524 functional group Chemical group 0.000 claims description 32
- 102000004169 proteins and genes Human genes 0.000 claims description 32
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 31
- 108090000623 proteins and genes Proteins 0.000 claims description 31
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 19
- 150000001299 aldehydes Chemical class 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 150000002576 ketones Chemical class 0.000 claims description 17
- 229910019142 PO4 Inorganic materials 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 16
- 239000010452 phosphate Substances 0.000 claims description 16
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 229920000233 poly(alkylene oxides) Polymers 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 14
- 150000001263 acyl chlorides Chemical class 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 14
- 125000004104 aryloxy group Chemical group 0.000 claims description 14
- 229910052805 deuterium Inorganic materials 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 150000007942 carboxylates Chemical class 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
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- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000011593 sulfur Substances 0.000 claims description 12
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 8
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 7
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 7
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
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- 150000002219 fluoranthenes Chemical class 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
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- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- IHDBZCJYSHDCKF-UHFFFAOYSA-N 4,6-dichlorotriazine Chemical compound ClC1=CC(Cl)=NN=N1 IHDBZCJYSHDCKF-UHFFFAOYSA-N 0.000 claims description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical group O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001266 acyl halides Chemical class 0.000 claims description 4
- 150000001345 alkine derivatives Chemical class 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 150000004982 aromatic amines Chemical class 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001720 carbohydrates Chemical class 0.000 claims description 4
- 235000014633 carbohydrates Nutrition 0.000 claims description 4
- VQXINLNPICQTLR-UHFFFAOYSA-N carbonyl diazide Chemical compound [N-]=[N+]=NC(=O)N=[N+]=[N-] VQXINLNPICQTLR-UHFFFAOYSA-N 0.000 claims description 4
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims description 4
- 150000004891 diazines Chemical class 0.000 claims description 4
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 4
- 229940015043 glyoxal Drugs 0.000 claims description 4
- 150000002463 imidates Chemical class 0.000 claims description 4
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
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- 125000001424 substituent group Chemical group 0.000 claims 52
- 125000003342 alkenyl group Chemical group 0.000 claims 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- 125000000542 sulfonic acid group Chemical group 0.000 claims 4
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 4
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims 2
- TXCDCPKCNAJMEE-UHFFFAOYSA-N Dibenzofuran Natural products C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims 2
- 125000000609 carbazolyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims 2
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- IYYZUPMFVPLQIF-ALWQSETLSA-N dibenzothiophene Chemical class C1=CC=CC=2[34S]C3=C(C=21)C=CC=C3 IYYZUPMFVPLQIF-ALWQSETLSA-N 0.000 claims 2
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene sulfoxide Natural products C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 claims 2
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- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims 2
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Classifications
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
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Abstract
본 발명은 신규한 시아닌계 화합물, 이를 포함하는 생체분자 표지용 염료, 키트 및 조영제 조성물에 관한 것이다.The present invention relates to a novel cyanine-based compound, a dye for labeling biomolecules containing the same, a kit, and a contrast agent composition.
Description
본 발명은 신규한 시아닌계 화합물, 이를 포함하는 생체분자 표지용 염료, 키트 및 조영제 조성물에 관한 것이다.The present invention relates to a novel cyanine-based compound, a dye for labeling biomolecules containing the same, a kit, and a contrast agent composition.
바이오 분야에서 생체 내(in vivo), 생체 외(in vitro)에서 세포수준의 생물학적인 현상을 관찰하거나, 생체 조영 및 질환부위를 검시하기 위해, 이를 가시화 할 수 있는 수단으로 형광 염료가 사용되고 있다. 그린형광단백질(GFP) 등의 자체적으로 발광하는 생체분자도 존재하지만, 일반적으로는 생체 조직이나 세포 및 그 이하 단계의 생체물질을 형광 염료로 염색하거나, 단백질, 핵산 등의 생체분자에 형광 염료를 표지한 후, 형광신호를 검출할 수 있는 광학장비를 동반하여, 다양한 기법으로 영상화한 자료를 얻고 있다. In the bio field, fluorescent dyes are used as a means of visualizing biological phenomena at the cellular level in vivo and in vitro, or to perform biopsy and autopsy of diseased areas. There are biomolecules that emit light on their own, such as green fluorescent protein (GFP), but in general, biological tissues, cells, and lower-level biomaterials are dyed with fluorescent dyes, or biomolecules such as proteins and nucleic acids are dyed with fluorescent dyes. After labeling, imaging data is obtained using various techniques using optical equipment that can detect fluorescence signals.
주로 사용되는 광학 분석 장비로는 세포 관찰을 위한 형광현미경(fluorescece microscope), 공초점현미경(confocal microscope), 유세포분석기(flow cytometry), 마이크로어레이(microarray), 정량 중합효소연쇄반응 장치(quantitative PCR system), 핵산 및 단백질 분리, 분석을 위한 전기영동(electrophoresis) 장치, 실시간 생체내 영상 장비(in vivo imaging system) 등 연구 목적의 장비 외에도, 면역 분석 기법(immnuno assay)이나 PCR 분석 및 통계 기술이 접목된 핵산 및 단백질 진단 키트(또는 바이오칩) 기반 체외 진단(in vitro diagnosis) 장비와 의료 영상 수술(image-guided surgery)을 위한 수술대 및 내시경 장비 등의 진단 및 치료를 위한 것들이 알려져 있으며, 지속적으로 새로운 응용 분야 및 더 높은 수준의 해상도 및 데이터 처리 능력을 가진 장비가 개발되고 있다.Mainly used optical analysis equipment include a fluorescence microscope, confocal microscope, flow cytometry, microarray, and quantitative PCR system for cell observation. ), in addition to equipment for research purposes such as electrophoresis equipment for separation and analysis of nucleic acids and proteins, and real-time in vivo imaging systems, immunoassay techniques, PCR analysis, and statistical techniques are applied. In vitro diagnosis equipment based on nucleic acid and protein diagnostic kits (or biochips) and operating tables and endoscopic equipment for medical image-guided surgery are known for diagnosis and treatment, and new applications are continuously being developed. Equipment with higher resolution and data processing capabilities is being developed.
바이오 분야에 형광 염료를 적용하기 위해서는, 일반적으로 대부분의 생체분자들이 존재하는 매질, 즉, 수용액 내에 존재할 때 광표백(photo bleaching) 및 소광(quenching) 현상이 적고, 몰흡광계수(molecular extinction coefficient)및 양자효율(quantum efficiency)이 크며, 다양한 pH 조건에서 안정한 것이 바람직하다.In order to apply fluorescent dyes in the bio field, they are generally photobleached when present in a medium where most biomolecules exist, that is, an aqueous solution. It is desirable that the bleaching and quenching phenomena are low, the molar extinction coefficient and quantum efficiency are high, and it is stable under various pH conditions.
여러 연구분야에서 다양한 형광 염료가 이용되어 오고 있으나, 바이오 분야에서 상술한 조건들을 모두 만족시키는 형광 염료는 드물며, 현재 사용되고 있는 대표적인 구조로는 쿠마린(coumarins), 시아닌(cyanine), 보디피(bodipy), 플로세인(fluoresceins), 로다민(rhodamines), 피렌(pyrenes), 카르보피로닌(carbopyronin), 옥사진(oxazine), 잔텐(xanthenes), 티오잔텐(thioxanthene) 및 아크리딘(acridines) 등이 있다. 이 중에서도 특히 로다민 유도체와 폴리메틴(polymethine) 계열의 시아닌 유도체가 주를 이루고 있다. 특히, 시아닌계 형광 염료는, 폴리메틴 양쪽 말단 부위에 질소를 포함한 헤테로 고리로 연결되어 있으며, 폴리메틴 길이를 조절함으로써 450nm에서 800nm의 가시광선, 근적외선 전영역에 걸쳐 다양한 형광을 구현할 수 있는 구조적 장점 뿐만 아니라, 일반적으로 매우 높은 흡광계수를 가지는 광학적 특징이 있다. 그러나, 폴리메틴의 길이가 증가함에 따라 시아닌계 염료의 광안정성(photo stability)이 저하되는 문제점이 제기 되고 있다.A variety of fluorescent dyes have been used in various research fields, but in the bio field, fluorescent dyes that satisfy all of the above-mentioned conditions are rare. Representative structures currently used include coumarins, cyanine, and bodipy. , fluoresceins, rhodamines, pyrenes, carbopyronin, oxazine, xanthenes, thioxanthene and acridines, etc. There is. Among these, rhodamine derivatives and polymethine series cyanine derivatives are the main ones. In particular, cyanine-based fluorescent dyes are connected to both ends of polymethine by a nitrogen-containing heterocycle, and have the structural advantage of being able to realize various fluorescence across the entire visible and near-infrared range from 450 nm to 800 nm by adjusting the length of polymethine. In addition, it has the optical characteristic of generally having a very high extinction coefficient. However, as the length of polymethine increases, a problem has been raised that the photo stability of cyanine-based dyes decreases.
따라서, 수용액 내에서 장시간 동안 광안정성을 유지할 수 있는 시아닌계 염료의 개발이 지속적으로 요구되고 있는 상황이다.Therefore, there is a continuous need for the development of cyanine-based dyes that can maintain photostability for a long time in aqueous solution.
본 발명은 광학 영상 분야에서 생체분자의 동정을 관찰하기 위하여 광범위하게 사용될 수 있는 신규한 시아닌계 화합물 및 이를 포함하는 생체분자 표지용 염료, 키트 및 조영제를 제공하는 것을 목적으로 한다.The purpose of the present invention is to provide a novel cyanine-based compound that can be widely used to observe the identification of biomolecules in the field of optical imaging, and a dye, kit, and contrast agent for labeling biomolecules containing the same.
또한, 본 발명은 수용액 중에서 장시간 동안 광안정성을 유지할 수 있는 신규한 시아닌계 화합물을 제공하는 것을 목적으로 한다.Additionally, the present invention aims to provide a novel cyanine-based compound that can maintain photostability in aqueous solution for a long time.
상술한 기술적 과제를 해결하기 위한 본 발명의 일 측면에 따르면, 하기의 화학식 1로 표시되는 시아닌계 화합물이 제공될 수 있다.According to one aspect of the present invention for solving the above-mentioned technical problem, a cyanine-based compound represented by the following formula (1) can be provided.
[화학식 1][Formula 1]
여기서,here,
Ar1 및 Ar2는 각각 독립적으로 치환 또는 비치환된 아릴 또는 치환 또는 비치환된 헤테로아릴이며, 상기 Ar1 및 Ar2 중 적어도 하나는 치환 또는 비치환된 플루오란텐(fluoranthene)이며,Ar 1 and Ar 2 are each independently substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and Ar 1 And at least one of Ar 2 is substituted or unsubstituted fluoranthene,
Y1 및 Y2는 각각 독립적으로 황, 산소, 셀레늄, NR4, CR4R5, SiR4R5 및 -CR4=CR5-으로부터 선택되며,Y 1 and Y 2 are each independently selected from sulfur, oxygen, selenium, NR 4 , CR 4 R 5 , SiR 4 R 5 and -CR 4 =CR 5 -,
R1 내지 R5는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 치환 또는 비치환된 아미노, 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 4차암모늄, 인산, 인산염, 케톤(-COR6), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택될 수 있다.R 1 to R 5 are each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl , substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted amide, sulfhydryl, nitro, carboxyl, carboxylate, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphate, ketone. (-COR 6 ), aldehyde, ester (-COOR 6 ), acylchloride, sulfonic acid, sulfonate and -LX functional groups.
케톤기(-COR6) 또는 에스터기(-COOR6)일 때, R6은 치환 또는 비치환된 C1-C10 알킬기, 치환 또는 비치환된 C2-C10 알케닐기, 치환 또는 비치환된 C2-C10 알키닐기, 치환 또는 비치환된 C2-C10 알콕시기, 치환 또는 비치환된 C1-C10 할로알킬기 및 치환 또는 비치환된 C1-C10 아미노알킬기로부터 선택되며, When a ketone group (-COR 6 ) or an ester group (-COOR 6 ), R 6 is a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted C 2 -C 10 alkenyl group, or a substituted or unsubstituted C 1 -C 10 alkyl group. selected from a C 2 -C 10 alkynyl group, a substituted or unsubstituted C 2 -C 10 alkoxy group, a substituted or unsubstituted C 1 -C 10 haloalkyl group, and a substituted or unsubstituted C 1 -C 10 aminoalkyl group; ,
-L-X 작용기에 있어서, L은 탄소, 질소, 산소 및 황으로부터 선택되는 1-20개의 원자, -NHCOO-, -CONH-, -CH2NH-, -CH2NR6-, -COO-, -SO2NH-, -HN-C(=NH)-NH-, -NR6-, -(CH2-CH2-O-)p-, -CH=CH-, -C≡C-, -Ar- 및 -CO-Ar-NR6-으로부터 선택되는 링커이며, R6은 수소, 치환 또는 비치환된 C1-C6알킬, 치환 또는 비치환된 C2-C10알케닐, 치환 또는 비치환된 C2-C10알키닐, 치환 또는 비치환된 C2-C6알콕시 및 치환 또는 비치환된 C1-C6할로알킬로부터 선택되며, Ar은 아릴이며, p는 1내지 100 의 정수이며, X는 카복실(carboxyl), 숙신이미딜 에스터(succinimidyl ester), 설포-숙신이미딜 에스터(sulfo-succinimidyl ester), 이소티오시아네이트(isothiocyanate), 말레이미드(maleimide), 할로아세트아마이드(haloacetamide), 하이드라자이드(hydrazide), 바이닐설폰(vinylsulphone), 다이클로로트리아진(dichlorotriazine), 포스포라미다이트(phosphoramidite), 알킬 할라이드(alkyl halide), 아실 할라이드(acyl halide), 카보하이드라자이드(carbohydrazide), 하이드록실아민(hydroxylamine), 케톤(ketone), 알카인(alkyne), 아자이드(azide), 지방족 및 방향족 아민(amine), 설포테트라플루오로페닐 에스터(sulfotetrafluorophenyl ester), 설포다이클로로페닐 에스터(sulfodichlorophenyl ester), 카보닐 아자이드(carbonyl azide), 설포닐 클로라이드(sulfonyl chloride), 설포닐 플루오라이드(sulfonyl fluoride), 보론산(boronic acid), 이소시아네이트(isocyanate), 할로겐-치환 트리아진(halogen-substituted triazine), 할로겐-치환 피리딘(halogen-substituted pyridine), 할로겐-치환 다이아진(halogen-substituted diazine), 테트라플루오로페닐 에스터(tetrafluorophenyl ester), 이미도 에스터(imido ester), 아지도나이트로페닐(azidonitrophenyl), 글리옥살(glyoxal) 및 알데하이드로부터 선택되는 반응성기이다. For the -LX functional group, L is 1-20 atoms selected from carbon, nitrogen, oxygen and sulfur, -NHCOO-, -CONH-, -CH 2 NH-, -CH 2 NR 6 -, -COO-, - SO 2 NH-, -HN-C(=NH)-NH-, -NR 6 -, -(CH 2 -CH 2 -O-)p-, -CH=CH-, -C≡C-, -Ar - and -CO-Ar-NR 6 -, and R 6 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted. is selected from C 2 -C 10 alkynyl, substituted or unsubstituted C 2 -C 6 alkoxy and substituted or unsubstituted C 1 -C 6 haloalkyl, Ar is aryl, and p is an integer of 1 to 100. , X is carboxyl, succinimidyl ester, sulfo-succinimidyl ester, isothiocyanate, maleimide, haloacetamide , hydrazide, vinylsulphone, dichlorotriazine, phosphoramidite, alkyl halide, acyl halide, carbohydrazide ), hydroxylamine, ketone, alkyne, azide, aliphatic and aromatic amine, sulfotetrafluorophenyl ester, sulfodichlorophenyl ester (sulfodichlorophenyl ester), carbonyl azide, sulfonyl chloride, sulfonyl fluoride, boronic acid, isocyanate, halogen-substituted triazine -substituted triazine, halogen-substituted pyridine, halogen-substituted diazine, tetrafluorophenyl ester, imido ester, azidonite. It is a reactive group selected from phenyl (azidonitrophenyl), glyoxal and aldehyde.
또한, R1, R2, R3, R4, R5 또는 R6가 치환된 경우, 상기 작용기 내 임의의 탄소 또는 말단 탄소는 설폰산, 설폰산염, 케톤, 알데하이드, 카복실산, 카복실산염, 인산, 인산염, 아실클로라이드, 폴리알킬렌 옥사이드, 4차 암모늄염, 에스터 및 아마이드로부터 선택되는 적어도 하나로 치환될 수 있으며, n은 0 또는 1 내지 5의 정수이다.In addition, when R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is substituted, any carbon or terminal carbon in the functional group is sulfonic acid, sulfonic acid salt, ketone, aldehyde, carboxylic acid, carboxylic acid salt, phosphoric acid. , phosphate, acyl chloride, polyalkylene oxide, quaternary ammonium salt, ester, and amide, and n is 0 or an integer of 1 to 5.
화학식 1로 표시되는 시아닌계 화합물은 대칭 또는 비대칭 골격을 가지고 있으며, 플루오란텐이 결합된 헤테로 고리를 포함한다.The cyanine-based compound represented by Formula 1 has a symmetric or asymmetric skeleton and contains a heterocycle to which fluoranthene is bonded.
본 발명의 실시예에 따른 시아닌계 화합물은 플루오란텐이 결합된 헤테로 고리를 대칭 또는 비대칭적으로 포함함에 따라 동일한 길이의 폴리메틴을 가지는 종래의 시아닌계 염료 대비 상대적으로 장파장대에서 형광 신호를 발생시킬 수 있다.The cyanine-based compound according to an embodiment of the present invention contains a heterocycle to which fluoranthene is bonded symmetrically or asymmetrically, and thus generates a fluorescence signal in a relatively long wavelength range compared to conventional cyanine-based dyes having polymethine of the same length. You can do it.
예를 들어, 시판되는 Cy3 염료와 동일한 길이의 폴리메틴을 가지는 본 발명의 일 실시예에 따른 시아닌계 화합물은 시판되는 Cy5 염료와 유사한 파장대에서 형광 신호를 발생시킬 수 있다.For example, the cyanine-based compound according to an embodiment of the present invention, which has polymethine of the same length as a commercially available Cy3 dye, can generate a fluorescence signal in a similar wavelength range as a commercially available Cy5 dye.
즉, 본 발명의 다양한 실시예에 따르면, 플루오란텐이 결합된 헤테로 고리를 도입함에 따라 종래의 상용화된 시아닌계 염료 대비 상대적으로 장파장대에서 여기 및 발광이 가능한 바, 유사한 파장대에서 여기 및 발광이 가능한 종래의 상용화된 시아닌계 염료 대비 광안정성을 향상시키는 것이 가능하다.That is, according to various embodiments of the present invention, by introducing a heterocycle to which fluoranthene is bonded, excitation and emission are possible in a relatively long wavelength range compared to conventional commercially available cyanine-based dyes, and excitation and emission in a similar wavelength range are possible. It is possible to improve photostability compared to conventional commercially available cyanine dyes.
또한, 본 발명의 다른 측면에 따르면, 화학식 1로 표시되는 시아닌계 화합물을 포함하는 생체분자 표지용 염료가 제공될 수 있다.Additionally, according to another aspect of the present invention, a dye for labeling biomolecules containing a cyanine-based compound represented by Formula 1 may be provided.
또한, 본 발명의 또 다른 측면에 따르면, 화학식 1로 표시되는 시아닌계 화합물을 포함하는 생체분자 표지용 키트가 제공될 수 있다.In addition, according to another aspect of the present invention, a kit for labeling biomolecules containing a cyanine-based compound represented by Formula 1 may be provided.
또한, 본 발명의 또 다른 측면에 따르면, 화학식 1로 표시되는 시아닌계 화합물을 포함하는 조영제 조성물이 제공될 수 있다.Additionally, according to another aspect of the present invention, a contrast medium composition containing a cyanine-based compound represented by Formula 1 may be provided.
본 발명에 따른 신규한 시아닌계 화합물은 헤테로고리에 플루오란텐을 포함하고 있어, 동일한 폴리메틴을 가진 종래의 시아닌계 염료대비, 보다 장파장의 빛의 흡수가 가능하다. 이에 따라 보다 짧은 폴리메틴 구조로, 종래의 시판되는 상대적으로 더 긴 폴리메틴을 가진 시아닌계 염료와 유사한 형광 신호를 구현할 수 있음과 동시에, 상대적으로 광안정성을 향상시킬 수 있다. The novel cyanine-based compound according to the present invention contains fluoranthene in the heterocycle, and is capable of absorbing longer wavelength light than conventional cyanine-based dyes with the same polymethine. Accordingly, with a shorter polymethine structure, a fluorescence signal similar to that of a conventional commercially available cyanine-based dye with a relatively longer polymethine can be realized, while photostability can be relatively improved.
본 발명을 더 쉽게 이해하기 위해 편의상 특정 용어를 본원에 정의한다. 본원에서 달리 정의하지 않는 한, 본 발명에 사용된 과학 용어 및 기술 용어들은 해당 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 의미를 가질 수 있다. To facilitate easier understanding of the present invention, certain terms are defined herein for convenience. Unless otherwise defined herein, scientific and technical terms used in the present invention may have meanings commonly understood by those skilled in the art.
또한, 문맥상 특별히 지정하지 않는 한, 단수 형태의 용어는 그것의 복수 형태도 포함하는 것이며, 복수 형태의 용어는 그것의 단수 형태도 포함할 수 있다.Additionally, unless otherwise specified by context, singular terms include their plural forms, and plural terms may also include their singular forms.
신규한 시아닌계 화합물Novel cyanine-based compounds
본 발명의 일 측면에 따르면, 하기의 화학식 1로 표시되는 시아닌계 화합물이 제공될 수 있다.According to one aspect of the present invention, a cyanine-based compound represented by the following formula (1) may be provided.
[화학식 1][Formula 1]
화학식 1로 표시되는 시아닌계 화합물에 있어서, Ar1 및 Ar2는 각각 독립적으로 치환 또는 비치환된 아릴 또는 치환 또는 비치환된 헤테로아릴이며, 상기 Ar1 및 Ar2 중 적어도 하나는 치환 또는 비치환된 플루오란텐(fluoranthene)인 대칭 또는 비대칭 골격을 가지고 있다.In the cyanine-based compound represented by Formula 1, Ar 1 and Ar 2 are each independently substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and Ar 1 And at least one of Ar 2 has a symmetric or asymmetric skeleton that is substituted or unsubstituted fluoranthene.
본 발명의 실시예에 따른 시아닌계 화합물은 플루오란텐이 결합된 헤테로 고리를 대칭 또는 비대칭적으로 포함함에 따라 동일한 길이의 폴리메틴을 가지는 종래의 시아닌계 염료 대비 상대적으로 장파장대에서 형광 신호를 발생시킬 수 있다.The cyanine-based compound according to an embodiment of the present invention contains a heterocycle to which fluoranthene is bonded symmetrically or asymmetrically, and thus generates a fluorescence signal in a relatively long wavelength range compared to conventional cyanine-based dyes having polymethine of the same length. You can do it.
예를 들어, 시판되는 Cy3 염료와 동일한 길이의 폴리메틴을 가지는 본 발명의 일 실시예에 따른 시아닌계 화합물은 시판되는 Cy5 염료와 유사한 파장대에서 형광 신호를 발생시킬 수 있다.For example, the cyanine-based compound according to an embodiment of the present invention, which has polymethine of the same length as a commercially available Cy3 dye, can generate a fluorescence signal in a similar wavelength range as a commercially available Cy5 dye.
즉, 본 발명의 다양한 실시예에 따르면, 플루오란텐이 결합된 헤테로 고리를 도입함에 따라 종래의 상용화된 시아닌계 염료 대비 상대적으로 장파장대에서 여기 및 발광이 가능한 바, 유사한 파장대에서 여기 및 발광이 가능한 종래의 상용화된 시아닌계 염료 대비 광안정성을 향상시키는 것이 가능하다.That is, according to various embodiments of the present invention, by introducing a heterocycle to which fluoranthene is bonded, excitation and emission are possible in a relatively long wavelength range compared to conventional commercially available cyanine-based dyes, and excitation and emission in a similar wavelength range are possible. It is possible to improve photostability compared to conventional commercially available cyanine dyes.
Y1 및 Y2는 각각 독립적으로 황, 산소, 셀레늄, NR4, CR4R5, SiR4R5 및 -CR4=CR5-으로부터 선택되며,Y 1 and Y 2 are each independently selected from sulfur, oxygen, selenium, NR 4 , CR 4 R 5 , SiR 4 R 5 and -CR 4 =CR 5 -,
R1 내지 R5는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 치환 또는 비치환된 아미노, 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 4차암모늄, 인산, 인산염, 케톤(-COR6), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택될 수 있다.R 1 to R 5 are each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl , substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted amide, sulfhydryl, nitro, carboxyl, carboxylate, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphate, ketone. (-COR 6 ), aldehyde, ester (-COOR 6 ), acylchloride, sulfonic acid, sulfonate and -LX functional groups.
Y1 또는 Y2가 CR4R5인 경우, R4 및 R5는 서로 결합하여 4원자, 5원자 또는 6원자 탄화수소 고리를 형성할 수 있다.When Y 1 or Y 2 is CR 4 R 5 , R 4 and R 5 may be combined with each other to form a 4-, 5-, or 6-membered hydrocarbon ring.
본원에서 Ca-Cb 작용기는 a 내지 b 개의 탄소 원자를 갖는 작용기를 의미한다. 예를 들어, Ca-Cb 알킬기는 a 내지 b 개의 탄소 원자를 갖는, 직쇄 알킬기 및 분쇄 알킬기 등을 포함하는 포화 지방족기를 의미한다. 직쇄 또는 분쇄 알킬기는 이의 주쇄에 10개 이하(예를 들어, C1-C10의 직쇄, C3-C10의 분쇄), 바람직하게는 4개 이하, 보다 바람직하게는 3개 이하의 탄소 원자를 가진다. As used herein, C a -C b functional group refers to a functional group having a to b carbon atoms. For example, C a -C b alkyl group refers to a saturated aliphatic group having a to b carbon atoms, including straight-chain alkyl groups and branched alkyl groups. A straight chain or branched alkyl group has in its main chain at most 10 carbon atoms (e.g. straight chain C 1 -C 10 , branched C 3 -C 10 ), preferably at most 4 carbon atoms, more preferably at most 3 carbon atoms. has
구체적으로, 알킬은 메틸, 에틸, n-프로필, i-프로필, n-부틸, s-부틸, i-부틸, t-부틸, 펜트-1-일, 펜트-2-일, 펜트-3-일, 3-메틸부트-1-일, 3-메틸부트-2-일, 2-메틸부트-2-일, 2,2,2-트리메틸에트-1-일, n-헥실, n-헵틸 및 n-옥틸일 수 있다.Specifically, alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl , 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, n-heptyl and n -Can be octyl.
또한, 본원에서 알콕시는 -O-(알킬)기와 -O-(비치환된 사이클로알킬)기 둘 다를 의미하는 것으로, 하나 이상의 에터기 및 1 내지 10 개의 탄소 원자를 갖는 직쇄 또는 분쇄 탄화 수소이다.Additionally, alkoxy herein refers to both an -O-(alkyl) group and an -O-(unsubstituted cycloalkyl) group, and is a straight-chain or branched hydrocarbon having one or more ether groups and 1 to 10 carbon atoms.
구체적으로, 메톡시, 에톡시, 프로폭시, 이소프로폭시, n-부톡시, tert-부톡시, sec-부톡시, n-펜톡시, n-헥속시, 1,2-다이메틸부톡시, 사이클로프로필옥시, 사이클로부틸옥시, 사이클로펜틸옥시, 사이클로헥실옥시 등을 포함하지만, 이에 한정되는 것은 아니다. Specifically, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, It includes, but is not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.
또한, 본원에서 할로겐은 플루오로(-F), 클로로(-Cl), 브로모(-Br) 또는 요오도(-I)을 의미하며, 할로알킬은 상술한 할로겐으로 치환된 알킬을 의미한다. 예를 들어, 할로메틸은 메틸의 수소 중 적어도 하나가 할로겐으로 대체된 메틸(-CH2X, -CHX2 또는 -CX3)을 의미한다.Additionally, as used herein, halogen refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I), and haloalkyl refers to alkyl substituted with the above-mentioned halogen. For example, halomethyl refers to methyl ( -CH 2
본원에서 아르알킬은 아릴이 알킬의 탄소에 치환된 형태의 작용기로서, -(CH2)nAr의 총칭이다. 아르알킬의 예로서, 벤질(-CH2C6H5) 또는 페네틸(-CH2CH2C6H5) 등이 있다.As used herein, aralkyl is a functional group in which aryl is substituted for the carbon of alkyl, and is a general term for -(CH 2 ) n Ar. Examples of aralkyl include benzyl (-CH 2 C 6 H 5 ) or phenethyl (-CH 2 CH 2 C 6 H 5 ).
-L-X 작용기에 있어서, L은 탄소, 질소, 산소 및 황으로부터 선택되는 1-20개의 원자, -NHCOO-, -CONH-, -CH2NH-, -CH2NR6-, -COO-, -SO2NH-, -HN-C(=NH)-NH-, -NR6-, -(CH2-CH2-O-)p-, -CH=CH-, -C≡C-, -Ar- 및 -CO-Ar-NR6-으로부터 선택되는 링커이며, 여기서, R6은 수소, 치환 또는 비치환된 C1-C6알킬, 치환 또는 비치환된 C2-C10알케닐, 치환 또는 비치환된 C2-C10알키닐, 치환 또는 비치환된 C2-C6알콕시 및 치환 또는 비치환된 C1-C6할로알킬로부터 선택되며, Ar은 아릴이며, p는 1내지 100 의 정수이다.For the -LX functional group, L is 1-20 atoms selected from carbon, nitrogen, oxygen and sulfur, -NHCOO-, -CONH-, -CH 2 NH-, -CH 2 NR 6 -, -COO-, - SO 2 NH-, -HN-C(=NH)-NH-, -NR 6 -, -(CH 2 -CH 2 -O-)p-, -CH=CH-, -C≡C-, -Ar - and -CO-Ar-NR 6 -, where R 6 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or is selected from unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 2 -C 6 alkoxy and substituted or unsubstituted C 1 -C 6 haloalkyl, Ar is aryl, and p is 1 to 100. It is an integer.
X는 카복실(carboxyl), 숙신이미딜 에스터(succinimidyl ester), 설포-숙신이미딜 에스터(sulfo-succinimidyl ester), 이소티오시아네이트(isothiocyanate), 말레이미드(maleimide), 할로아세트아마이드(haloacetamide), 하이드라자이드(hydrazide), 바이닐설폰(vinylsulphone), 다이클로로트리아진(dichlorotriazine), 포스포라미다이트(phosphoramidite), 알킬 할라이드(alkyl halide), 아실 할라이드(acyl halide), 카보하이드라자이드(carbohydrazide), 하이드록실아민(hydroxylamine), 케톤(ketone), 알카인(alkyne), 아자이드(azide), 지방족 및 방향족 아민(amine), 설포테트라플루오로페닐 에스터(sulfotetrafluorophenyl ester), 설포다이클로로페닐 에스터(sulfodichlorophenyl ester), 카보닐 아자이드(carbonyl azide), 설포닐 클로라이드(sulfonyl chloride), 설포닐 플루오라이드(sulfonyl fluoride), 보론산(boronic acid), 이소시아네이트(isocyanate), 할로겐-치환 트리아진(halogen-substituted triazine), 할로겐-치환 피리딘(halogen-substituted pyridine), 할로겐-치환 다이아진(halogen-substituted diazine), 테트라플루오로페닐 에스터(tetrafluorophenyl ester), 이미도 에스터(imido ester), 아지도나이트로페닐(azidonitrophenyl), 글리옥살(glyoxal) 및 알데하이드로부터 선택되는 반응성기이다. X is carboxyl, succinimidyl ester, sulfo-succinimidyl ester, isothiocyanate, maleimide, haloacetamide, Hydrazide, vinylsulphone, dichlorotriazine, phosphoramidite, alkyl halide, acyl halide, carbohydrazide , hydroxylamine, ketone, alkyne, azide, aliphatic and aromatic amine, sulfotetrafluorophenyl ester, sulfodichlorophenyl ester ( sulfodichlorophenyl ester, carbonyl azide, sulfonyl chloride, sulfonyl fluoride, boronic acid, isocyanate, halogen-substituted triazine substituted triazine, halogen-substituted pyridine, halogen-substituted diazine, tetrafluorophenyl ester, imido ester, azidonitrophenyl It is a reactive group selected from (azidonitrophenyl), glyoxal, and aldehyde.
본 발명의 다양한 실시예에 따른 시아닌계 화합물은 상술한 반응성기를 통해 타겟 생체분자와 결합하여 표지하는 것이 가능할 수 있다.Cyanine-based compounds according to various embodiments of the present invention may be capable of binding to and labeling target biomolecules through the above-mentioned reactive group.
여기서, 상술한 반응성기들은 타겟 생체분자의 아미노기, 이미노기, 티올기 또는 하이드록실기 등과 같은 작용기와 반응할 수 있는 관능기로서, 시아닌계 화합물과 타겟 생체분자 사이에 아미드 결합, 이미드 결합, 우레탄 결합, 에스터 결합 또는 구아니딘 결합과 같은 공유결합을 형성할 수 있다.Here, the above-mentioned reactive groups are functional groups that can react with functional groups such as amino, imino, thiol, or hydroxyl groups of the target biomolecule, and form amide bonds, imide bonds, and urethane between the cyanine-based compound and the target biomolecule. It can form a covalent bond such as a bond, an ester bond, or a guanidine bond.
아울러, 반응성기(X)는 링커(L)를 매개로 하여 시아닌계 화합물의 본 골격에 결합됨으로써 생체분자와 시아닌계 화합물 사이의 입체 장애를 완화할 수 있으며, 이에 따라 복잡한 구조를 가지는 핵산, 단백질, 탄수화물 등과 같은 생체분자에 대한 표지율을 향상시킬 수 있다.In addition, the reactive group (X) can alleviate steric hindrance between the biomolecule and the cyanine compound by being bound to the main skeleton of the cyanine compound through the linker (L), thereby forming nucleic acids and proteins with complex structures. , can improve the labeling rate for biomolecules such as carbohydrates, etc.
또한, R1, R2, R3, R4, R5 또는 R6가 치환된 경우, 상기 작용기 내 임의의 탄소 또는 말단 탄소는 설폰산, 설폰산염, 케톤, 알데하이드, 카복실산, 카복실산염, 인산, 인산염, 아실클로라이드, 폴리알킬렌 옥사이드, 4차 암모늄염, 에스터 및 아마이드로부터 선택되는 적어도 하나로 치환될 수 있으며, n은 0 또는 1 내지 5의 정수이다. In addition, when R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is substituted, any carbon or terminal carbon in the functional group is sulfonic acid, sulfonic acid salt, ketone, aldehyde, carboxylic acid, carboxylic acid salt, phosphoric acid. , phosphate, acyl chloride, polyalkylene oxide, quaternary ammonium salt, ester, and amide, and n is 0 or an integer of 1 to 5.
여기서, 폴리알킬렌 옥사이드는 수용성 폴리머 작용기로서 폴리에틸렌 글라이콜(PEG), 폴리프로필렌 글라이콜(PPG), 폴리에틸렌 글라이콜-폴리프로필렌 글라이콜(PEG-PPG) 코폴리머 및 N-치환된 메타크릴아마이드-함유 폴리머 및 코폴리머를 포함한다.Here, polyalkylene oxide is a water-soluble polymer functional group such as polyethylene glycol (PEG), polypropylene glycol (PPG), polyethylene glycol-polypropylene glycol (PEG-PPG) copolymer, and N-substituted polymer. Includes methacrylamide-containing polymers and copolymers.
여기서, 폴리알킬렌 옥사이드는 폴리머의 특성이 유지되는 한도 내에서 필요에 따라 추가적으로 치환될 수 있다. 예를 들어, 상기 치환은 폴리머의 화학적 또는 생물학적 안정성을 증가 또는 감소시키기 위한 화학적 결합일 수 있다. 구체적인 예로서, 폴리알킬렌 옥사이드 내 임의의 탄소 또는 말단 탄소는 하이드록시, 알킬 에터(메틸 에터, 에틸 에터, 프로필 에터 등), 카복실메틸 에터, 카복시에틸 에터, 벤질 에터, 다이벤질메틸렌 에터 또는 다이메틸아민으로 치환될 수 있다. 일 실시예에 있어서, 폴리알킬렌 옥사이드는 메틸 에터로 종결되는 폴리알킬렌 옥사이드(mPEG)일 수 있으며, 여기서 mPEG는 -(CH2CH2O)nCH3의 화학식으로 표현되며, 에틸렌 글라이콜 반복 단위의 수에 해당하는 n의 크기에 따라 mPEG의 크기가 달라질 수 있다.Here, polyalkylene oxide may be additionally substituted as needed within the extent that the properties of the polymer are maintained. For example, the substitution may be a chemical bond to increase or decrease the chemical or biological stability of the polymer. As a specific example, any carbon or terminal carbon in the polyalkylene oxide may be hydroxy, alkyl ether (methyl ether, ethyl ether, propyl ether, etc.), carboxymethyl ether, carboxyethyl ether, benzyl ether, dibenzylmethylene ether, or dibenzylmethylene ether. Can be substituted with methylamine. In one embodiment, the polyalkylene oxide may be a methyl ether terminated polyalkylene oxide (mPEG), where mPEG is represented by the formula -(CH 2 CH 2 O) n CH 3 and is an ethylene glycol oxide. The size of mPEG may vary depending on the size of n, which corresponds to the number of call repeat units.
또한, 화학식 1로 표시되는 시아닌계 화합물은 카운터 이온을 더 포함하는 구조를 가질 수 있다. 카운터 이온은 유기 또는 무기 음이온으로서 시아닌계 화합물의 용해도 및 안정성 등을 고려하여 적절히 선택될 수 있다.Additionally, the cyanine-based compound represented by Formula 1 may have a structure that further includes a counter ion. The counter ion is an organic or inorganic anion and can be appropriately selected considering the solubility and stability of the cyanine-based compound.
본 발명의 일 실시예에 따른 시아닌계 화합물의 카운터 이온의 예로서, 포스포릭산 육플루오라이드 이온, 할로겐 이온, 포스포릭산 이온, 과염소산 이온, 과요오드산 이온, 안티몬 육플루오라이드 이온, 주석산 육플루오라이드 이온, 플루오로보릭산 이온 및 사플루오르 이온 등과 같은 무기산 음이온과 티오시안산 이온, 벤젠설폰산 이온, 나프탈렌설폰산 이온, p-톨루엔설폰산 이온, 알킬설폰산 이온, 벤젠카르복실산 이온, 알킬카르복실산 이온, 삼할로알킬카르복실산 이온, 알킬설폰산 이온, 트라이할로알킬설폰산 이온, 및 니코틴산 이온 등과 같은 유기산 이온이 있다. 또한, 비스페닐디톨, 티오비스페놀 킬레이트 및 비스디올-α-디켄톤 등과 같은 금속 화합물 이온, 소듐 및 포타슘 등과 같은 금속 이온과 4차 암모늄 염도 카운터 이온으로서 선택될 수 있다.Examples of counter ions of the cyanine-based compound according to an embodiment of the present invention include phosphoric acid hexafluoride ion, halogen ion, phosphoric acid ion, perchlorate ion, periodate ion, antimony hexafluoride ion, and tartaric acid hexafluoride ion. Inorganic acid anions such as fluoride ion, fluoroboric acid ion and safluoride ion, thiocyanate ion, benzenesulfonic acid ion, naphthalenesulfonic acid ion, p-toluenesulfonic acid ion, alkylsulfonic acid ion, benzenecarboxylic acid ion, There are organic acid ions such as alkylcarboxylic acid ion, trihaloalkylcarboxylic acid ion, alkylsulfonic acid ion, trihaloalkylsulfonic acid ion, and nicotinic acid ion. Additionally, metal compound ions such as bisphenylditol, thiobisphenol chelate and bisdiol-α-dickenthone, metal ions such as sodium and potassium, and quaternary ammonium salts may also be selected as counter ions.
화학식 1로 표시되는 시아닌계 화합물에 있어서, n이 1 이상일 때, 인접한 두 R3은 서로 결합하여 탄화수소 고리를 형성할 수 있다. 이 때, 탄화수소 고리는 4원자, 5원자 또는 6원자 고리일 수 있으며, -S-, -O-, -Se-, >NR4 및 >SiR4R5 로부터 선택되는 적어도 하나의 헤테로 원자를 선택적으로 포함할 수 있다.In the cyanine-based compound represented by Formula 1, when n is 1 or more, two adjacent R 3 may be combined with each other to form a hydrocarbon ring. At this time, the hydrocarbon ring may be a 4-, 5-, or 6-membered ring, and at least one hetero atom selected from -S-, -O-, -Se-, >NR 4 and >SiR 4 R 5 is optional. It can be included.
또한, Ar1 또는 Ar2가 치환된 경우, 상기 작용기 내 임의의 탄소는 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 치환 또는 비치환된 아미노, 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 4차암모늄, 인산, 인산염, 케톤(-COR6), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환될 수 있다.In addition, when Ar 1 or Ar 2 is substituted, any carbon in the functional group is deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, halogen, cyano, hydroxy, Substituted or unsubstituted amino, substituted or unsubstituted amide, sulfhydryl, nitro, carboxyl, carboxylate, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, 4 It may be substituted with at least one selected from hypoammonium, phosphoric acid, phosphate, ketone (-COR 6 ), aldehyde, ester (-COOR 6 ), acyl chloride, sulfonic acid, sulfonate, and -LX functional group.
보다 구체적으로, 화학식 1로 표시되는 시아닌계 화합물은 하기의 화학식 2 내지 화학식 6으로 표시될 수 있다.More specifically, the cyanine-based compound represented by Formula 1 may be represented by Formulas 2 to 6 below.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
여기서, R11 내지 R26은 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 치환 또는 비치환된 아미노, 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 4차암모늄, 인산, 인산염, 케톤(-COR6), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되며, Y3은 황, 산소, 셀레늄, NR4, CR4R5, SiR4R5 또는 -CR4=CR5-이다.Here, R 11 to R 26 are each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 Alkynyl, substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, halogen, cyano, hydroxy, substituted or unsubstituted amino , substituted or unsubstituted amide, sulfhydryl, nitro, carboxyl, carboxylate, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphate. , ketone (-COR 6 ), aldehyde, ester (-COOR 6 ), acyl chloride, sulfonic acid, sulfonate and -LX functional groups, and Y 3 is sulfur, oxygen, selenium, NR 4 , CR 4 R 5 , SiR 4 R 5 or -CR 4 =CR 5 -.
상기 화학식 1 내지 화학식 6으로 표시되는 화합물의 구체적인 예는 다음과 같다.Specific examples of compounds represented by Formulas 1 to 6 are as follows.
[화합물 1][Compound 1]
[화합물 2][Compound 2]
[화합물 3][Compound 3]
[화합물 4][Compound 4]
[화합물 5][Compound 5]
[화합물 6][Compound 6]
[화합물 7][Compound 7]
[화합물 8][Compound 8]
[화합물 9][Compound 9]
[화합물 10][Compound 10]
[화합물 11][Compound 11]
[화합물 12][Compound 12]
[화합물 13][Compound 13]
[화합물 14][Compound 14]
[화합물 15][Compound 15]
[화합물 16][Compound 16]
[화합물 17][Compound 17]
[화합물 18][Compound 18]
[화합물 19][Compound 19]
[화합물 20][Compound 20]
[화합물 21][Compound 21]
[화합물 22][Compound 22]
[화합물 23][Compound 23]
[화합물 24][Compound 24]
[화합물 25][Compound 25]
[화합물 26][Compound 26]
[화합물 27][Compound 27]
[화합물 28][Compound 28]
[화합물 29][Compound 29]
[화합물 30][Compound 30]
[화합물 31][Compound 31]
[화합물 32][Compound 32]
[화합물 33][Compound 33]
[화합물 34][Compound 34]
[화합물 35][Compound 35]
[화합물 36][Compound 36]
본 발명의 다양한 실시예에 따른 시아닌계 화합물의 여기 및 발광 특성은 발색단에 해당하는 폴리메틴 구조와 이의 양단에 대칭 또는 비대칭적으로 결합된 플루오란텐이 결합된 헤테로 고리에 의해 결정되는 것으로서, 화학식 1 내지 화학식 6에 표시되는 화합물에 도입된 반응기의 종류와 무관하게 본 발명에서 의도하는 시아닌계 화합물의 여기 및 발광 특성은 유지될 수 있는 것으로 이해되어야 할 것이다.The excitation and luminescence properties of cyanine-based compounds according to various embodiments of the present invention are determined by a heterocycle in which a polymethine structure corresponding to the chromophore and fluoranthene symmetrically or asymmetrically bonded to both ends thereof are bonded, and the chemical formula It should be understood that the excitation and luminescence properties of the cyanine-based compound intended in the present invention can be maintained regardless of the type of reactive group introduced into the compounds shown in Formulas 1 to 6.
본원에서 개시된 화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물의 타겟이 되는 생체분자는 항체, 지질, 단백질, 펩타이드, 탄수화물, 핵산(뉴클레오타이드 포함)로부터 선택되는 적어도 하나일 수 있다.The target biomolecule of the cyanine-based compounds represented by Formulas 1 to 6 disclosed herein may be at least one selected from antibodies, lipids, proteins, peptides, carbohydrates, and nucleic acids (including nucleotides).
지질의 구체적인 예로는 지방산(fatty acids), 인지질(phospholipids), 리포폴리당류(lipopolysaccharides) 등이 있으며, 탄수화물의 구체적인 예로는 단당류, 이당류, 다당류(예를 들어, 덱스트란)을 포함한다.Specific examples of lipids include fatty acids, phospholipids, and lipopolysaccharides, and specific examples of carbohydrates include monosaccharides, disaccharides, and polysaccharides (e.g., dextran).
이 때, 생체분자는 화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물의 임의의 작용기 또는 화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물에 결합된 반응성기와 반응하기 위한 작용기로서, 아미노, 설프하이드릴(sulphydryl), 카보닐, 하이드록실, 카복실, 포스페이트 및 티오포스페이트로부터 선택되는 적어도 하나를 포함하거나 이의 유도체 형태를 가질 수 있다.At this time, the biomolecule is a functional group for reacting with any functional group of the cyanine-based compound represented by Formulas 1 to 6 or a reactive group bonded to the cyanine-based compound represented by Formulas 1 to 6, and includes amino, sulfhydryl ( It may contain at least one selected from sulphydryl), carbonyl, hydroxyl, carboxyl, phosphate, and thiophosphate, or may have a derivative form thereof.
또한, 생체분자는 아미노, 설프하이드릴(sulphydryl), 카보닐, 하이드록실, 카복실, 포스페이트 및 티오포스페이트로부터 선택되는 적어도 하나를 포함하거나 이의 유도체 형태를 가지는 옥시 또는 디옥시 폴리핵산일 수 있다.Additionally, the biomolecule may be an oxy- or deoxy-polynucleic acid containing at least one selected from amino, sulfhydryl, carbonyl, hydroxyl, carboxyl, phosphate, and thiophosphate, or having a derivative form thereof.
아울러, 생체분자 이외에 화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물은 아미노, 설프하이드릴(sulphydryl), 카보닐, 하이드록실, 카복실, 포스페이트 및 티오포스페이트로부터 선택되는 적어도 하나를 포함하는 약물, 호르몬(수용체 리간드 포함), 수용체, 효소 또는 효소 기질, 세포, 세포막, 독소, 미생물 또는 나노 바이오 소재(폴리스타이렌 마이크로스피어 등) 등을 표지하기 위해 사용될 수 있다.In addition, in addition to biomolecules, the cyanine-based compounds represented by Formulas 1 to 6 include drugs, hormones ( It can be used to label receptors (including receptor ligands), receptors, enzymes or enzyme substrates, cells, cell membranes, toxins, microorganisms, or nano-bio materials (polystyrene microspheres, etc.).
생체분자 표지용 염료, 키트 및 조영제 조성물Dyes, kits, and contrast agent compositions for labeling biomolecules
본 발명의 다른 측면에 따르면, 화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물로부터 선택되는 적어도 하나를 포함하는 생체분자 표지용 염료, 키트 및 조영제 조성물이 제공될 수 있다.According to another aspect of the present invention, a dye, kit, and contrast agent composition for labeling biomolecules containing at least one selected from cyanine-based compounds represented by Formulas 1 to 6 may be provided.
또한, 필요에 따라, 생체분자 표지용 키트는 타겟 생체분자와의 반응을 위한 효소, 용매(완충액 등) 및 기타 시약 등을 더 포함할 수 있다.Additionally, if necessary, the biomolecule labeling kit may further include enzymes, solvents (buffers, etc.), and other reagents for reaction with the target biomolecule.
여기서 용매로는 포스페이트 완충액, 카보네이트 완충액 및 트리스 완충액으로 구성된 군에서 선택되는 완충액, 다이메틸설폭사이드, 다이메틸포름아미드, 다이클로로메탄, 메탄올, 에탄올 및 아세토나이트릴로부터 선택되는 유기 용매 또는 물 등이 사용될 수 있으며, 용매의 종류에 따라 시아닌계 화합물에 다양한 작용기를 도입함으로써 용해도를 조절하는 것이 가능하다.Here, the solvent includes a buffer selected from the group consisting of phosphate buffer, carbonate buffer, and Tris buffer, an organic solvent selected from dimethyl sulfoxide, dimethylformamide, dichloromethane, methanol, ethanol, and acetonitrile, or water. It can be used, and its solubility can be adjusted by introducing various functional groups into the cyanine-based compound depending on the type of solvent.
또한, 상기 실시예에 따른 조영제 조성물은 경구 또는 비경구 방식으로 투여되기 위해 화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물 외에 약학적으로 허용하는 담체를 더 포함할 수 있다. In addition, the contrast medium composition according to the above example may further include a pharmaceutically acceptable carrier in addition to the cyanine-based compounds represented by Formulas 1 to 6 in order to be administered orally or parenterally.
약학적으로 허용되는 담체의 구체적인 예로는 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등이 있다.Specific examples of pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose. , water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
이하에서는 상술한 생체분자 표지용 염료 또는 생체분자 표지용 키트를 이용한 생체분자의 검출 방법에 대하여 설명하도록 한다.Hereinafter, a method for detecting biomolecules using the above-described biomolecule labeling dye or biomolecule labeling kit will be described.
생체분자 표지용 염료를 이용한 생체분자의 검출 방법Method for detecting biomolecules using dye for biomolecule labeling
화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물로 생체분자를 표지하는 방법으로는 표지된 고체 또는 반고체 상태의 생체분자의 형광을 측정하는 검출 방법이 가능한 모든 생체분자의 검출에 적용될 수 있다.The method of labeling biomolecules with cyanine-based compounds represented by Formulas 1 to 6 can be applied to the detection of all biomolecules for which a detection method of measuring the fluorescence of labeled biomolecules in a solid or semi-solid state is possible.
종래의 형광 염료 대신 시아닌계 화합물을 사용함으로써, 고감도로 화학적으로 안정적이고 조작성이 뛰어난 검출 방법을 제공할 수 있다.By using cyanine-based compounds instead of conventional fluorescent dyes, it is possible to provide a detection method that is highly sensitive, chemically stable, and highly operable.
본 발명의 다양한 실시예에 따르면, 타겟 생체분자에 시아닌계 화합물을 직접 반응시켜 생체분자를 표지하거나 타겟 생체분자와 시아닌계 화합물로 표지된 프로브를 반응시켜 표지하는 방법 등이 구현될 수 있다.According to various embodiments of the present invention, a method of labeling a biomolecule by reacting a target biomolecule directly with a cyanine-based compound or a method of labeling a target biomolecule by reacting a probe labeled with a cyanine-based compound can be implemented.
또한, 타겟 생체분자의 종류에 따라 시아닌계 화합물에 적절한 반응성기를 도입함으로써 타겟-특이적 상호작용을 이용한 생체분자의 검출 방법이 구현될 수도 있다.Additionally, a method for detecting biomolecules using target-specific interaction may be implemented by introducing an appropriate reactive group into a cyanine-based compound depending on the type of target biomolecule.
아울러, 시아닌계 화합물로 표지한 생체분자를 전기영동을 통해 동정하는 방법이 구현될 수도 있다.In addition, a method of identifying biomolecules labeled with a cyanine-based compound through electrophoresis may be implemented.
DNA 마이크로어레이법DNA microarray method
DNA 마이크로 어레이법은 검출해야 할 표적 핵산에 염료를 반응시켜 표지하는 한편, 표적 핵산에 대하여 상보적인 염기서열을 가지는 단일사슬의 프로브 핵산을 준비하고, 단일사슬으로 변성시킨 표적 핵산과 프로브 핵산을 기판 위에서 혼성화하여, 표적 핵산의 형광을 측정한다.The DNA microarray method labels the target nucleic acid to be detected by reacting it with a dye, prepares a single-chain probe nucleic acid with a base sequence complementary to the target nucleic acid, and uses the single-chain denatured target nucleic acid and probe nucleic acid as a substrate. By hybridization above, the fluorescence of the target nucleic acid is measured.
본 검출 방법에서 기판에 고정하는 프로브 핵산으로는, 유전자의 발현을 조사하는 경우, cDNA 등의 cDNA의 라이브러리, 게놈의 라이브러리 또는 모든 게놈을 주형(鑄型)으로 하여 PCR법에 의해 증폭하여 조제한 것을 사용할 수 있다.In this detection method, the probe nucleic acid immobilized on the substrate is one prepared by amplification by PCR using a library of cDNA such as cDNA, a library of genomes, or all genomes when examining gene expression. You can use it.
또한, 유전자의 변이 등을 조사하는 경우, 표준이 되는 이미 알려진 서열을 근거로 하여, 변이 등에 대응하는 여러가지 올리고뉴클레오티드를 합성한 것을 사용할 수 있다.In addition, when investigating genetic mutations, etc., various oligonucleotides corresponding to mutations, etc., can be synthesized based on already known sequences that serve as standards.
프로브 핵산을 기판 위에 고정하는 것은, 핵산의 종류나 기판의 종류에 따라 적당한 방법을 선택할 수 있다. 예를 들어, DNA의 전하를 이용하여, 폴리리신 등의 양이온으로 표면처리한 기판에 정전결합시키는 방법을 이용할 수도 있다.For immobilizing the probe nucleic acid on the substrate, an appropriate method can be selected depending on the type of nucleic acid or the type of substrate. For example, a method of using the charge of DNA to electrostatically bind to a substrate whose surface has been treated with cations such as polylysine can be used.
한편, 단일사슬으로 변성시킨 표적 핵산과 표지용 염료를 혼합하여 반응시킴으로써, 표지용 염료에 의해 표지된 표적 핵산을 조제한다. 반응온도는 실온~60℃, 반응시간은 2~48시간으로 하는 것이 바람직하다.Meanwhile, a target nucleic acid labeled with a labeling dye is prepared by mixing and reacting a target nucleic acid modified into a single chain with a labeling dye. The reaction temperature is preferably from room temperature to 60°C, and the reaction time is preferably 2 to 48 hours.
이어서, 표지된 표적 핵산을 기판 위에 점적하고, 혼성화한다.Then, the labeled target nucleic acid is spotted onto the substrate and hybridized.
혼성화는 실온~70℃, 그리고 2~48시간의 범위에서 하는 것이 바람직하다. 혼성화에 의해 프로브 핵산과 상보적인 염기서열을 가지는 표적 핵산이 선택적으로 프로브 핵산과 결합한다. 그 후, 기판을 세정하고 실온에서 건조한다.Hybridization is preferably performed at room temperature to 70°C and for 2 to 48 hours. Through hybridization, a target nucleic acid having a base sequence complementary to the probe nucleic acid selectively binds to the probe nucleic acid. Afterwards, the substrate is washed and dried at room temperature.
이어서, 건조한 기판 표면의 형광강도를 형광 레이저 스캐너법에 의해 측정한다. 형광강도에 의해 유전자 발현의 레벨을 모니터링할 수 있다.Next, the fluorescence intensity of the dried substrate surface is measured using a fluorescence laser scanner method. The level of gene expression can be monitored by fluorescence intensity.
한편, 상기 혼성화는 프로브 핵산을 기판에 고정하는 방법에 대해서 설명하였지만, 미리 염료로 표지한 표적 핵산을 기판에 고정하고, 프로브 핵산을 기판 위에 점적하는 방법을 이용할 수도 있다.Meanwhile, although the hybridization described above involves fixing a probe nucleic acid to a substrate, a method of fixing a target nucleic acid previously labeled with a dye to the substrate and spotting the probe nucleic acid on the substrate can also be used.
PCR 법PCR method
PCR법은, 검출해야 할 표적 핵산의 염기서열에 상보적인 프로브를 염료로 표지하고, 표적 핵산의 증폭에 앞서 혹은 증폭시킨 후에 표적 핵산과 프로브를 반응시켜, 표적 핵산의 형광을 측정한다.In the PCR method, a probe complementary to the base sequence of the target nucleic acid to be detected is labeled with a dye, the target nucleic acid and the probe are reacted before or after amplification of the target nucleic acid, and the fluorescence of the target nucleic acid is measured.
구체적으로는 표적 핵산의 신장반응은 효소(DNA 중합효소polymerase, RNA 중합효소)에 의해 이루어지며, 이 때 표적 핵산과 올리고뉴클레오티드로 이루어지는 프라이머가 형성한 이중사슬 핵산서열을 효소가 인식하여, 이 인식한 위치로부터 신장반응이 이루어지고, 목적으로 하는 유전자 영역만을 증폭시킨다. Specifically, the elongation reaction of the target nucleic acid is carried out by an enzyme (DNA polymerase, RNA polymerase), and at this time, the enzyme recognizes the double-stranded nucleic acid sequence formed by a primer made of the target nucleic acid and an oligonucleotide. An elongation reaction occurs from one location, and only the target gene region is amplified.
효소가 합성을 할 때, 뉴클레오티드(dNTP, NTP)를 원료로 하여 합성반응이 이루어진다.When an enzyme performs synthesis, the synthesis reaction takes place using nucleotides (dNTP, NTP) as raw materials.
이 때 통상의 뉴클레오티드(dNTP, NTP)에 염료를 가지는 뉴클레오티드를 임의의 비율로 혼합하면, 그 비율의 염료가 도입된 핵산을 합성할 수 있다. At this time, by mixing regular nucleotides (dNTP, NTP) with nucleotides containing a dye in an arbitrary ratio, a nucleic acid into which the dye is introduced in that ratio can be synthesized.
또한, PCR에 의해 임의의 비율로 아미노기를 가지는 뉴클레오티드를 도입한 후에 표지용 염료를 결합하여, 표지용 염료가 도입된 핵산을 합성할 수도 있다.In addition, a nucleic acid into which a labeling dye has been introduced can be synthesized by introducing nucleotides having an amino group in an arbitrary ratio by PCR and then combining them with a labeling dye.
효소가 합성을 할 때 뉴클레오티드를 원료로 합성반응이 이루어지는데, 이 때의 뉴클레오티드의 3'의 OH를 H로 바꾼 것을 사용한 경우, 더 이상 핵산의 신장반응이 이루어지지 않고, 그 시점에서 반응이 종료한다.When an enzyme synthesizes, a synthesis reaction is carried out using nucleotides as a raw material. In this case, if the 3' OH of the nucleotide is changed to H, the nucleic acid elongation reaction no longer occurs, and the reaction ends at that point. do.
이 뉴클레오티드, ddNTP (dideoxy nucleotide triphospate)는 터미네이터라고 불린다.This nucleotide, ddNTP (dideoxy nucleotide triphospate), is called a terminator.
통상의 뉴클레오티드에 터미네이터를 섞어 핵산을 합성하면, 일정한 확율로 터미네이터가 도입되어 반응이 종료하기 때문에, 여러가지 길이의 핵산이 합성된다. When nucleic acids are synthesized by mixing regular nucleotides with terminators, the terminator is introduced with a certain probability to complete the reaction, so nucleic acids of various lengths are synthesized.
이것을 겔 전기영동에 의해 크기 분리하면, 길이의 순번마다 DNA가 늘어서게 된다. 여기서, 터미네이터의 각 염기의 종류마다 다른 표지용 염료로 표지해두면, 합성반응의 종점(3' 말단)에는 각 염기에 의존한 경향이 관찰되어, 터미네이터에 표지한 표지용 염료를 기점으로 형광정보를 읽어냄으로써, 그 표적 핵산의 염기서열 정보를 얻을 수 있다.When this is size separated by gel electrophoresis, DNA is lined up in each order of length. Here, when each type of base of the terminator is labeled with a different labeling dye, a trend depending on each base is observed at the end point (3' end) of the synthesis reaction, and the fluorescence information is generated starting from the labeling dye labeled on the terminator. By reading, base sequence information of the target nucleic acid can be obtained.
또한, 터미네이터 대신에 미리 표지용 염료로 표지한 프라이머를 사용하여 표적 핵산과 혼성화할 수도 있다.Additionally, instead of a terminator, primers previously labeled with a labeling dye can be used to hybridize with the target nucleic acid.
또한, 프로브로서 PNA (펩티드 핵산)를 사용할 수도 있다. PNA는 핵산의 기본 골격 구조인 오탄당·인산골격을, 글리신을 단위로 하는 폴리아미드 골격으로 치환한 것으로, 핵산과 많이 닮은 3차원 구조를 가지고, 상보적인 염기서열을 가지는 핵산에 대하여 매우 특이적이며 강력하게 결합한다. 이를 통해, ISH (in-situ hybridization)법 등 기존의 DNA 해석방법 뿐만 아니라, 텔로미어(telomere, 말단소립) PNA 프로브에 응용함으로써, 텔로미어 연구의 시약으로서 사용할 수도 있다.Additionally, PNA (peptide nucleic acid) can also be used as a probe. PNA replaces the pentose-phosphate skeleton, which is the basic skeleton structure of nucleic acids, with a polyamide skeleton containing glycine as a unit. It has a three-dimensional structure very similar to nucleic acids and is very specific for nucleic acids with complementary base sequences. Combines strongly. Through this, it can be used as a reagent for telomere research by applying it to telomere (telomere) PNA probes as well as existing DNA analysis methods such as ISH (in-situ hybridization).
검출에는 예를 들어, 이중사슬 DNA를, DNA의 염기서열의 전부 또는 일부에 상보적인 염기서열을 가지며 표지용 염료로 표지된 PNA와 접촉시켜 혼성화하고, 그 혼합물을 가열하여 단일사슬 DNA를 생성하며, 혼합물을 천천히 실온까지 냉각하여 PNA-DNA 복합체를 조제하고, 그 형광을 측정함으로써 진행할 수 있다.For detection, for example, double-stranded DNA is contacted with PNA, which has a base sequence complementary to all or part of the DNA base sequence and is labeled with a labeling dye, and is hybridized, and the mixture is heated to produce single-stranded DNA. , the mixture can be slowly cooled to room temperature to prepare a PNA-DNA complex and its fluorescence can be measured.
상기 예에서는 표적 핵산을 PCR법에 의해 증폭시켜 생성물의 형광을 측정하는 방법에 대하여 설명하였지만, 이 방법에서는 전기영동으로 생성물의 크기를 확인하고, 그 후 형광강도를 측정함으로써 증폭생성물의 양을 조사할 필요가 있다.In the above example, a method of amplifying the target nucleic acid by PCR method and measuring the fluorescence of the product was explained. However, in this method, the size of the product is confirmed by electrophoresis, and the amount of the amplification product is then investigated by measuring the fluorescence intensity. Needs to be.
이를 위해, 형광염료의 에너지 트랜스퍼를 이용하고, PCR법의 생성물에 혼성화시킴으로써 형광이 발생하도록 고안된 프로브를 사용하여, 실시간으로 생성물의 양을 측정할 수도 있다. For this purpose, the amount of the product can be measured in real time using a probe designed to generate fluorescence by using the energy transfer of a fluorescent dye and hybridizing to the product of the PCR method.
예를 들어, 도너와 억셉터를 표지한 DNA를 사용할 수 있다. 구체적인 검출 방법으로는 특정 서열의 핵산의 존재를 확인하는 분자비콘법이나 TaqMan-PCR법이나 사이클링 프로브(cycling probe)법 등을 들 수 있다.For example, DNA labeled with a donor and an acceptor can be used. Specific detection methods include the molecular beacon method, TaqMan-PCR method, or cycling probe method, which confirms the presence of nucleic acids of a specific sequence.
또한, 단백질을 검출대상으로 하는 경우, 전기영동 후의 단백질의 검출에는 염색염료가 사용되고 있다.Additionally, when a protein is the object of detection, a dye is used to detect the protein after electrophoresis.
통상, 전기영동 후의 겔 안에 염색염료 예를 들어, CBB(Coomassie Brilliant Blue)를 침투시켜 단백질을 염색하고, UV를 조사하여 발광시키는 방법이 사용된다. Typically, a method is used to dye the protein by infiltrating a dye, such as CBB (Coomassie Brilliant Blue), into the gel after electrophoresis, and then emitting light by irradiating UV.
다만, 종래의 염색 염료를 사용하는 방법은 간단하지만, 감도가 100ng 정도로 낮아, 미량의 단백질 검출에는 적합하지 않다. 또한, 겔을 통하여 염색염료를 침투시키기 때문에, 염색에 많은 시간을 요한다는 문제도 있다.However, although the method using conventional dyes is simple, the sensitivity is low to about 100ng, so it is not suitable for detecting trace amounts of protein. Additionally, because the dye penetrates through the gel, there is a problem that it takes a lot of time to dye.
이에 대하여, 본 발명에서는 단백질을 전기영동에 의해 크기 분리한 후, 분리한 단백질에 표지용 염료를 결합시킴으로써 단백질을 표지한다.In contrast, in the present invention, proteins are size-separated by electrophoresis, and then the proteins are labeled by binding a labeling dye to the separated proteins.
본 발명의 표지용 염료는 반응성기를 가지고 있으며, 단백질과 빠르게 정량적으로 반응하고, 더욱이 고감도이어서, 미량의 단백질 검출에 적합하다. 더욱이, 크기 분리한 단백질을 질량 분석하여 동정(同定)할 수도 있다.The labeling dye of the present invention has a reactive group, reacts quickly and quantitatively with proteins, and is highly sensitive, making it suitable for detecting trace amounts of proteins. Moreover, size-separated proteins can also be identified by mass spectrometry.
여기서, 단백질에는 알부민, 글로불린, 글루테린, 히스톤, 프로타민, 그리고 콜라겐 등의 단순 단백질, 핵단백질, 당단백질, 리보단백질, 인단백질, 금속단백질 등의 복합 단백질 중 어느 것이든 검출대상으로 할 수 있다.Here, the protein can be any of simple proteins such as albumin, globulin, gluterin, histone, protamine, and collagen, and complex proteins such as nuclear protein, glycoprotein, riboprotein, phosphoprotein, and metalloprotein. .
예를 들어, 인단백질, 당단백질, 총단백질의 염색염료에 대응시켜 3종의 표지용 염료를 사용하고, 2차원 전기영동으로 분리한 단백질 시료에 있어서, 인단백질, 당단백질 및 총단백질을 염색할 수 있다.For example, three types of labeling dyes are used to correspond to the staining dyes for phosphoprotein, glycoprotein, and total protein, and in protein samples separated by two-dimensional electrophoresis, phosphoprotein, glycoprotein, and total protein are dyed. can do.
또한, TOF-Mass 등의 질량분석을 함으로써 단백질을 동정할 수 있기 때문에, 특수한 단백질을 생성시키는 암이나 바이러스에 의한 감염증 등의 질병의 진단이나 치료에 응용할 수 있다.In addition, since proteins can be identified through mass spectrometry such as TOF-Mass, it can be applied to the diagnosis or treatment of diseases such as cancer or viral infections that produce special proteins.
또한, 콜라겐은 동물의 결합조직을 구성하는 단백질이며, 독특한 섬유형상 구조를 가진다. 즉, 3중 폴리펩티드 사슬로 이루어지며, 그 펩티드 사슬이 모여 3중 사슬을 형성한다. 콜라겐은 일반적으로 매우 면역원성이 낮은 단백질로서, 식품, 화장품, 의약품 등의 분야에서 널리 사용되고 있다. Additionally, collagen is a protein that makes up the connective tissue of animals and has a unique fibrous structure. In other words, it consists of a triple polypeptide chain, and the peptide chains come together to form a triple chain. Collagen is generally a protein with very low immunogenicity and is widely used in fields such as food, cosmetics, and pharmaceuticals.
또한, 프로브에 압타머(aptamer)를 사용할 수도 있다. 압타머는 올리고 핵산으로 이루어지며, 염기서열에 의존하여 여러가지 특징있는 입체구조를 가질 수 있기 때문에, 그 입체구조를 통하여 단백질을 포함하는 모든 생체분자에 결합할 수 있다. 이 성질을 이용하여, 표지용 염료로 표지한 압타머를 특정 단백질에 결합시켜, 피검체와의 결합에 의한 단백질의 구조 변화에 따른 형광 변화로부터 간접적으로 피검체를 검출할 수 있다.Additionally, an aptamer may be used as a probe. Aptamers are made of oligonucleotides and can have various characteristic three-dimensional structures depending on their base sequence, so they can bind to all biomolecules, including proteins, through their three-dimensional structures. Using this property, an aptamer labeled with a labeling dye can be bound to a specific protein, and the subject can be indirectly detected from the fluorescence change caused by the structural change of the protein due to binding to the subject.
기타 검출 방법Other detection methods
또한, 본 발명의 표지용 염료를 특이결합을 사용한 생체분자의 검출 방법에도 사용할 수 있다.Additionally, the labeling dye of the present invention can also be used in a method for detecting biomolecules using specific binding.
즉, 생체분자로 이루어지는 피검체 또는 수식물질에 의해 수식된 이 피검체의 검출에 있어, 피검체에 특이적으로 결합하는 결합 물질 또는 수식 물질에 특이적으로 결합하는 결합물질 중 하나를, 표지용 염료로 표지하고, 표지된 결합물질로부터의 형광을 측정할 수 있다.That is, in the detection of a subject made of biomolecules or a subject modified by a modifying substance, either a binding substance that specifically binds to the subject or a binding substance that specifically binds to the modifying substance is used for labeling. It can be labeled with a dye and the fluorescence from the labeled binding substance can be measured.
여기서, 상기 피검체 또는 수식물질과 상기 결합물질의 조합에는, 항원-항체, 합텐-항합텐 항체, 비오틴-아비딘, Tag-항 Tag항체, 렉틴-당단백질 또는 호르몬-수용체를 사용할 수 있다.Here, in the combination of the subject or modification substance and the binding substance, an antigen-antibody, hapten-antihapten antibody, biotin-avidin, Tag-anti-Tag antibody, lectin-glycoprotein, or hormone-receptor can be used.
구체적으로는 기판, 용액, 비즈 또는 항체에 존재하는 항원에 대하여 표지용 염료로 표지한 항체 등의 결합 물질을 반응시켜, 항체의 항원 특이적 상호작용을 통해 특정 항원을 검출할 수 있다.Specifically, a specific antigen can be detected through antigen-specific interaction of the antibody by reacting a binding substance such as an antibody labeled with a labeling dye with an antigen present in a substrate, solution, beads, or antibody.
항원으로는 단백질, 다당류, 핵산, 펩티드 등이 가능하며, 항원 이외에 FITC나 디니트로페닐기 등의 저분자량 분자과 같은 합텐도 사용 가능하다. 이 때, 항원(또는 합텐)과 항체의 조합으로는 GFP와 항 GFP항체, FITC와 항FITC 항체 등이 있다.Antigens can include proteins, polysaccharides, nucleic acids, and peptides. In addition to antigens, haptens such as low molecular weight molecules such as FITC or dinitrophenyl group can also be used. At this time, combinations of antigens (or haptens) and antibodies include GFP and anti-GFP antibodies, FITC and anti-FITC antibodies, etc.
표지된 항원들은 면역염색, ELISA, 웨스턴 블롯팅(Western blotting), 플로우 사이토미트리(Flow cytometry) 등의 각종 측정방법에 사용할 수 있다.Labeled antigens can be used in various measurement methods such as immunostaining, ELISA, Western blotting, and flow cytometry.
또한, 본 발명의 표지용 염료를 이용하여, 세포 내 신호 전달(signaling) 현상을 관찰할 수도 있다. 내부 신호 전달 또는 이에 따른 세포의 반응에는 다양한 효소 등이 관여하고 있다. 대표적인 신호 전달 현상에서는 특수한 단백질 인산화효소(protein kinase)가 활성화되며, 이에 따라 단백질의 인산화가 유도되어 신호 전달의 개시되는 것으로 알려져 있다.Additionally, intracellular signaling phenomenon can also be observed using the labeling dye of the present invention. Various enzymes are involved in internal signal transduction or the resulting cellular response. It is known that in a typical signal transduction phenomenon, a special protein kinase is activated, which induces protein phosphorylation and initiates signal transduction.
뉴클레오티드(예를 들어, ATP 또는 ADP)의 결합과 가수분해는 이들의 활성에 중대한 역할을 하고 있으며, 뉴클레오티드 유도체에 표지용 염료를 도입함으로써, 세포 내 신호 전달 현상을 고감도로 관찰할 수 있다.Binding and hydrolysis of nucleotides (e.g., ATP or ADP) play a critical role in their activity, and by introducing a labeling dye into a nucleotide derivative, intracellular signal transduction phenomena can be observed with high sensitivity.
또한, 본 발명의 표지용 염료를 RNA 간섭작용(RNAi)을 이용한 유전자 발현 현상의 관찰에 이용할 수도 있다.Additionally, the labeling dye of the present invention can be used to observe gene expression phenomenon using RNA interference (RNAi).
RNAi는 이중사슬 RNA(dsRNA)를 세포에 도입함으로써, 표적 유전자의 mRNA를 분해하여 발현을 억제하는 것으로서, 설계된 dsRNA를 표지용 염료로 표지함으로써 RNAi 현상을 관찰하는 것이 가능하다.RNAi decomposes the mRNA of a target gene and suppresses its expression by introducing double-stranded RNA (dsRNA) into cells. It is possible to observe the RNAi phenomenon by labeling the designed dsRNA with a labeling dye.
또한, 본 발명의 표지용 염료는 조직 또는 세포 내의 표적 핵산 또는 표적 단백질을 표지할 수 있는 반응성기를 포함함으로써 표적 핵산의 전사 수준 또는 표적 단백질의 발현 수준을 확인하기 위한 염료로서 사용될 수 있다.In addition, the labeling dye of the present invention contains a reactive group capable of labeling a target nucleic acid or target protein in a tissue or cell, and thus can be used as a dye to confirm the transcription level of the target nucleic acid or the expression level of the target protein.
제조예Manufacturing example
제조예 1: 화합물 1의 제조Preparation Example 1: Preparation of Compound 1
중간체 1-1 (한국공개특허공보 제10-2012-0020818호, Journal of the American Chemical Society, 1998, vol. 120, # 26, p. 6621 - 6622 및 유럽공개특허공보 제2006289호 참조) 2.0g과 1,3-프로판설톤 2.2g 및 설폴란 20mL를 반응기에 투입하고 140℃에서 36시간 동안 교반시켰다. 반응액을 상온으로 냉각한 다음, 아이소프로필알콜을 투입하고, 여과하여 중간체 1-2 2.3g을 얻었다.Intermediate 1-1 (see Korean Patent Publication No. 10-2012-0020818, Journal of the American Chemical Society, 1998, vol. 120, # 26, p. 6621 - 6622 and European Patent Publication No. 2006289) 2.0 g 2.2 g of 1,3-propane sultone and 20 mL of sulfolane were added to the reactor and stirred at 140°C for 36 hours. The reaction solution was cooled to room temperature, then isopropyl alcohol was added and filtered to obtain 2.3 g of Intermediate 1-2.
중간체 1-2 2.3g과 다이페닐포름아미딘 3.4g 및 아세트산 69mL를 반응기에 투입하고 18시간 동안 환류 교반시켰다. 반응액을 상온으로 냉각한 후, EA를 투입하고 여과하여 중간체 1-3 2.5g을 얻었다.2.3 g of Intermediate 1-2, 3.4 g of diphenylformamidine, and 69 mL of acetic acid were added to the reactor and stirred under reflux for 18 hours. After cooling the reaction solution to room temperature, EA was added and filtered to obtain 2.5 g of Intermediate 1-3.
중간체 1-3 0.3g과 중간체 1-4 (Tetrahedron letters,48(33),5825;2007) 0.2g, 트리에틸아민 0.2g, 아세트산무수물 0.2g, N,N-다이메틸포름아마이드 9mL를 반응기에 투입하고, 상온에서 4시간 동안 교반시켰다. 이어서, 반응액에 에틸아세테이트를 투입하고 여과한 다음 ODS컬럼크로마토그래피로 분리하여 화합물 1 30mg을 얻었다(MS (ESI): m/z 953.2).0.3g of intermediate 1-3, 0.2g of intermediate 1-4 (Tetrahedron letters, 48(33), 5825;2007), 0.2g of triethylamine, 0.2g of acetic anhydride, and 9mL of N,N-dimethylformamide were added to the reactor. Added and stirred at room temperature for 4 hours. Next, ethyl acetate was added to the reaction solution, filtered, and separated by ODS column chromatography to obtain 30 mg of Compound 1 (MS (ESI): m/z 953.2).
제조예 2: 화합물 2의 제조Preparation Example 2: Preparation of Compound 2
제조예 1과 동일한 방법으로 중간체 1-3과 중간체 1-5 (Bioorganic and medicinal chemistry letters,22(2),1242;2012)를 반응시켜 화합물 2를 제조하였다(MS (ESI): m/z 874.2).Compound 2 was prepared by reacting Intermediate 1-3 with Intermediate 1-5 (Bioorganic and medicinal chemistry letters, 22(2), 1242;2012) in the same manner as Preparation Example 1 (MS (ESI): m/z 874.2 ).
제조예 3: 화합물 3의 제조Preparation Example 3: Preparation of Compound 3
제조예 1과 동일한 방법으로 중간체 1-6과 중간체 1-7를 반응시켜 화합물 3를 제조하였다(MS (ESI): m/z 605.3).Compound 3 was prepared by reacting Intermediate 1-6 with Intermediate 1-7 in the same manner as Preparation Example 1 (MS (ESI): m/z 605.3).
실험예Experiment example
상기 제조예 1 내지 3에서 얻어진 각각의 화합물에 대하여, 흡수 스펙트럼, 발광 스펙트럼, 몰 흡광계수 및 양자 효율을 측정하여 하기 표 1에 나타내었다.For each compound obtained in Preparation Examples 1 to 3, the absorption spectrum, emission spectrum, molar extinction coefficient, and quantum efficiency were measured and shown in Table 1 below.
상기 표 1에 기재된 바와 같이, 제조예 1 내지 제조예 3에 따라 합성된 화합물 1, 화합물 2 및 화합물 3의 경우, 플루오란텐이 결합된 헤테로 고리를 대칭 또는 비대칭적으로 포함하고 있다.As shown in Table 1, Compound 1, Compound 2, and Compound 3 synthesized according to Preparation Examples 1 to 3 contain heterocycles to which fluoranthene is bonded symmetrically or asymmetrically.
이 때, 화합물 1, 화합물 2 및 화합물 3에 있어서 발색단(색원체)에 해당하는 폴리메틴의 길이는 시판되는 Cy3 염료에서의 폴리메틴의 길이와 동일함에도 불구하고, 여기 및 발광이 일어나는 파장대는 시판되는 Cy5 염료와 유사한 것으로 확인할 수 있다.At this time, although the length of polymethine corresponding to the chromophore (chromogen) in Compound 1, Compound 2, and Compound 3 is the same as the length of polymethine in the commercially available Cy3 dye, the wavelength in which excitation and emission occurs is that of the commercially available Cy3 dye. It can be confirmed that it is similar to the Cy5 dye.
즉, 본 발명의 다양한 실시예에 따르면, 플루오란텐이 결합된 헤테로 고리를 도입함에 따라 단순한 인돌 구조를 가지는 시아닌계 화합물에 비해 상대적으로 장파장대에서 여기 및 발광이 가능하기 때문에 장파장대에서의 여기 및 발광을 위해 폴리메틴의 길이를 늘림으로써 구조적 불안정성을 야기할 필요가 없다.That is, according to various embodiments of the present invention, by introducing a heterocycle to which fluoranthene is bonded, excitation and emission in a relatively long wavelength range are possible compared to cyanine-based compounds with a simple indole structure, so excitation in a long wavelength range is possible. and there is no need to cause structural instability by increasing the length of polymethine for luminescence.
상기 실시예에서는 화합물 1, 화합물 2 및 화합물 3의 경우에 한하여 여기 및 발광이 일어나는 파장대를 확인하였으나, 화학식 1 내지 화학식 6으로 표시되는 시아닌계 화합물 역시 플루오란텐이 결합된 헤테로 고리 구조가 도입됨에 따라 폴리메틴의 길이로부터 예상되는 여기 및 발광 파장대보다 장파장대에서의 형광 특성을 나타낼 것으로 충분히 예상 가능하다.In the above example, the wavelength range in which excitation and emission occurs only in the case of Compound 1, Compound 2, and Compound 3 was confirmed, but the cyanine-based compounds represented by Formulas 1 to 6 also have a heterocyclic structure in which fluoranthene is bonded. Accordingly, it can be fully expected to exhibit fluorescence characteristics in a longer wavelength range than the excitation and emission wavelength ranges expected from the length of polymethine.
이상, 본 발명의 일 실시예에 대하여 설명하였으나, 해당 기술 분야에서 통상의 지식을 가진 자라면 특허청구범위에 기재된 본 발명의 사상으로부터 벗어나지 않는 범위 내에서, 구성 요소의 부가, 변경, 삭제 또는 추가 등에 의해 본 발명을 다양하게 수정 및 변경시킬 수 있을 것이며, 이 또한 본 발명의 권리범위 내에 포함된다고 할 것이다.Above, an embodiment of the present invention has been described, but those skilled in the art can add, change, delete or add components without departing from the spirit of the present invention as set forth in the patent claims. The present invention may be modified and changed in various ways, and this will also be included within the scope of rights of the present invention.
Claims (8)
[화학식 1]
여기서,
Ar1 및 Ar2는 각각 독립적으로 치환 또는 비치환된 페닐, 치환 또는 비치환된 나프틸, 치환 또는 비치환된 플루오렌, 치환 또는 비치환된 플루오란텐, 치환 또는 비치환된 카바졸, 치환 또는 비치환된 디벤조퓨란, 치환 또는 비치환된 디벤조싸이오펜이며, 상기 Ar1 및 Ar2 중 적어도 하나는 치환 또는 비치환된 플루오란텐(fluoranthene)이며,
Ar1 또는 Ar2가 치환된 경우, 상기 작용기 내 임의의 탄소는 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알콕시, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴옥시, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 적어도 하나의 치환기로 치환 또는 비치환된 아미노, 적어도 하나의 치환기로 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴, 적어도 하나의 치환기로 치환 또는 비치환된 C5-C23 헤테로아릴, 적어도 하나의 치환기로 치환 또는 비치환된 아르알킬, 4차 암모늄, 인산, 인산염, 케톤(-COR6), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환되며,
Y1 및 Y2는 각각 독립적으로 황, 산소 및 CR4R5로부터 선택되며,
R1 및 R2는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 및 -L-X 작용기로부터 선택되며,
R3은 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 치환 또는 비치환된 아미노, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬 또는 -L-X 작용기이며,
R4 및 R5는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬 및 -L-X 작용기로부터 선택되며,
-L-X 작용기에 있어서, L은 탄소, 질소, 산소 및 황으로부터 선택되는 1-20개의 원자, -NHCOO-, -CONH-, -CH2NH-, -CH2NR6-, -COO-, -SO2NH-, -HN-C(=NH)-NH-, -NR6-, -(CH2-CH2-O-)p-, -CH=CH-, -C≡C-, -Ar- 및 -CO-Ar-NR6-으로부터 선택되는 링커이며, R6은 수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C6알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C6알콕시 및 적어도 하나의 치환기로 치환 또는 비치환된 C1-C6할로알킬로부터 선택되며, Ar은 아릴이며, p는 1 내지 100 의 정수이며, X는 카복실(carboxyl), 숙신이미딜 에스터(succinimidyl ester), 설포-숙신이미딜 에스터(sulfo-succinimidyl ester), 이소티오시아네이트(isothiocyanate), 말레이미드(maleimide), 할로아세트아마이드(haloacetamide), 하이드라자이드(hydrazide), 바이닐설폰(vinylsulphone), 다이클로로트리아진(dichlorotriazine), 포스포라미다이트(phosphoramidite), 알킬 할라이드(alkyl halide), 아실 할라이드(acyl halide), 카보하이드라자이드(carbohydrazide), 하이드록실아민(hydroxylamine), 케톤(ketone), 알카인(alkyne), 아자이드(azide), 지방족 및 방향족 아민(amine), 설포테트라플루오로페닐 에스터(sulfotetrafluorophenyl ester), 설포다이클로로페닐 에스터(sulfodichlorophenyl ester), 카보닐 아자이드(carbonyl azide), 설포닐 클로라이드(sulfonyl chloride), 설포닐 플루오라이드(sulfonyl fluoride), 보론산(boronic acid), 이소시아네이트(isocyanate), 할로겐-치환 트리아진(halogen-substituted triazine), 할로겐-치환 피리딘(halogen-substituted pyridine), 할로겐-치환 다이아진(halogen-substituted diazine), 테트라플루오로페닐 에스터(tetrafluorophenyl ester), 이미도 에스터(imido ester), 아지도나이트로페닐(azidonitrophenyl), 글리옥살(glyoxal) 및 알데하이드로부터 선택되는 반응성기이며,
n은 0 또는 1 내지 5의 정수이며,
상기 아릴은 단일 고리이거나, 서로 접합 또는 공유 결합으로 연결된 2 내지 4개의 고리를 포함하는 불포화 방향족성 고리이며,
상기 헤테로아릴은 상기 아릴 내 하나 이상의 탄소 원자가 헤테로 원자로 치환된 불포화 방향족성 고리이며,
상기 헤테로 원자는 질소(N), 산소(O) 및 황(S)을 포함하는 비-탄소 원자로부터 선택되며,
상기 치환기는 설폰산, 설폰산염, 케톤, 알데하이드, 카복실산, 카복실산염, 인산, 인산염, 아실클로라이드, 하이드록시, 폴리알킬렌 옥사이드, 4차 암모늄염, C6-C24 아릴, 에스터 및 아마이드로부터 선택되며, 여기서, 폴리알킬렌 옥사이드는 메틸 에터로 종결되며, 에틸렌 글라이콜을 반복 단위로서 포함한다.
Cyanine-based compound represented by the following formula (1):
[Formula 1]
here,
Ar 1 and Ar 2 are each independently substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted fluorene, substituted or unsubstituted fluoranthene, substituted or unsubstituted carbazole, substituted or unsubstituted dibenzofuran, substituted or unsubstituted dibenzothiophene, and Ar 1 And at least one of Ar 2 is substituted or unsubstituted fluoranthene,
When Ar 1 or Ar 2 is substituted, any carbon in the functional group is deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, C 2 -C substituted or unsubstituted with at least one substituent. 10 alkenyl, C 2 -C 10 alkynyl, substituted or unsubstituted with at least one substituent, C 2 -C 10 alkoxy, substituted or unsubstituted with at least one substituent. 6 -C 24 Aryloxy, C 1 -C 10 haloalkyl, substituted or unsubstituted with at least one substituent, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, Substituted or unsubstituted amide, sulfhydryl, nitro, carboxyl, carboxylate, C 6 -C 24 aryl substituted or unsubstituted with at least one substituent, C 5 -C substituted or unsubstituted with at least one substituent 23 heteroaryl, aralkyl substituted or unsubstituted with at least one substituent, quaternary ammonium, phosphoric acid, phosphate, ketone (-COR 6 ), aldehyde, ester (-COOR 6 ), acyl chloride, sulfonic acid, sulfonic acid salt and - is substituted with at least one selected from the LX functional group,
Y 1 and Y 2 are each independently selected from sulfur, oxygen and CR 4 R 5 ;
R 1 and R 2 are each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl , substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, and -LX functional groups,
R 3 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted aralkyl or -LX functional group,
R 4 and R 5 are each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl , substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or is selected from unsubstituted aralkyl and -LX functional groups,
For the -LX functional group, L is 1-20 atoms selected from carbon, nitrogen, oxygen and sulfur, -NHCOO-, -CONH-, -CH 2 NH-, -CH 2 NR 6 -, -COO-, - SO 2 NH-, -HN-C(=NH)-NH-, -NR 6 -, -(CH 2 -CH 2 -O-)p-, -CH=CH-, -C≡C-, -Ar - and -CO-Ar-NR 6 -, wherein R 6 is hydrogen, C 1 -C 6 alkyl substituted or unsubstituted with at least one substituent, C 2 substituted or unsubstituted with at least one substituent. -C 10 alkenyl, C 2 -C 10 alkynyl substituted or unsubstituted with at least one substituent, C 2 -C 6 alkoxy substituted or unsubstituted with at least one substituent and substituted or unsubstituted with at least one substituent. is selected from C 1 -C 6 haloalkyl, Ar is aryl, p is an integer of 1 to 100, and X is carboxyl, succinimidyl ester, sulfo-succinimidyl ester (sulfo) -succinimidyl ester, isothiocyanate, maleimide, haloacetamide, hydrazide, vinylsulphone, dichlorotriazine, phosphoramidide Phosphoramidite, alkyl halide, acyl halide, carbohydrazide, hydroxylamine, ketone, alkyne, azide , aliphatic and aromatic amines, sulfotetrafluorophenyl ester, sulfodichlorophenyl ester, carbonyl azide, sulfonyl chloride, sulfonyl fluoride sulfonyl fluoride, boronic acid, isocyanate, halogen-substituted triazine, halogen-substituted pyridine, halogen-substituted diazine It is a reactive group selected from diazine, tetrafluorophenyl ester, imido ester, azidonitrophenyl, glyoxal, and aldehyde,
n is 0 or an integer from 1 to 5,
The aryl is a single ring or an unsaturated aromatic ring containing 2 to 4 rings connected to each other by conjugation or covalent bonds,
The heteroaryl is an unsaturated aromatic ring in which at least one carbon atom in the aryl is replaced with a hetero atom,
The heteroatoms are selected from non-carbon atoms including nitrogen (N), oxygen (O) and sulfur (S),
The substituent is selected from sulfonic acid, sulfonate, ketone, aldehyde, carboxylic acid, carboxylate, phosphoric acid, phosphate, acyl chloride, hydroxy, polyalkylene oxide, quaternary ammonium salt, C 6 -C 24 aryl, ester and amide; , where the polyalkylene oxide is terminated with methyl ether and contains ethylene glycol as a repeating unit.
[화학식 1]
여기서,
Ar1 및 Ar2는 각각 독립적으로 치환 또는 비치환된 페닐, 치환 또는 비치환된 나프틸, 치환 또는 비치환된 플루오렌, 치환 또는 비치환된 플루오란텐, 치환 또는 비치환된 카바졸, 치환 또는 비치환된 디벤조퓨란, 치환 또는 비치환된 디벤조싸이오펜이며, 상기 Ar1 및 Ar2 중 적어도 하나는 치환 또는 비치환된 플루오란텐(fluoranthene)이며,
Ar1 또는 Ar2가 치환된 경우, 상기 작용기 내 임의의 탄소는 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알콕시, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴옥시, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 적어도 하나의 치환기로 치환 또는 비치환된 아미노, 적어도 하나의 치환기로 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴, 적어도 하나의 치환기로 치환 또는 비치환된 C5-C23 헤테로아릴, 적어도 하나의 치환기로 치환 또는 비치환된 아르알킬, 4차 암모늄, 인산, 인산염, 케톤(-COR6), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환되며,
Y1 및 Y2는 각각 독립적으로 황, 산소 및 CR4R5로부터 선택되며,
R1 및 R2는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 및 -L-X 작용기로부터 선택되며,
R3은 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 치환 또는 비치환된 아미노, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬 또는 -L-X 작용기이며,
R4 및 R5는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 아릴옥시, 치환 또는 비치환된 C1-C10 할로알킬, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬 및 -L-X 작용기로부터 선택되며,
-L-X 작용기에 있어서, L은 탄소, 질소, 산소 및 황으로부터 선택되는 1-20개의 원자, -NHCOO-, -CONH-, -CH2NH-, -CH2NR6-, -COO-, -SO2NH-, -HN-C(=NH)-NH-, -NR6-, -(CH2-CH2-O-)p-, -CH=CH-, -C≡C-, -Ar- 및 -CO-Ar-NR6-으로부터 선택되는 링커이며, R6은 수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C6알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C6알콕시 및 적어도 하나의 치환기로 치환 또는 비치환된 C1-C6할로알킬로부터 선택되며, Ar은 아릴이며, p는 1 내지 100 의 정수이며, X는 카복실(carboxyl), 숙신이미딜 에스터(succinimidyl ester), 설포-숙신이미딜 에스터(sulfo-succinimidyl ester), 이소티오시아네이트(isothiocyanate), 말레이미드(maleimide), 할로아세트아마이드(haloacetamide), 하이드라자이드(hydrazide), 바이닐설폰(vinylsulphone), 다이클로로트리아진(dichlorotriazine), 포스포라미다이트(phosphoramidite), 알킬 할라이드(alkyl halide), 아실 할라이드(acyl halide), 카보하이드라자이드(carbohydrazide), 하이드록실아민(hydroxylamine), 케톤(ketone), 알카인(alkyne), 아자이드(azide), 지방족 및 방향족 아민(amine), 설포테트라플루오로페닐 에스터(sulfotetrafluorophenyl ester), 설포다이클로로페닐 에스터(sulfodichlorophenyl ester), 카보닐 아자이드(carbonyl azide), 설포닐 클로라이드(sulfonyl chloride), 설포닐 플루오라이드(sulfonyl fluoride), 보론산(boronic acid), 이소시아네이트(isocyanate), 할로겐-치환 트리아진(halogen-substituted triazine), 할로겐-치환 피리딘(halogen-substituted pyridine), 할로겐-치환 다이아진(halogen-substituted diazine), 테트라플루오로페닐 에스터(tetrafluorophenyl ester), 이미도 에스터(imido ester), 아지도나이트로페닐(azidonitrophenyl), 글리옥살(glyoxal) 및 알데하이드로부터 선택되는 반응성기이며,
n은 1 내지 5의 정수이며
인접한 두 R3는 서로 결합하여 적어도 하나의 헤테로 원자를 선택적으로 포함하는 4원자 내지 6원자 탄화수소 고리를 형성하며,
상기 아릴은 단일 고리이거나, 서로 접합 또는 공유 결합으로 연결된 2 내지 4개의 고리를 포함하는 불포화 방향족성 고리이며,
상기 헤테로아릴은 상기 아릴 내 하나 이상의 탄소 원자가 헤테로 원자로 치환된 불포화 방향족성 고리이며,
상기 헤테로 원자는 질소(N), 산소(O) 및 황(S)을 포함하는 비-탄소 원자로부터 선택되며,
상기 치환기는 설폰산, 설폰산염, 케톤, 알데하이드, 카복실산, 카복실산염, 인산, 인산염, 아실클로라이드, 하이드록시, 폴리알킬렌 옥사이드, 4차 암모늄염, C6-C24 아릴, 에스터 및 아마이드로부터 선택되며, 여기서, 폴리알킬렌 옥사이드는 메틸 에터로 종결되며, 에틸렌 글라이콜을 반복 단위로서 포함한다.
Cyanine-based compound represented by the following formula (1):
[Formula 1]
here,
Ar 1 and Ar 2 are each independently substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted fluorene, substituted or unsubstituted fluoranthene, substituted or unsubstituted carbazole, substituted or unsubstituted dibenzofuran, substituted or unsubstituted dibenzothiophene, and Ar 1 And at least one of Ar 2 is substituted or unsubstituted fluoranthene,
When Ar 1 or Ar 2 is substituted, any carbon in the functional group is deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, C 2 -C substituted or unsubstituted with at least one substituent. 10 alkenyl, C 2 -C 10 alkynyl, substituted or unsubstituted with at least one substituent, C 2 -C 10 alkoxy, substituted or unsubstituted with at least one substituent. 6 -C 24 Aryloxy, C 1 -C 10 haloalkyl, substituted or unsubstituted with at least one substituent, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, Substituted or unsubstituted amide, sulfhydryl, nitro, carboxyl, carboxylate, C 6 -C 24 aryl substituted or unsubstituted with at least one substituent, C 5 -C substituted or unsubstituted with at least one substituent 23 heteroaryl, aralkyl substituted or unsubstituted with at least one substituent, quaternary ammonium, phosphoric acid, phosphate, ketone (-COR 6 ), aldehyde, ester (-COOR 6 ), acyl chloride, sulfonic acid, sulfonic acid salt and - is substituted with at least one selected from the LX functional group,
Y 1 and Y 2 are each independently selected from sulfur, oxygen and CR 4 R 5 ;
R 1 and R 2 are each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl , substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, and -LX functional groups,
R 3 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted aralkyl or -LX functional group,
R 4 and R 5 are each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl , substituted or unsubstituted C 2 -C 10 alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted C 1 -C 10 haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or is selected from unsubstituted aralkyl and -LX functional groups,
For the -LX functional group, L is 1-20 atoms selected from carbon, nitrogen, oxygen and sulfur, -NHCOO-, -CONH-, -CH 2 NH-, -CH 2 NR 6 -, -COO-, - SO 2 NH-, -HN-C(=NH)-NH-, -NR 6 -, -(CH 2 -CH 2 -O-) p -, -CH=CH-, -C≡C-, -Ar - and -CO-Ar-NR 6 -, wherein R 6 is hydrogen, C 1 -C 6 alkyl substituted or unsubstituted with at least one substituent, C 2 substituted or unsubstituted with at least one substituent. -C 10 alkenyl, C 2 -C 10 alkynyl substituted or unsubstituted with at least one substituent, C 2 -C 6 alkoxy substituted or unsubstituted with at least one substituent and substituted or unsubstituted with at least one substituent. is selected from C 1 -C 6 haloalkyl, Ar is aryl, p is an integer of 1 to 100, and X is carboxyl, succinimidyl ester, sulfo-succinimidyl ester (sulfo) -succinimidyl ester, isothiocyanate, maleimide, haloacetamide, hydrazide, vinylsulphone, dichlorotriazine, phosphoramidide Phosphoramidite, alkyl halide, acyl halide, carbohydrazide, hydroxylamine, ketone, alkyne, azide , aliphatic and aromatic amines, sulfotetrafluorophenyl ester, sulfodichlorophenyl ester, carbonyl azide, sulfonyl chloride, sulfonyl fluoride sulfonyl fluoride, boronic acid, isocyanate, halogen-substituted triazine, halogen-substituted pyridine, halogen-substituted diazine It is a reactive group selected from diazine, tetrafluorophenyl ester, imido ester, azidonitrophenyl, glyoxal, and aldehyde,
n is an integer from 1 to 5
Two adjacent R 3 are bonded to each other to form a 4- to 6-membered hydrocarbon ring optionally containing at least one hetero atom,
The aryl is a single ring or an unsaturated aromatic ring containing 2 to 4 rings connected to each other by conjugation or covalent bonds,
The heteroaryl is an unsaturated aromatic ring in which at least one carbon atom in the aryl is replaced with a hetero atom,
The heteroatoms are selected from non-carbon atoms including nitrogen (N), oxygen (O) and sulfur (S),
The substituent is selected from sulfonic acid, sulfonate, ketone, aldehyde, carboxylic acid, carboxylate, phosphoric acid, phosphate, acyl chloride, hydroxy, polyalkylene oxide, quaternary ammonium salt, C 6 -C 24 aryl, ester and amide; , where the polyalkylene oxide is terminated with methyl ether and contains ethylene glycol as a repeating unit.
인접한 두 R3가 서로 결합하여 형성된 고리는 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알콕시, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴옥시, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 적어도 하나의 치환기로 치환 또는 비치환된 아미노, 적어도 하나의 치환기로 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴, 적어도 하나의 치환기로 치환 또는 비치환된 C5-C23 헤테로아릴, 적어도 하나의 치환기로 치환 또는 비치환된 아르알킬, 4차 암모늄, 인산, 인산염, 옥소(=O), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환되며,
상기 치환기는 설폰산, 설폰산염, 케톤, 알데하이드, 카복실산, 카복실산염, 인산, 인산염, 아실클로라이드, 하이드록시, 폴리알킬렌 옥사이드, 4차 암모늄염, C6-C24 아릴, 에스터 및 아마이드로부터 선택되며, 여기서, 폴리알킬렌 옥사이드는 메틸 에터로 종결되며, 에틸렌 글라이콜을 반복 단위로서 포함하는,
시아닌계 화합물.
According to paragraph 2,
The ring formed by combining two adjacent R 3s is deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, C 2 -C 10 alkenyl substituted or unsubstituted with at least one substituent, at least one C 2 -C 10 alkynyl substituted or unsubstituted with a substituent, C 2 -C 10 alkoxy substituted or unsubstituted with at least one substituent, C 6 -C 24 aryloxy substituted or unsubstituted with at least one substituent. , C 1 -C 10 haloalkyl substituted or unsubstituted with at least one substituent, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, amide substituted or unsubstituted with at least one substituent. , sulfhydryl, nitro, carboxyl, carboxylate, C 6 -C 24 aryl substituted or unsubstituted with at least one substituent, C 5 -C 23 heteroaryl substituted or unsubstituted with at least one substituent, at least one At least selected from aralkyl, quaternary ammonium, phosphoric acid, phosphate, oxo (=O), aldehyde, ester (-COOR 6 ), acyl chloride, sulfonic acid, sulfonic acid salt and -LX functional group substituted or unsubstituted with a substituent of is replaced with one,
The substituent is selected from sulfonic acid, sulfonate, ketone, aldehyde, carboxylic acid, carboxylate, phosphoric acid, phosphate, acyl chloride, hydroxy, polyalkylene oxide, quaternary ammonium salt, C 6 -C 24 aryl, ester and amide; , wherein the polyalkylene oxide is terminated with methyl ether and contains ethylene glycol as a repeating unit,
Cyanine-based compounds.
상기 시아닌계 화합물은 하기의 화학식으로 표시되는 화합물로부터 선택되는 적어도 하나인,
시아닌계 화합물:
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[화학식 6]
여기서,
R11 내지 R26은 수소, 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알콕시, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴옥시, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 할로알킬, 할로겐, 사이아노, 하이드록시, 적어도 하나의 치환기로 치환 또는 비치환된 아미노, 적어도 하나의 치환기로 치환 또는 비치환된 아마이드, 설프하이드릴, 나이트로, 카복실, 카복실산염, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴, 적어도 하나의 치환기로 치환 또는 비치환된 C5-C23 헤테로아릴, 적어도 하나의 치환기로 치환 또는 비치환된 아르알킬, 4차암모늄, 인산, 인산염, 케톤(-COR6), 알데하이드, 에스터(-COOR6), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되며,
상기 치환기는 설폰산, 설폰산염, 케톤, 알데하이드, 카복실산, 카복실산염, 인산, 인산염, 아실클로라이드, 하이드록시, 폴리알킬렌 옥사이드, 4차 암모늄염, C6-C24 아릴, 에스터 및 아마이드로부터 선택되며, 여기서, 폴리알킬렌 옥사이드는 메틸 에터로 종결되며, 에틸렌 글라이콜을 반복 단위로서 포함하며,
Y3은 황, 산소 또는 CR4R5이다.
According to claim 1 or 2,
The cyanine-based compound is at least one selected from compounds represented by the following formula,
Cyanine-based compounds:
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
[Formula 6]
here,
R 11 to R 26 are hydrogen, deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, C 2 -C 10 alkenyl substituted or unsubstituted with at least one substituent, Substituted or unsubstituted C 2 -C 10 alkynyl, C 2 -C 10 alkoxy substituted or unsubstituted with at least one substituent, C 6 -C 24 aryloxy substituted or unsubstituted with at least one substituent, at least one C 1 -C 10 haloalkyl substituted or unsubstituted with a substituent, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, amide substituted or unsubstituted with at least one substituent, sulfhy drill, nitro, carboxyl, carboxylate, C 6 -C 24 aryl substituted or unsubstituted with at least one substituent, C 5 -C 23 heteroaryl substituted or unsubstituted with at least one substituent, selected from substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphate, ketone (-COR 6 ), aldehyde, ester (-COOR 6 ), acyl chloride, sulfonic acid, sulfonic acid salt and -LX functional groups;
The substituent is selected from sulfonic acid, sulfonate, ketone, aldehyde, carboxylic acid, carboxylate, phosphoric acid, phosphate, acyl chloride, hydroxy, polyalkylene oxide, quaternary ammonium salt, C 6 -C 24 aryl, ester and amide; , wherein the polyalkylene oxide is terminated with methyl ether and contains ethylene glycol as a repeating unit,
Y 3 is sulfur, oxygen or CR 4 R 5 .
A dye for labeling biomolecules containing the cyanine-based compound according to claim 1 or 2.
상기 생체분자는 항체, 지질, 단백질, 펩타이드, 탄수화물 및 핵산으로부터 선택되는 적어도 하나인,
생체분자 표지용 염료.
According to clause 5,
The biomolecule is at least one selected from antibodies, lipids, proteins, peptides, carbohydrates, and nucleic acids,
Dye for labeling biomolecules.
생체분자 표지용 키트.
Containing a dye for biomolecule labeling according to paragraph 5,
Kit for biomolecule labeling.
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