KR20230038676A - 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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- KR20230038676A KR20230038676A KR1020230030426A KR20230030426A KR20230038676A KR 20230038676 A KR20230038676 A KR 20230038676A KR 1020230030426 A KR1020230030426 A KR 1020230030426A KR 20230030426 A KR20230030426 A KR 20230030426A KR 20230038676 A KR20230038676 A KR 20230038676A
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- Prior art keywords
- substituted
- substituent
- unsubstituted
- alkyl
- heteroalkyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 60
- 238000002372 labelling Methods 0.000 title claims description 60
- 239000000203 mixture Substances 0.000 title claims description 10
- 239000002872 contrast media Substances 0.000 title claims description 8
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title abstract description 45
- -1 cyano, hydroxy, amino Chemical group 0.000 claims description 88
- 125000000524 functional group Chemical group 0.000 claims description 46
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- 108020004707 nucleic acids Proteins 0.000 claims description 45
- 239000000975 dye Substances 0.000 claims description 44
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 102000004169 proteins and genes Human genes 0.000 claims description 34
- 108090000623 proteins and genes Proteins 0.000 claims description 33
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 30
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 229920000233 poly(alkylene oxides) Chemical group 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
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- 125000003545 alkoxy group Chemical group 0.000 claims description 11
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
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- 125000004104 aryloxy group Chemical group 0.000 claims description 8
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- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- IHDBZCJYSHDCKF-UHFFFAOYSA-N 4,6-dichlorotriazine Chemical compound ClC1=CC(Cl)=NN=N1 IHDBZCJYSHDCKF-UHFFFAOYSA-N 0.000 claims description 4
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- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 4
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- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims description 4
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- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 claims 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 6
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims 4
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- 150000001734 carboxylic acid salts Chemical class 0.000 claims 4
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims 4
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Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- 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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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract
Description
본 발명은 생체분자 표지용 염료에 관한 것으로, 보다 상세하게는 450nm 이상의 가시광선 및 근적외선 영역의 파장대에서 형광 신호를 나타내고 생체분자의 검출에 사용할 수 있는 신규한 시아닌계 화합물에 관한 것이다.The present invention relates to a dye for biomolecule labeling, and more particularly, to a novel cyanine-based compound that can be used for detecting biomolecules and exhibits a fluorescent signal in a wavelength range of 450 nm or higher in the visible and near-infrared regions.
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.In the bio field, fluorescent dyes are used as a means to visualize biological phenomena at the cell level in vivo or in vitro, or to examine biomarkers and diseased areas.
그린형광단백질(GFP) 등의 자체적으로 발광하는 생체분자도 존재하지만, 일반적으로는 생체 조직이나 세포 및 그 이하 단계의 생체분자를 형광 염료로 염색하거나, 단백질, 핵산 등의 생체분자에 형광 염료를 표지한 후, 형광 신호를 검출할 수 있는 광학장비를 동반하여, 다양한 기법으로 영상화한 자료를 얻고 있다. Although there are biomolecules that emit light on their own, such as green fluorescent protein (GFP), in general, biological tissues, cells and lower biomolecules are dyed with fluorescent dyes, or biomolecules such as proteins and nucleic acids are dyed with fluorescent dyes. After labeling, imaging data is obtained with various techniques accompanied by optical equipment capable of detecting 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.Optical analysis equipment mainly used is a fluorescence microscope for cell observation, a confocal microscope, a flow cytometry, a microarray, and a quantitative PCR system. ), nucleic acid and protein separation, electrophoresis device for analysis, real-time in vivo imaging system, etc. In addition to equipment for research purposes, immunoassay techniques (immnuno assay), PCR analysis and statistical technology are grafted In vitro diagnosis equipment based on nucleic acid and protein diagnostic kits (or biochips), operating tables for image-guided surgery, and endoscopic equipment for diagnosis and treatment are known, and new applications are continuously emerging. Equipment with higher resolution and data processing capabilities are 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, photobleaching (photo It is preferable that the bleaching and quenching phenomena are low, the molar extinction coefficient and quantum efficiency are high, and the material 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.Various fluorescent dyes have been used in various research fields, but fluorescent dyes that satisfy all of the above conditions are rare in the bio field, and typical structures currently used are coumarins, cyanine, and bodipy. , fluoresceins, rhodamines, pyrenes, carbopyronin, oxazine, xanthenes, thioxanthene and acridines, etc. there is Among them, rhodamine derivatives and polymethine-based cyanine derivatives are mainly used.
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 장점뿐만 아니라, 일반적으로 매우 높은 흡광계수를 가지는 광학적 특징이 있다.In particular, cyanine-based fluorescent dyes are linked to heterocycles containing nitrogen at both ends of polymethine, and by controlling the length of polymethine, it has the structural advantage of realizing various fluorescence over the entire visible and near-infrared range from 450 nm to 800 nm. In addition, there is an optical characteristic that generally has a very high extinction coefficient.
본 발명은 광학 영상 분야에서 생체분자의 동정을 관찰하기 위하여 광범위하게 사용될 수 있는 화합물로서 신규한 시아닌계 화합물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a novel cyanine-based compound as a compound that can be widely used for identification and observation of biomolecules in the field of optical imaging.
또한, 본 발명은 상기 신규한 시아닌계 화합물을 포함하는 생체분자 표지용 염료, 키트 및 조영제 조성물을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a dye for biomolecule labeling, a kit, and a contrast medium composition containing the novel cyanine-based compound.
상술한 기술적 과제를 해결하기 위한 본 발명의 일 측면에 따르면, 하기의 화학식 1로 표시되는 시아닌(cyanine)계 화합물이 제공될 수 있다.According to one aspect of the present invention for solving the above-described technical problem, a cyanine-based compound represented by Formula 1 below may be provided.
[화학식 1][Formula 1]
여기서,here,
Ar1 및 Ar2는 각각 독립적으로 치환 또는 비치환된 아릴 또는 치환 또는 비치환된 헤테로아릴이며, Y1 및 Y2는 각각 독립적으로 황, 산소, 셀레늄, NR3, CR3R4, SiR3R4 및 -CR3=CR4-으로부터 선택될 수 있다.Ar 1 and Ar 2 are each independently a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Y 1 and Y 2 are each independently sulfur, oxygen, selenium, NR 3 , CR 3 R 4 , SiR 3 R 4 and -CR 3 =CR 4 -.
R1은 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬, 폴리알킬렌 옥사이드 및 -L-X 작용기로부터 선택되며, R2 내지 R4는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 설프하이드릴, 나이트로, 카복실, 카복실산염, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 4차 암모늄, 인산, 인산염, 케톤(-COR5), 알데하이드, 에스터(-COOR5), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택될 수 있다.R 1 is selected from C 1 -C 10 alkyl substituted with sulfonic acid or sulfonate, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonate, polyalkylene oxide and -LX functional groups, and R 2 to R 4 is each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 heteroalkyl containing at least one heteroatom, 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, carbamate, sulfhydryl, nitro, carboxyl, carboxylate, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryls, substituted or unsubstituted aralkyls, quaternary ammoniums, phosphoric acids, phosphates, ketones (-COR 5 ), aldehydes, esters (-COOR 5 ), acylchlorides, sulfonic acids, sulfonates and -LX functional groups. can
R2, R3 또는 R4가 케톤기(-COR5) 또는 에스터기(-COOR5)일 때, R5는 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C2-C10 헤테로알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 C1-C10 할로알킬 및 치환 또는 비치환된 C1-C10 아미노알킬로부터 선택될 수 있다.When R 2 , R 3 or R 4 is a ketone group (-COR 5 ) or an ester group (-COOR 5 ), R 5 is a substituted or unsubstituted C 1 -C 10 alkyl containing at least one heteroatom. Substituted or unsubstituted C 2 -C 10 heteroalkyl, 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 C 1 -C 10 haloalkyl and substituted or unsubstituted C 1 -C 10 aminoalkyl.
-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, 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C2-C10 헤테로알킬, 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.In 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 containing at least one heteroatom 10 heteroalkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 2 -C 6 alkoxy, and substituted or unsubstituted C 1 - C 6 is selected from haloalkyl, Ar is aryl, p is an integer from 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, carbonyl azide, sulfonyl chloride, sulfonyl flue sulfonyl fluoride, boronic acid, isocyanate, halogen-substituted triazine, halogen-substituted pyridine, halogen-substituted diazine substituted diazine), tetrafluorophenyl ester, imido ester, azidonitrophenyl, glyoxal, and a reactive group selected from aldehydes.
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 있다.When 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, sulfonate, ketone, aldehyde, carboxylic acid, carboxylate, phosphoric acid, phosphate, acylchloride , at least one selected from polyalkylene oxides, quaternary ammonium salts, esters and amides.
T는 Ar1에 포함된 탄소이며, T와 질소는 서로 결합되어 적어도 하나의 헤테로 원자를 선택적으로 포함하는 치환 또는 비치환된 5 내지 7원자 고리(H)를 형성할 수 있다.T is carbon included in Ar 1 , and T and nitrogen may be bonded to each other to form a substituted or unsubstituted 5- to 7-membered ring (H) optionally including at least one heteroatom.
n은 0 또는 1 내지 4의 정수이며, R1이 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬 또는 폴리알킬렌 옥사이드인 경우, 상기 화합물은 적어도 하나의 -L-X 작용기를 포함한다.n is 0 or an integer from 1 to 4, and R 1 is C 1 -C 10 alkyl substituted with sulfonic acid or sulfonate, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonate, or polyalkylene oxide. In this case, the compound contains at least one -LX functional group.
또한, 본 발명의 다른 측면에 따르면, 화학식 1로 표시되는 시아닌계 화합물을 포함하는 생체분자 표지용 염료가 제공될 수 있다.In addition, according to another aspect of the present invention, a dye for labeling biomolecules including the cyanine-based compound represented by Chemical 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 biomolecule labeling kit including the cyanine-based compound represented by Chemical Formula 1 may be provided.
또한, 본 발명의 또 다른 측면에 따르면, 화학식 1로 표시되는 시아닌계 화합물을 포함하는 조영제 조성물이 제공될 수 있다.Also, according to another aspect of the present invention, a contrast agent composition including the cyanine-based compound represented by Chemical Formula 1 may be provided.
본 발명에 따른 신규한 시아닌계 화합물은 생체분자와 결합하여 450nm 이상의 가시광선 및 근적외선의 파장 영역에 있어서 형광 신호를 나타낼 수 있다. 이를 기반으로 본 발명에 따른 시아닌계 화합물은 생체분자 표지용 염료, 생체분자 표지용 키트 및 조영제 조성물 등으로 유용하게 사용될 수 있다.The novel cyanine-based compound according to the present invention can bind to biomolecules and exhibit fluorescence signals in the wavelength range of 450 nm or more of visible light and near-infrared light. Based on this, the cyanine-based compound according to the present invention can be usefully used as a dye for biomolecule labeling, a kit for biomolecule labeling, and a contrast agent composition.
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. Certain terms are defined herein for convenience in order to more readily understand the present invention. Unless otherwise defined herein, scientific terms and technical terms used in the present invention may have meanings commonly understood by one of ordinary skill 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.In addition, unless otherwise specified in 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 시아닌(cyanine)계 화합물이 제공될 수 있다.According to one aspect of the present invention, a cyanine-based compound represented by Formula 1 below may be provided.
[화학식 1][Formula 1]
또한, 본 발명의 일 실시예에 따른 시아닌계 화합물은 하기의 화학식 2로 표시되는 공명 구조로도 존재할 수 있는 것으로 이해되어야 할 것이다.In addition, it should be understood that the cyanine-based compound according to an embodiment of the present invention may also exist as a resonance structure represented by Formula 2 below.
[화학식 2][Formula 2]
여기서,here,
Ar1 및 Ar2는 각각 독립적으로 치환 또는 비치환된 아릴 또는 치환 또는 비치환된 헤테로아릴이며, Y1 및 Y2는 각각 독립적으로 황, 산소, 셀레늄, NR3, CR3R4, SiR3R4 및 -CR3=CR4-으로부터 선택될 수 있다. 또한, n은 0 또는 1 내지 4의 정수이다.Ar 1 and Ar 2 are each independently a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Y 1 and Y 2 are each independently sulfur, oxygen, selenium, NR 3 , CR 3 R 4 , SiR 3 R 4 and -CR 3 =CR 4 -. Moreover, n is 0 or an integer of 1-4.
이 때, Y1 또는 Y2가 CR4R5인 경우, R4 및 R5는 서로 결합하여 4원자, 5원자 또는 6원자 탄화수소 고리를 형성할 수 있다.In this case, when Y 1 or Y 2 is CR 4 R 5 , R 4 and R 5 may combine with each other to form a 4-membered, 5-membered or 6-membered hydrocarbon ring.
R1은 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬, 폴리알킬렌 옥사이드 및 -L-X 작용기로부터 선택되며, R2 내지 R4는 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 설프하이드릴, 나이트로, 카복실, 카복실산염, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 4차 암모늄, 인산, 인산염, 케톤(-COR5), 알데하이드, 에스터(-COOR5), 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택될 수 있다.R 1 is selected from C 1 -C 10 alkyl substituted with sulfonic acid or sulfonate, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonate, polyalkylene oxide and -LX functional groups, and R 2 to R 4 is each independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 heteroalkyl containing at least one heteroatom, 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, carbamate, sulfhydryl, nitro, carboxyl, carboxylate, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryls, substituted or unsubstituted aralkyls, quaternary ammoniums, phosphoric acids, phosphates, ketones (-COR 5 ), aldehydes, esters (-COOR 5 ), acylchlorides, sulfonic acids, sulfonates and -LX functional groups. can
Ra (여기서, a는 2 내지 4의 정수)가 케톤기(-COR5) 또는 에스터기(-COOR5)일 때, R5는 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C2-C10 헤테로알킬, 치환 또는 비치환된 C2-C10 알케닐, 치환 또는 비치환된 C2-C10 알키닐, 치환 또는 비치환된 C2-C10 알콕시, 치환 또는 비치환된 C1-C10 할로알킬 및 치환 또는 비치환된 C1-C10 아미노알킬로부터 선택될 수 있다.When R a (where a is an integer of 2 to 4) is a ketone group (-COR 5 ) or an ester group (-COOR 5 ), R 5 is a substituted or unsubstituted C 1 -C 10 alkyl, at least one Substituted or unsubstituted C 2 -C 10 heteroalkyl containing a hetero atom, 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 C 1 -C 10 haloalkyl and substituted or unsubstituted C 1 -C 10 aminoalkyl.
Ra가 알케닐 또는 알키닐일 때, 알케닐의 sp2-혼성 탄소 또는 알키닐의 sp-혼성 탄소가 직접적으로 결합되거나 알케닐의 sp2-혼성 탄소 또는 알키닐의 sp-혼성 탄소에 결합된 알킬의 sp3-혼성 탄소에 의해 간접적으로 결합된 형태일 수 있다.When R a is alkenyl or alkynyl, the sp 2 -hybrid carbon of alkenyl or the sp-hybrid carbon of alkynyl is directly bonded or bonded to the sp 2 -hybrid carbon of alkenyl or the sp-hybrid carbon of alkynyl. It may be indirectly bonded by the sp 3 -hybridized carbon of alkyl.
본원에서 Ca-Cb 작용기는 a 내지 b 개의 탄소 원자를 갖는 작용기를 의미한다. 예를 들어, Ca-Cb 알킬은 a 내지 b 개의 탄소 원자를 갖는, 직쇄 알킬 및 분쇄 알킬 등을 포함하는 포화 지방족기를 의미한다. 직쇄 또는 분쇄 알킬은 이의 주쇄에 10개 이하(예를 들어, C1-C10의 직쇄, C3-C10의 분쇄), 바람직하게는 4개 이하, 보다 바람직하게는 3개 이하의 탄소 원자를 가진다. A C a -C b functional group herein means a functional group having a to b carbon atoms. For example, C a -C b alkyl refers to a saturated aliphatic group having from a to b carbon atoms, including straight chain alkyl and branched alkyl and the like. A straight chain or branched alkyl has no more than 10 (eg C 1 -C 10 straight chain, C 3 -C 10 branched), preferably no more than 4, more preferably no more than 3 carbon atoms in its main chain. have
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 -may 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.In addition, alkoxy here refers to both an -O-(alkyl) group and an -O-(unsubstituted cycloalkyl) group, and is a straight-chain or branched hydrocarbon having at least one ether group 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like, but are not limited thereto.
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.Further, in the present application, halogen means fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I), and haloalkyl means the above-mentioned alkyl substituted with halogen. For example, halomethyl means methyl in which at least one of the hydrogens of methyl is replaced with a halogen (-CH 2 X, -CHX 2 or -CX 3 ).
본원에서 아르알킬은 아릴이 알킬의 탄소에 치환된 형태의 작용기로서, -(CH2)nAr의 총칭이다. 아르알킬의 예로서, 벤질(-CH2C6H5) 또는 페네틸(-CH2CH2C6H5) 등이 있다.In the present application, aralkyl is a functional group in which aryl is substituted on 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 ).
본원에서 아릴은 달리 정의되지 않는 한, 단일 고리 또는 서로 접합 또는 공유결합으로 연결된 다중 고리(바람직하게는 1 내지 4개의 고리)를 포함하는 불포화 방향족성 고리를 의미한다. 아릴의 비제한적인 예로는 페닐, 바이페닐, o- 터페닐(terphenyl), m-터페닐, p-터페닐, 1-나프틸, 2-나프틸, 1-안트릴(anthryl), 2-안트릴, 9-안트릴, 1-페난트레닐(phenanthrenyl), 2-페난트레닐, 3--페난트레닐, 4--페난트레닐, 9-페난트레닐, 1-피레닐, 2-피레닐 및 4-피레닐 등이 있다.As used herein, unless otherwise defined, aryl refers to an unsaturated aromatic ring comprising a single ring or multiple rings (preferably 1 to 4 rings) linked to each other by conjugated or covalent bonds. Non-limiting examples of aryl include phenyl, biphenyl, o-terphenyl, m-terphenyl, p-terphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- Anthryl, 9-anthryl, 1-phenanthrenyl, 2-phenanthrenyl, 3-phenanthrenyl, 4--phenanthrenyl, 9-phenanthrenyl, 1-pyrenyl, 2- pyrenyl and 4-pyrenyl; and the like.
본원에서 헤테로 아릴은 상기에서 정의된 아릴 내 하나 이상의 탄소 원자가 질소, 산소 또는 황과 같은 비-탄소 원자로 치환된 작용기를 의미한다. 헤테로 아릴의 비제한적인 예로는, 퓨릴(furyl), 테트라하이드로퓨릴, 피로릴(phrrolyl), 피롤리디닐(pyrrolidinyl), 티에닐(thienyl), 테트라하이드로티에닐, 옥사졸릴(oxazolyl), 아이소옥사졸릴(isoxazolyl), 트리아졸릴(triazolyl), 티아졸릴(thiazolyl), 아이소티아졸릴(isothiazolyl), 피라졸릴(pyrazolyl), 피라졸리디닐(pyrazolidinyl), 옥사디아졸릴(oxadiazolyl), 티아디아졸릴(thiadiazolyl), 이미다졸릴(imidazolyl), 이미다졸리닐(imidazolinyl), 피리딜(pyridyl), 피리다지일(pyridaziyl), 트리아지닐(triazinyl), 피페리디닐(piperidinyl), 모르포리닐(morpholinyl), 티오모르포리닐(thiomorpholinyl), 피라지닐(pyrazinyl), 피페라이닐(piperainyl), 피리미디닐(pyrimidinyl), 나프티리디닐(naphthyridinyl), 벤조퓨라닐, 벤조티에닐, 인돌릴(indolyl), 인도리닐, 인돌리지닐, 인다졸릴(indazolyl), 퀴놀리지닐, 퀴놀리닐, 아이소퀴놀리닐, 시놀리닐(cinnolinyl), 프탈라지닐(phthalazinyl), 퀴나졸리닐, 퀴녹사리닐, 프테리디닐(pteridinyl), 퀴누클리디닐(quinuclidinyl), 카바조일, 아크리디닐, 페나지닐, 페노티지닐(phenothizinyl), 페녹사지닐, 퓨리닐, 벤즈이미다졸릴(benzimidazolyl) 및 벤조티아졸릴 등과 이들이 접합된 유사체들이 있다.As used herein, heteroaryl refers to a functional group in which one or more carbon atoms in the aryl defined above are substituted with a non-carbon atom such as nitrogen, oxygen or sulfur. Non-limiting examples of heteroaryl include furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, thienyl, tetrahydrothienyl, oxazolyl, isoxa isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolidinyl, oxadiazolyl, thiadiazolyl , imidazolyl, imidazolinyl, pyridyl, pyridaziyl, triazinyl, piperidinyl, morpholinyl, thio Thiomorpholinyl, pyrazinyl, piperainyl, pyrimidinyl, naphthyridinyl, benzofuranyl, benzothienyl, indolyl, indolinyl ( pteridinyl, quinuclidinyl, carbazolyl, acridinyl, phenazinyl, phenothizinyl, phenoxazinyl, purinyl, benzimidazolyl and benzothiazolyl and their conjugated analogues. there are
본원에서 탄화수소 고리(cycloalkyl) 또는 헤테로 원자를 포함하는 탄화수소 고리(heterocycloalkyl)은 달리 정의되지 않는 한 각각 알킬 또는 헤테로 알킬의 고리형 구조로 이해될 수 있을 것이다.A hydrocarbon ring (cycloalkyl) or a hydrocarbon ring containing a hetero atom (heterocycloalkyl) herein may be understood as a cyclic structure of alkyl or heteroalkyl, respectively, unless otherwise defined.
탄화수소 고리의 비제한적인 예로는 사이클로펜틸, 사이클로헥실, 1-사이클로헥세닐, 3-사이클로헥세닐 및 사이클로헵틸 등이 있다. 헤테로 원자를 포함하는 탄화수소 고리의 비제한적인 예로는 1-(1,2,5,6-테트라하이드로피리딜), 1-피페리디닐, 2-피페리디닐, 3-피페리디닐, 4-모르포리닐, 3-모르포리닐, 테트라하이드로퓨란-2-일, 테트라하드로퓨란-3-일, 테트라하이드로티엔-2-일, 테트라하이드로티엔-3-일, 1-피페라지닐, 2-피페라지닐 등이 있다.Non-limiting examples of hydrocarbon rings include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl and cycloheptyl. Non-limiting examples of hydrocarbon rings containing heteroatoms include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- Morpholinil, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2 - Piperazinil, etc.
또한, 탄화수소 고리 또는 헤테로 원자를 포함하는 탄화수소 고리는 여기에 탄화수소 고리, 헤테로 원자를 포함하는 탄화수소 고리, 아릴 또는 헤테로 아릴이 접합되거나 공유결합으로 연결된 형태를 가질 수 있다.In addition, a hydrocarbon ring or a hydrocarbon ring including a hetero atom may have a form in which a hydrocarbon ring, a hydrocarbon ring including a hetero atom, an aryl, or a hetero aryl are conjugated or covalently bonded thereto.
-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, 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C2-C10 헤테로알킬, 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.In 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 containing at least one heteroatom 10 heteroalkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, substituted or unsubstituted C 2 -C 6 alkoxy, and substituted or unsubstituted C 1 - C 6 is selected from haloalkyl, Ar is aryl, p is an integer from 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, carbonyl azide, sulfonyl chloride, sulfonyl flue sulfonyl fluoride, boronic acid, isocyanate, halogen-substituted triazine, halogen-substituted pyridine, halogen-substituted diazine substituted diazine), tetrafluorophenyl ester, imido ester, azidonitrophenyl, glyoxal, and a reactive group selected from aldehydes.
본 발명의 다양한 실시예에 따른 시아닌계 화합물은 상술한 반응성기를 통해 타겟 생체분자와 결합하여 표지하는 것이 가능할 수 있다.The cyanine-based compound according to various embodiments of the present invention may be labeled by binding to a target biomolecule through the aforementioned 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 capable of reacting with functional groups such as an amino group, an imino group, a thiol group, or a hydroxyl group of a target biomolecule, and an amide bond, an imide bond, or a urethane bond between a cyanine-based compound and a 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) is bonded to the main skeleton of the cyanine-based compound via the linker (L), thereby relieving the steric hindrance between the biomolecule and the cyanine-based compound, and thereby nucleic acids and proteins having complex structures. , the labeling rate for biomolecules such as carbohydrates can be improved.
또한, Rb (여기서, b는 2 내지 5의 정수)가 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 있다.Also, Rb (where b is an integer from 2 to 5) is substituted, any carbon or terminal carbon in the functional group is sulfonic acid, sulfonate, ketone, aldehyde, carboxylic acid, carboxylate, phosphoric acid, phosphate, acylchloride, polyalkyl It may be substituted with at least one selected from rene oxide, quaternary ammonium salts, esters and amides.
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, the polyalkylene oxide is a water-soluble polymer functional group, polyethylene glycol (PEG), polypropylene glycol (PPG), polyethylene glycol-polypropylene glycol (PEG-PPG) copolymer and N-substituted 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, the polyalkylene oxide may be additionally substituted as needed within the limit of maintaining the properties of the polymer. 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 is hydroxy, an alkyl ether (methyl ether, ethyl ether, propyl ether, etc.), carboxylmethyl ether, carboxyethyl ether, benzyl ether, dibenzylmethylene ether, or may be substituted with methylamine. In one embodiment, the polyalkylene oxide may be a polyalkylene oxide (mPEG) terminated with methyl ether, wherein mPEG is represented by the formula -(CH 2 CH 2 O) n CH 3 , ethylene glycol The size of mPEG may vary depending on the size of n corresponding 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.In addition, the cyanine-based compound represented by Chemical Formula 1 may have a structure further including a counter ion. The counter ion is an organic or inorganic anion and may be appropriately selected in consideration of 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.As an example of the counter ion of the cyanine-based compound according to an embodiment of the present invention, phosphoric acid hexafluoride ion, halogen ion, phosphoric acid ion, perchlorate ion, periodate ion, antimony hexafluoride ion, tartrate hexafluoride ion, Inorganic acid anions such as fluoride ions, fluoroboric acid ions and tetrafluoric ions, thiocyanate ions, benzenesulfonate ions, naphthalenesulfonate ions, p-toluenesulfonate ions, alkylsulfonate ions, benzenecarboxylic acid ions, organic acid ions such as alkyl carboxylic acid ions, trihaloalkyl carboxylic acid ions, alkyl sulfonic acid ions, trihaloalkyl sulfonic acid ions, and nicotinic acid ions. In addition, metal compound ions such as bisphenylditol, thiobisphenol chelate and bisdiol-α-dikethone, 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 R2는 서로 결합하여 탄화수소 고리를 형성할 수 있다. 이 때, 탄화수소 고리는 4원자, 5원자 또는 6원자 고리일 수 있으며, -S-, -O-, -Se-, >NR3 및 >SiR3R4 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 2 may bond to each other to form a hydrocarbon ring. At this time, the hydrocarbon ring may be a 4-membered, 5-membered or 6-membered ring, and optionally at least one heteroatom selected from -S-, -O-, -Se-, >NR 3 and >SiR 3 R 4 can be included as
T는 Ar1에 포함된 탄소이며, T와 질소는 서로 결합되어 적어도 하나의 헤테로 원자를 선택적으로 포함하는 치환 또는 비치환된 5 내지 7원자 고리(H)를 형성할 수 있다.T is carbon included in Ar 1 , and T and nitrogen may be bonded to each other to form a substituted or unsubstituted 5- to 7-membered ring (H) optionally including at least one heteroatom.
본 발명의 일 실시예에 따른 시아닌계 화합물은 R1이 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬 또는 폴리알킬렌 옥사이드인 경우, 적어도 하나의 -L-X 작용기를 포함하는 것을 특징으로 한다.The cyanine-based compound according to an embodiment of the present invention is C 1 -C 10 alkyl substituted with sulfonic acid or sulfonic acid salt, C 2 -C 10 heteroalkyl or polyalkylene oxide substituted with sulfonic acid or sulfonic acid salt . In the case of, it is characterized in that it comprises at least one -LX functional group.
또한, Ar1 또는 Ar2가 치환된 경우, 상기 작용기 내 임의의 탄소는 중수소, 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 설프하이드릴, 나이트로, 카복실, 카복실산염, 치환 또는 비치환된 아릴, 치환 또는 비치환된 헤테로아릴, 치환 또는 비치환된 아르알킬, 4차 암모늄, 인산, 인산염, 케톤(-COR5), 알데하이드, 에스터(-COOR5), 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 including at least one hetero atom. 10 heteroalkyl, 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, carbamate, sulfhydryl, nitro, carboxyl, carboxylate; Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphate, ketone (-COR 5 ), aldehyde, ester (-COOR 5 ), acyl chloride, It may be substituted with at least one selected from sulfonic acids, sulfonic acid salts and -LX functional groups.
이 때, R1이 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬 또는 폴리알킬렌 옥사이드인 경우, R2, R3 또는 R4가 -L-X 작용기이거나, Ar1 및 Ar2 중 적어도 하나는 -L-X 작용기로 치환될 수 있다.In this case, when R 1 is sulfonic acid or C 1 -C 10 alkyl substituted with sulfonic acid salt, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonic acid salt, or polyalkylene oxide, R 2 , R 3 or R 4 is a -LX functional group, or Ar 1 and Ar 2 At least one of them may be substituted with a -LX functional group.
본 발명의 다양한 실시예에 따른 시아닌계 화합물의 여기 및 발광 특성은 화학식 1에서 정의된 비대칭적인 헤테로 고리를 포함하는 구조에 의해 결정되는 것으로서, 화학식 1로 표시되는 화합물에 도입된 반응기의 종류와 무관하게 본 발명에서 의도하는 시아닌계 화합물의 여기 및 발광 특성은 유지될 수 있는 것으로 이해되어야 할 것이다.Excitation and emission characteristics of cyanine-based compounds according to various embodiments of the present invention are determined by a structure including an asymmetric heterocyclic ring defined in Formula 1, regardless of the type of reactive group introduced into the compound represented by Formula 1 It should be understood that the excitation and emission characteristics of the cyanine-based compound intended in the present invention can be maintained.
화학식 1로 표시되는 시아닌계 화합물의 구체적인 예는 다음과 같다.Specific examples of the cyanine-based compound represented by Formula 1 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]
[화합물 37][Compound 37]
[화합물 38][Compound 38]
[화합물 39][Compound 39]
[화합물 40][Compound 40]
[화합물 41][Compound 41]
[화합물 42][Compound 42]
[화합물 43][Compound 43]
[화합물 44][Compound 44]
[화합물 45][Compound 45]
본원에서 개시된 화학식 1로 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 compound represented by Chemical Formula 1 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, lipopolysaccharides, and the like, and specific examples of carbohydrates include monosaccharides, disaccharides, and polysaccharides (eg, dextran).
이 때, 생체분자는 화학식 1로 표시되는 시아닌계 화합물의 임의의 작용기 또는 화학식 1로 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 an arbitrary functional group of the cyanine-based compound represented by Formula 1 or a reactive group bonded to the cyanine-based compound represented by Formula 1, and is selected from amino, sulfhydryl, carbonyl, It may contain at least one selected from hydroxyl, carboxyl, phosphate and thiophosphate or 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.In addition, the biomolecule may be an oxy or deoxy polynucleic acid containing at least one selected from amino, sulphydryl, carbonyl, hydroxyl, carboxyl, phosphate and thiophosphate or having a derivative form thereof.
아울러, 생체분자 이외에 화학식 1로 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 compound represented by Formula 1 is a drug or hormone (including receptor ligands) including at least one selected from amino, sulphydryl, carbonyl, hydroxyl, carboxyl, phosphate, and thiophosphate. ), receptors, enzymes or enzyme substrates, cells, cell membranes, toxins, microorganisms or nano-biomaterials (such as polystyrene microspheres).
생체분자 표지용 염료, 키트 및 조영제 조성물Dyes, kits and contrast agent compositions for labeling biomolecules
본 발명의 다른 측면에 따르면, 화학식 1로 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 for biomolecule labeling, a kit, and a contrast agent composition including at least one selected from cyanine-based compounds represented by Formula 1 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.Also, if necessary, the biomolecule labeling kit may further include enzymes, solvents (buffers, etc.) and other reagents for reacting with target biomolecules.
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, as the solvent, a buffer selected from the group consisting of a phosphate buffer, a carbonate buffer, and a Tris buffer, an organic solvent selected from dimethyl sulfoxide, dimethylformamide, dichloromethane, methanol, ethanol, and acetonitrile, or water. It can be used, and it is possible to adjust the solubility by introducing various functional groups to the cyanine-based compound according to the type of solvent.
본 발명의 일 실시예에 따른 생체분자 표지용 키트는 생체분자를 크기별로 분리한 후 상기 생체분자 표지용 염료로 표지하는 전기영동 키트로 구성될 수도 있으며, 이에 따라 단백질의 크기를 동정하거나 핵산의 시퀀싱 용도로 사용할 수 있다.A kit for biomolecule labeling according to an embodiment of the present invention may also consist of an electrophoresis kit that separates biomolecules by size and then labels them with the biomolecule labeling dye, thereby identifying the size of a protein or nucleic acid. It can be used for sequencing purposes.
또한, 상기 실시예에 따른 생체분자 표지용 키트는 고상(solid phase) 또는 반-고상(semi-solid phase)의 지지 매트릭스와 상기 지지 매트릭스 상에 고착화된 화학식 1로 표시되는 시아닌계 화합물을 포함할 수 있다.In addition, the biomolecule labeling kit according to the above embodiment may include a solid phase or semi-solid phase support matrix and a cyanine-based compound represented by Formula 1 fixed on the support matrix. can
이에 따라, 생체분자 표지용 키트 내로 주입된 샘플 내 생체분자는 지지 매트릭스 상에 고착화된 시아닌계 화합물과의 상호작용을 통해 지지 매트릭스 상에 고정될 수 있다.Accordingly, the biomolecules in the sample injected into the biomolecule labeling kit can be immobilized on the supporting matrix through interaction with the cyanine-based compound immobilized on the supporting matrix.
상기 지지 매트릭스는 알지네이트, 콜라겐, 펩타이드, 피브린, 히알루론산, 아가로즈, 폴리하이드록시에틸메타크릴레이트, 폴리바이닐알코올, 폴리에틸렌글라이콜, 폴리에틸렌옥사이드, 폴리에틸렌글라이콜다이아크릴레이트, 젤라틴, 매트리젤(matrigel), 폴리락트산, 카르복시메틸셀룰로오스, 덱스트란, 키토산, 라텍스 및 세파로즈로부터 선택되는 적어도 하나로 제조될 수 있으며, 비드 또는 멤브레인 형태일 수 있다.The support matrix is alginate, collagen, peptide, fibrin, hyaluronic acid, agarose, polyhydroxyethyl methacrylate, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, polyethylene glycol diacrylate, gelatin, matrigel (matrigel), polylactic acid, carboxymethylcellulose, dextran, chitosan, latex, and sepharose, and may be prepared in the form of beads or membranes.
또한, 상기 실시예에 따른 조영제 조성물은 경구 또는 비경구 방식으로 투여되기 위해 화학식 1로 표시되는 시아닌계 화합물 외에 약학적으로 허용하는 담체를 더 포함할 수 있다. In addition, the contrast medium composition according to the embodiment may further include a pharmaceutically acceptable carrier in addition to the cyanine-based compound represented by Formula 1 for oral or parenteral administration.
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, alginates, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, and cellulose. , water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
이하에서는 상술한 생체분자 표지용 염료 또는 생체분자 표지용 키트를 이용한 생체분자의 표지 방법에 대하여 설명하도록 한다.Hereinafter, a biomolecule labeling method using the aforementioned biomolecule labeling dye or biomolecule labeling kit will be described.
생체분자 표지용 염료를 이용한 생체분자의 표지 방법Biomolecule labeling method using a biomolecule labeling dye
화학식 1로 표시되는 시아닌계 화합물로 생체분자를 표지하는 방법으로는 표지된 고체 또는 반고체 상태의 생체분자의 형광을 측정하는 표지 방법이 가능한 모든 생체분자의 표지에 적용될 수 있다.As a method of labeling a biomolecule with a cyanine-based compound represented by Formula 1, a labeling method of measuring the fluorescence of a labeled biomolecule in a solid or semi-solid state can be applied to all available biomolecule labels.
종래의 형광 염료 대신 시아닌계 화합물을 사용함으로써, 고감도로 화학적으로 안정적이고 조작성이 뛰어난 표지 방법을 제공할 수 있다.By using a cyanine-based compound instead of a conventional fluorescent dye, it is possible to provide a highly sensitive, chemically stable, and excellent operability labeling method.
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 directly reacting a target biomolecule with a cyanine-based compound or by reacting a target biomolecule with a probe labeled with a cyanine-based compound may be implemented.
또한, 타겟 생체분자의 종류에 따라 시아닌계 화합물에 적절한 반응성기를 도입함으로써 타겟-특이적 상호작용을 이용한 생체분자의 표지 방법이 구현될 수도 있다.In addition, a biomolecule labeling method using a target-specific interaction may be implemented by introducing an appropriate reactive group into a cyanine-based compound according to 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 표지해야 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.In the DNA microarray method, a target nucleic acid to be labeled is labeled by reacting with a dye, while a single-chain probe nucleic acid having a nucleotide sequence complementary to the target nucleic acid is prepared, and the target nucleic acid denatured into a single chain and the probe nucleic acid are placed on a substrate. By hybridization above, the fluorescence of the target nucleic acid is measured.
본 표지 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.As the probe nucleic acid to be immobilized on the substrate in this labeling method, in the case of investigating gene expression, a cDNA library such as cDNA, a genomic library, or a nucleic acid prepared by amplification by the PCR method using all genomes as a template can be used
또한, 유전자의 변이 등을 조사하는 경우, 표준이 되는 이미 알려진 서열을 근거로 하여, 변이 등에 대응하는 여러가지 올리고뉴클레오티드를 합성한 것을 사용할 수 있다.Further, in the case of investigating gene mutations, etc., various oligonucleotides synthesized corresponding to mutations or the like can be used based on a known standard sequence.
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.An appropriate method can be selected for immobilizing the probe nucleic acid on the substrate depending on the type of nucleic acid or the type of substrate. For example, a method of electrostatic bonding to a substrate surface-treated with cations such as polylysine using the charge of DNA can also 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 the labeling dye is prepared by mixing and reacting the target nucleic acid modified into a single chain with the labeling dye. The reaction temperature is 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 carried out at room temperature to 70 ° C. and in the range of 2 to 48 hours. By hybridization, a target nucleic acid having a nucleotide sequence complementary to the probe nucleic acid selectively binds to the probe nucleic acid. After that, the substrate is cleaned and dried at room temperature.
이어서, 건조한 기판 표면의 형광강도를 형광 레이저 스캐너법에 의해 측정한다. 형광강도에 의해 유전자 발현의 레벨을 모니터링할 수 있다.Then, the fluorescence intensity of the dry substrate surface is measured by 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.On the other hand, although the method of immobilizing the probe nucleic acid to the substrate has been described for the hybridization, a method of immobilizing the target nucleic acid previously labeled with a dye on the substrate and spotting the probe nucleic acid on the substrate may also be used.
PCR 법PCR method
PCR법은, 표지해야 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 a nucleotide sequence of a target nucleic acid to be labeled is labeled with a dye, the target nucleic acid is reacted with the probe prior to or after amplification of the target nucleic acid, and the fluorescence of the target nucleic acid is measured.
구체적으로는 표적 핵산의 신장반응은 효소(DNA 중합효소, 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 enzymes (DNA polymerase, RNA polymerase), and at this time, the enzyme recognizes the double-stranded nucleic acid sequence formed by the primer composed of the target nucleic acid and oligonucleotide, An elongation reaction is performed from the site, and only the gene region of interest is amplified.
효소가 합성을 할 때, 뉴클레오티드(dNTP, NTP)를 원료로 하여 합성반응이 이루어진다.When an enzyme is synthesized, a synthesis reaction is performed 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, when a nucleotide having a dye is mixed with a normal nucleotide (dNTP, NTP) in an arbitrary ratio, a nucleic acid into which the dye is introduced 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 the dye for labeling has been introduced can be synthesized by introducing a nucleotide having an amino group in an arbitrary ratio by PCR and then combining the dye for labeling.
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 is synthesized, a synthesis reaction is carried out using nucleotide as a raw material. When 3' OH of a nucleotide at this time is changed to H, the nucleic acid elongation reaction does not take place anymore, 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 a terminator with a normal nucleotide, nucleic acids of various lengths are synthesized because the terminator is introduced with a certain probability and the reaction is terminated.
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 lines up in order of length. Here, when each base of the terminator is labeled with a different labeling dye, a trend dependent on each base is observed at the end point (3' end) of the synthesis reaction, and fluorescence information is obtained starting from the labeling dye labeled with the terminator. By reading, the nucleotide sequence information of the target nucleic acid can be obtained.
또한, 터미네이터 대신에 미리 표지용 염료로 표지한 프라이머를 사용하여 표적 핵산과 혼성화할 수도 있다.Alternatively, hybridization with the target nucleic acid may be performed using a primer previously labeled with a labeling dye instead of a terminator.
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.In addition, PNA (peptide nucleic acid) can also be used as a probe. PNA replaces the pentose/phosphate backbone, which is the basic backbone of nucleic acids, with a polyamide backbone made of glycine as a unit. combine 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).
표지에는 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 labeling, for example, double-stranded DNA is brought into contact with PNA, which has a base sequence complementary to all or part of the DNA base sequence and is labeled with a labeling dye, hybridized, and the mixture is heated to generate single-stranded DNA. , by slowly cooling the mixture to room temperature to prepare a PNA-DNA complex, and measuring its fluorescence.
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 for amplifying a target nucleic acid by PCR method and measuring the fluorescence of the product has been described, but in this method, the size of the product is confirmed by electrophoresis and then the fluorescence intensity is measured to investigate the amount of the amplification product. Needs to be.
이를 위해, 형광염료의 에너지 트랜스퍼를 이용하고, PCR법의 생성물에 혼성화시킴으로써 형광이 발생하도록 고안된 프로브를 사용하여, 실시간으로 생성물의 양을 측정할 수도 있다. To this end, the amount of the product may be measured in real time using a probe designed to generate fluorescence by hybridizing to the product of the PCR method using energy transfer of a fluorescent dye.
예를 들어, 도너와 억셉터를 표지한 DNA를 사용할 수 있다. 구체적인 표지 방법으로는 특정 서열의 핵산의 존재를 확인하는 분자비콘법이나 TaqMan-PCR법이나 사이클링 프로브(cycling probe)법 등을 들 수 있다.For example, DNA labeled with donor and acceptor can be used. Specific labeling methods include a molecular beacon method, a TaqMan-PCR method, and a cycling probe method for confirming the presence of a nucleic acid having a specific sequence.
또한, 단백질을 표지대상으로 하는 경우, 전기영동 후의 단백질의 표지에는 염색염료가 사용되고 있다.In addition, when proteins are to be labeled, dyes are used to label proteins after electrophoresis.
통상, 전기영동 후의 겔 안에 염색염료 예를 들어, CBB (Coomassie Brilliant Blue)를 침투시켜 단백질을 염색하고, UV를 조사하여 발광시키는 방법이 사용된다. In general, a method of infiltrating a dye, for example, CBB (Coomassie Brilliant Blue) into the gel after electrophoresis to dye the protein, and irradiating UV to emit light is used.
다만, 종래의 염색 염료를 사용하는 방법은 간단하지만, 감도가 100ng 정도로 낮아, 미량의 단백질 표지에는 적합하지 않다. 또한, 겔을 통하여 염색염료를 침투시키기 때문에, 염색에 많은 시간을 요한다는 문제도 있다.However, although the method using a conventional staining dye is simple, the sensitivity is as low as 100 ng, so it is not suitable for labeling a small amount of protein. In addition, since the dye is permeated through the gel, there is also a problem that a lot of time is required for dyeing.
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 labeled by size-separating proteins by electrophoresis and binding a dye for labeling to the separated proteins.
본 발명의 표지용 염료는 반응성기를 가지고 있으며, 단백질과 빠르게 정량적으로 반응하고, 더욱이 고감도이어서, 미량의 단백질 표지에 적합하다. 더욱이, 크기 분리한 단백질을 질량 분석하여 동정(同定)할 수도 있다.The dye for labeling of the present invention has a reactive group, rapidly and quantitatively reacts with proteins, and is highly sensitive, so it is suitable for labeling trace amounts of proteins. Furthermore, 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 표지대상으로 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 nucleoprotein, 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, in a protein sample separated by two-dimensional electrophoresis using three types of labeling dyes corresponding to dyes for phosphoprotein, glycoprotein, and total protein, phosphoprotein, glycoprotein, and total protein are stained. 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 by 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. In addition, collagen is a protein constituting animal connective tissue and has a unique fibrous structure. That is, it is composed of triplex polypeptide chains, and the peptide chains gather to form a triplex chain. Collagen is generally a protein with very low immunogenicity and is widely used in the fields of 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 표지할 수 있다.In addition, an aptamer may be used for the probe. Since aptamers are composed of oligonucleic acids and can have various characteristic three-dimensional structures depending on their base sequences, they can bind to all biomolecules including proteins through their three-dimensional structures. Using this property, an aptamer labeled with a dye for labeling can be bound to a specific protein, and the test subject can be indirectly labeled from the fluorescence change due to the structural change of the protein caused by the binding to the test subject.
기타 표지 방법Other labeling methods
또한, 본 발명의 표지용 염료를 특이결합을 사용한 생체분자의 표지 방법에도 사용할 수 있다.In addition, the dye for labeling of the present invention can also be used for a method for labeling biomolecules using specific binding.
즉, 생체분자로 이루어지는 피검체 또는 수식물질에 의해 수식된 이 피검체의 표지에 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 labeling a test subject composed of biomolecules or a test subject modified by a modifier, one of the binding material specifically binding to the subject or the binding material specifically binding to the modifying material is used for labeling. It can be labeled with a dye, and fluorescence from the labeled binding material can be measured.
여기서, 상기 피검체 또는 수식물질과 상기 결합물질의 조합에는, 항원-항체, 합텐-항합텐 항체, 비오틴-아비딘, Tag 항원, Tag항체, 렉틴-당단백질 또는 호르몬-수용체를 사용할 수 있다.Here, antigen-antibody, hapten-anti-hapten antibody, biotin-avidin, Tag antigen, Tag antibody, lectin-glycoprotein or hormone-receptor may be used for the combination of the test subject or modifier and the binding material.
구체적으로는 기판, 용액, 비즈 또는 항체에 존재하는 항원에 대하여 표지용 염료로 표지한 항체 등의 결합 물질을 반응시켜, 항체의 항원 특이적 상호작용을 통해 특정 항원을 표지할 수 있다.Specifically, a specific antigen can be labeled through antigen-specific interaction of the antibody by reacting a binding material such as an antibody labeled with a labeling dye with respect to 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.As an antigen, proteins, polysaccharides, nucleic acids, peptides, etc. may be used, and haptens such as low molecular weight molecules such as FITC or dinitrophenyl group may also be used in addition to antigens. At this time, the combination of antigen (or hapten) and antibody includes GFP and anti-GFP antibody, FITC and anti-FITC antibody, and the like.
표지된 항원들은 면역염색, ELISA, Western blotting 또는 Flow cytometry 등과 같은 각종 측정 방법에 사용할 수 있다.Labeled antigens can be used for various measurement methods such as immunostaining, ELISA, Western blotting or 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.In addition, intracellular signal transduction can be observed using the dye for labeling of the present invention. Various enzymes and the like are involved in internal signal transduction or the cell's response thereto. In a typical signal transduction phenomenon, it is known that a specific protein kinase is activated, and thus phosphorylation of a protein is induced to initiate 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 (eg, ATP or ADP) play an important role in their activity, and intracellular signal transduction phenomena can be observed with high sensitivity by introducing a dye for labeling into nucleotide derivatives.
또한, 본 발명의 표지용 염료를 RNA 간섭작용(RNAi)을 이용한 유전자 발현 현상의 관찰에 이용할 수도 있다.In addition, the dye for labeling of the present invention can be used for observation of gene expression 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 inhibits expression by degrading mRNA of a target gene by introducing double-stranded RNA (dsRNA) into cells, and it is possible to observe the RNAi phenomenon by labeling the designed dsRNA with a dye for labeling.
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 dye for labeling 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 for checking the level of transcription of a target nucleic acid or expression level of a target protein.
이하에서는 본 발명의 구체적인 실시예들을 제시한다. 다만, 하기에 기재된 실시예들은 본 발명을 구체적으로 예시하거나 설명하기 위한 것에 불과하며, 이로서 본 발명이 제한되어서는 아니된다.Hereinafter, specific embodiments of the present invention are presented. However, the embodiments described below are only intended to specifically illustrate or explain the present invention, and the present invention should not be limited thereto.
제조예manufacturing example
제조예 1: 화합물 1의 제조Preparation Example 1: Preparation of Compound 1
중간체 1 (Journal of Heterocyclic Chemistry,41(1),103-108;2004) 1.0g과 중간체 2 (Organic letters,11(5),1123;2009) 1.7g 및 피리딘 10mL를 반응기에 투입하고, 90℃에서 30분 동안 교반시켰다. 이어서, 반응액을 농축한 후, 실리카겔컬럼크로마토그래피로 화합물 1 0.5g을 분리하여 얻었다(MS (ESI): m/z 495.3 [M-I]+).1.0 g of Intermediate 1 (Journal of Heterocyclic Chemistry, 41(1), 103-108;2004) and 1.7 g of Intermediate 2 (Organic letters, 11(5), 1123;2009) and 10 mL of pyridine were put into a reactor, and 90 ° C. was stirred for 30 min. Then, after concentrating the reaction solution, 0.5 g of Compound 1 was separated and obtained by silica gel column chromatography (MS (ESI): m/z 495.3 [MI] + ).
제조예 2: 화합물 2의 제조Preparation Example 2: Preparation of Compound 2
제조예 1과 동일한 방법으로 중간체 2와 중간체 3을 반응시켜 화합물 2를 제조하였다(MS (ESI): m/z 509.3 [M-I]+).Compound 2 was prepared by reacting Intermediate 2 and Intermediate 3 in the same manner as in Preparation Example 1 (MS (ESI): m/z 509.3 [MI] + ).
실험예Experimental example
상기 제조예 1 및 2에서 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 and 2, 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 및 제조예 2에 따라 합성된 화합물 1과 화합물 2의 경우, 450nm 이상의 가시광선 및 근적외선의 파장 영역에 있어서 형광 신호를 나타내는 것을 확인할 수 있다. 또한, 몰 흡광계수 및 양자 효율 측면에서도 종래의 상용화된 형광 염료에 비해 우수한 것을 확인할 수 있다.As described in Table 1, in the case of Compound 1 and Compound 2 synthesized according to Preparation Example 1 and Preparation Example 2, it can be confirmed that they exhibit fluorescence signals in the wavelength range of 450 nm or more of visible and near infrared rays. In addition, it can be confirmed that it is superior to conventional commercially available fluorescent dyes in terms of molar extinction coefficient and quantum efficiency.
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.Although one embodiment of the present invention has been described above, those skilled in the art can add, change, delete, or add components within the scope not departing from the spirit of the present invention described in the claims. The present invention can be variously modified and changed by the like, and this will also be said to be included within the scope of the present invention.
Claims (9)
[화학식 1]
여기서,
Ar1 및 Ar2는 각각 독립적으로 치환 또는 비치환된 C6-C24 아릴 또는 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C5-C23 헤테로아릴이며, 이 때, Ar1 및 Ar2는 각각 독립적으로 벤젠, 피리딘, 나프탈렌, 페난트렌, 다이벤조퓨란, 다이벤조싸이오펜, 퀴놀린, 아세나프틸렌, 플루오란텐 및 플루오렌으로부터 선택되며,
Ar1 또는 Ar2가 치환된 아릴 또는 헤테로아릴인 경우, 상기 아릴 또는 헤테로아릴은 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 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 C7-C34 아르알킬, 4차 암모늄, 인산, 인산염, 케톤, 알데하이드, 에스터, 아실클로라이드, 설폰산, 설폰산염, 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환되며,
Y1 및 Y2는 각각 독립적으로 황, 산소, NR3 및 CR3R4로부터 선택되며,
R1은 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬, 폴리알킬렌 옥사이드 및 -L-X 작용기로부터 선택되며,
R2는 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 할로겐, 사이아노, 카복실, 카복실산염 및 -L-X 작용기로부터 선택되며,
R3은 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬 및 -L-X 작용기로부터 선택되며,
R4는 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬 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 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C6 알콕시 및 적어도 하나의 치환기로 치환 또는 비치환된 C1-C6 할로알킬로부터 선택되며, Ar은 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴이며, p는 1 내지 30의 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), 하이드록시(hydroxy), 하이드록실아민(hydroxylamine), 케톤(ketone), 알카인(alkyne), 아자이드(azide), 아미노(amino), 지방족 아민, 방향족 아민, 설포테트라플루오로페닐 에스터(sulfotetrafluorophenyl ester), 설포다이클로로페닐 에스터(sulfodichlorophenyl ester), 카보닐 아자이드(carbonyl azide), 설포닐 클로라이드(sulfonyl chloride), 설포닐 플루오라이드(sulfonyl fluoride), 이소시아네이트(isocyanate), 할로겐-치환 트리아진(halogen-substituted triazine), 테트라플루오로페닐 에스터(tetrafluorophenyl ester), 이미도 에스터(imido ester), 아지도나이트로페닐(azidonitrophenyl), 글리옥살(glyoxal) 및 알데하이드로부터 선택되는 반응성기이며,
T는 Ar1에 포함된 탄소이며,
T와 질소는 서로 결합되어 적어도 하나의 헤테로 원자를 선택적으로 포함하는 치환 또는 비치환된 5 내지 7원자 고리(H)를 형성하며,
상기 고리(H)가 치환된 고리인 경우, 상기 고리(H)는 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 설프하이드릴, 나이트로, 카복실, 카복실산염, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C5-C23 헤테로아릴, 적어도 하나의 치환기로 치환 또는 비치환된 C7-C34 아르알킬, 4차 암모늄, 인산, 인산염, 케톤, 알데하이드, 에스터, 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환되며,
n은 0 또는 1 내지 4의 정수이며,
R1이 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬 또는 폴리알킬렌 옥사이드인 경우, 상기 화합물은 적어도 하나의 -L-X 작용기를 포함하며,
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), 황(S), 셀레늄(Se) 및 실리콘(Si)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.
A cyanine-based compound represented by Formula 1 below:
[Formula 1]
here,
Ar 1 and Ar 2 are each independently a substituted or unsubstituted C 6 -C 24 aryl or a substituted or unsubstituted C 5 -C 23 heteroaryl containing at least one hetero atom, wherein Ar 1 and Ar 2 is each independently selected from benzene, pyridine, naphthalene, phenanthrene, dibenzofuran, dibenzothiophene, quinoline, acenaphthylene, fluoranthene and fluorene;
When Ar 1 or Ar 2 is a substituted aryl or heteroaryl, the aryl or heteroaryl is deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, at least one heteroatom containing substituted or unsubstituted C 2 -C 10 heteroalkyl with at least one substituent, C 2 -C 10 alkenyl substituted or unsubstituted with at least one substituent, C 2 -C 10 alky which is unsubstituted or substituted with at least one substituent Nyl, C 2 -C 10 alkoxy unsubstituted or substituted with at least one substituent, C 6 -C 24 aryloxy unsubstituted or substituted with at least one substituent, C 1 - C 10 haloalkyl, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, amide substituted or unsubstituted with at least one substituent, carbamate, sulfhydryl, nitro, carboxyl, carboxylic acid salt, C 6 -C 24 aryl optionally substituted with at least one substituent, C 5 -C 23 heteroaryl optionally substituted with at least one substituent, C 7 - unsubstituted or substituted with at least one substituent substituted with at least one selected from C 34 aralkyl, quaternary ammonium, phosphoric acid, phosphate salts, ketones, aldehydes, esters, acylchlorides, sulfonic acids, sulfonates, and -LX functional groups;
Y 1 and Y 2 are each independently selected from sulfur, oxygen, NR 3 and CR 3 R 4 ;
R 1 is selected from C 1 -C 10 alkyl substituted with sulfonic acid or sulfonate, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonate, polyalkylene oxide and -LX functional group;
R 2 is C 1 -C 10 alkyl unsubstituted or substituted with at least one substituent, C 2 -C 10 heteroalkyl unsubstituted or substituted with at least one substituent containing at least one heteroatom, halogen, cyano , selected from carboxyl, carboxylate and -LX functional groups,
R 3 is from C 1 -C 10 alkyl unsubstituted or substituted with at least one substituent, C 2 -C 10 heteroalkyl unsubstituted or substituted with at least one substituent containing at least one heteroatom, and -LX functional group. is selected,
R 4 is selected from C 1 -C 10 alkyl unsubstituted or substituted with at least one substituent, C 2 -C 10 heteroalkyl unsubstituted or substituted with at least one substituent containing at least one hetero atom, and -LX functional group. is selected,
In 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 -, R 6 is hydrogen, C 1 -C 6 alkyl substituted or unsubstituted with at least one substituent, substituted or unsubstituted with at least one substituent containing at least one heteroatom C 2 -C 10 heteroalkyl, C 2 -C 10 alkenyl optionally substituted with at least one substituent, C 2 -C 10 alkynyl optionally substituted with at least one substituent, substituted with at least one substituent or unsubstituted C 2 -C 6 alkoxy and C 1 -C 6 haloalkyl unsubstituted or substituted with at least one substituent, Ar is C 6 -C 24 aryl optionally substituted with at least one substituent And, p is an integer from 1 to 30,
X is carboxyl, succinimidyl ester, sulfo-succinimidyl ester, isothiocyanate, maleimide, haloacetamide, Hydrazide, vinylsulphone, dichlorotriazine, phosphoramidite, alkyl halide, acyl halide, carbohydrazide , hydroxy, hydroxylamine, ketone, alkyne, azide, amino, aliphatic amine, aromatic amine, sulfotetrafluorophenyl ester ester), sulfodichlorophenyl ester, carbonyl azide, sulfonyl chloride, sulfonyl fluoride, isocyanate, halogen-substituted triazine ( halogen-substituted triazine), tetrafluorophenyl ester, imido ester, azidonitrophenyl, glyoxal, and a reactive group selected from aldehydes,
T is carbon included in Ar 1 ,
T and nitrogen are bonded to each other to form a substituted or unsubstituted 5 to 7 membered ring (H) optionally containing at least one heteroatom,
When the ring (H) is a substituted ring, the ring (H) is a deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, or at least one substituent including at least one heteroatom. substituted or unsubstituted C 2 -C 10 heteroalkyl, C 2 -C 10 alkenyl substituted or unsubstituted with at least one substituent, C 2 -C 10 alkynyl substituted or unsubstituted with at least one substituent, at least C 2 -C 10 alkoxy optionally substituted with one substituent, C 6 -C 24 aryloxy optionally substituted with at least one substituent, C 1 -C 10 halo optionally substituted with one substituent alkyl, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, amide substituted or unsubstituted with at least one substituent, carbamate, sulfhydryl, nitro, carboxyl, carboxylate, at least C 6 -C 24 aryl unsubstituted or substituted with one substituent, C 5 -C 23 heteroaryl unsubstituted or substituted with at least one substituent containing at least one heteroatom, substituted or unsubstituted with at least one substituent substituted with at least one selected from cyclic C 7 -C 34 aralkyl, quaternary ammonium, phosphoric acid, phosphoric acid salt, ketone, aldehyde, ester, acyl chloride, sulfonic acid, sulfonic acid salt and -LX functional group;
n is 0 or an integer from 1 to 4;
When R 1 is C 1 -C 10 alkyl substituted with sulfonic acid or sulfonate, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonate, or polyalkylene oxide, the compound has at least one -LX functional group. Including,
The aryl is a single ring or an unsaturated aromatic ring including 2 to 4 rings connected to each other by conjugation or covalent bonds,
The heteroaryl is an unsaturated aromatic ring in which one or more carbon atoms in the aryl are substituted with a hetero atom,
The hetero atom is selected from non-carbon atoms including nitrogen (N), oxygen (O), sulfur (S), selenium (Se) and silicon (Si),
The substituents are selected from sulfonic acids, sulfonates, ketones, aldehydes, carboxylic acids, carboxylates, phosphoric acids, phosphates, acylchlorides, hydroxyl, polyalkylene oxides, quaternary ammonium salts, C 6 -C 24 aryls, esters and amides; , wherein 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 C6-C24 아릴 또는 적어도 하나의 헤테로 원자를 포함하는 치환 또는 비치환된 C5-C23 헤테로아릴이며, 이 때, Ar1 및 Ar2는 각각 독립적으로 벤젠, 피리딘, 나프탈렌, 페난트렌, 다이벤조퓨란, 다이벤조싸이오펜, 퀴놀린, 아세나프틸렌, 플루오란텐 및 플루오렌으로부터 선택되며,
Ar1 또는 Ar2가 치환된 아릴 또는 헤테로아릴인 경우, 상기 아릴 또는 헤테로아릴은 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 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 C7-C34 아르알킬, 4차 암모늄, 인산, 인산염, 케톤, 알데하이드, 에스터, 아실클로라이드, 설폰산, 설폰산염, 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환되며,
Y1 및 Y2는 각각 독립적으로 황, 산소, NR3 및 CR3R4 로부터 선택되며,
R1은 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬, 폴리알킬렌 옥사이드 및 -L-X 작용기로부터 선택되며,
R2는 하이드록시 또는 -L-X 작용기이며,
R3은 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬 및 -L-X 작용기로부터 선택되며,
R4는 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬 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≡-Ar- 및 -CO-Ar-NR6-으로부터 선택되는 링커이며, R6은 수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C6알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10알케닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 알키닐, 적어도 하나의 치환기로 치환 또는 비치환된 C2-C6 알콕시 및 적어도 하나의 치환기로 치환 또는 비치환된 C1-C6 할로알킬로부터 선택되며, Ar은 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴이며, p는 1 내지 30의 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), 하이드록시(hydroxy), 하이드록실아민(hydroxylamine), 케톤(ketone), 알카인(alkyne), 아자이드(azide), 아미노(amino), 지방족 아민, 방향족 아민, 설포테트라플루오로페닐 에스터(sulfotetrafluorophenyl ester), 설포다이클로로페닐 에스터(sulfodichlorophenyl ester), 카보닐 아자이드(carbonyl azide), 설포닐 클로라이드(sulfonyl chloride), 설포닐 플루오라이드(sulfonyl fluoride), 이소시아네이트(isocyanate), 할로겐-치환 트리아진(halogen-substituted triazine), 테트라플루오로페닐 에스터(tetrafluorophenyl ester), 이미도 에스터(imido ester), 아지도나이트로페닐(azidonitrophenyl), 글리옥살(glyoxal) 및 알데하이드로부터 선택되는 반응성기이며,
T는 Ar1에 포함된 탄소이며,
T와 질소는 서로 결합되어 적어도 하나의 헤테로 원자를 선택적으로 포함하는 치환 또는 비치환된 5 내지 7원자 고리(H)를 형성하며,
상기 고리(H)가 치환된 고리인 경우, 상기 고리(H)는 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 설프하이드릴, 나이트로, 카복실, 카복실산염, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C5-C23 헤테로아릴, 적어도 하나의 치환기로 치환 또는 비치환된 C7-C34 아르알킬, 4차 암모늄, 인산, 인산염, 케톤, 알데하이드, 에스터, 아실클로라이드, 설폰산, 설폰산염 및 -L-X 작용기로부터 선택되는 적어도 하나로 치환되며,
n은 1 내지 4의 정수이며,
인접한 두 R2는 서로 결합하여 적어도 하나의 헤테로 원자를 선택적으로 포함하는 4원자 내지 6원자 탄화수소 고리를 형성하며,
R1이 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬 또는 폴리알킬렌 옥사이드인 경우, 상기 화합물은 적어도 하나의 -L-X 작용기를 포함하며,
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), 황(S), 셀레늄(Se) 및 실리콘(Si)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.
A cyanine-based compound represented by Formula 1 below:
[Formula 1]
here,
Ar 1 and Ar 2 are each independently a substituted or unsubstituted C 6 -C 24 aryl or a substituted or unsubstituted C 5 -C 23 heteroaryl containing at least one hetero atom, wherein Ar 1 and Ar 2 is each independently selected from benzene, pyridine, naphthalene, phenanthrene, dibenzofuran, dibenzothiophene, quinoline, acenaphthylene, fluoranthene and fluorene;
When Ar 1 or Ar 2 is a substituted aryl or heteroaryl, the aryl or heteroaryl is deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, at least one heteroatom containing substituted or unsubstituted C 2 -C 10 heteroalkyl with at least one substituent, C 2 -C 10 alkenyl substituted or unsubstituted with at least one substituent, C 2 -C 10 alky which is unsubstituted or substituted with at least one substituent Nyl, C 2 -C 10 alkoxy unsubstituted or substituted with at least one substituent, C 6 -C 24 aryloxy unsubstituted or substituted with at least one substituent, C 1 - C 10 haloalkyl, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, amide substituted or unsubstituted with at least one substituent, carbamate, sulfhydryl, nitro, carboxyl, carboxylic acid salt, C 6 -C 24 aryl optionally substituted with at least one substituent, C 5 -C 23 heteroaryl optionally substituted with at least one substituent, C 7 - unsubstituted or substituted with at least one substituent substituted with at least one selected from C 34 aralkyl, quaternary ammonium, phosphoric acid, phosphate salts, ketones, aldehydes, esters, acylchlorides, sulfonic acids, sulfonates, and -LX functional groups;
Y 1 and Y 2 are each independently selected from sulfur, oxygen, NR 3 and CR 3 R 4 ;
R 1 is selected from C 1 -C 10 alkyl substituted with sulfonic acid or sulfonate, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonate, polyalkylene oxide and -LX functional group;
R 2 is a hydroxy or -LX functional group;
R 3 is from C 1 -C 10 alkyl unsubstituted or substituted with at least one substituent, C 2 -C 10 heteroalkyl unsubstituted or substituted with at least one substituent containing at least one heteroatom, and -LX functional group. is selected,
R 4 is selected from C 1 -C 10 alkyl unsubstituted or substituted with at least one substituent, C 2 -C 10 heteroalkyl unsubstituted or substituted with at least one substituent containing at least one hetero atom, and -LX functional group. is selected,
In 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≡-Ar- and -CO-Ar-NR 6 -, wherein R 6 is hydrogen, C 1 -C 6 alkyl optionally substituted with at least one substituent, C 2 - optionally substituted with at least one substituent containing at least one heteroatom C 10 heteroalkyl, C 2 -C 10 alkenyl optionally substituted with at least one substituent, C 2 -C 10 alkynyl optionally substituted with at least one substituent, unsubstituted or substituted with at least one substituent C 2 -C 6 alkoxy and C 1 -C 6 haloalkyl optionally substituted with at least one substituent, Ar is C 6 -C 24 aryl optionally substituted with at least one substituent, and p is an integer from 1 to 30,
X is carboxyl, succinimidyl ester, sulfo-succinimidyl ester, isothiocyanate, maleimide, haloacetamide, Hydrazide, vinylsulphone, dichlorotriazine, phosphoramidite, alkyl halide, acyl halide, carbohydrazide , hydroxy, hydroxylamine, ketone, alkyne, azide, amino, aliphatic amine, aromatic amine, sulfotetrafluorophenyl ester ester), sulfodichlorophenyl ester, carbonyl azide, sulfonyl chloride, sulfonyl fluoride, isocyanate, halogen-substituted triazine ( halogen-substituted triazine), tetrafluorophenyl ester, imido ester, azidonitrophenyl, glyoxal, and a reactive group selected from aldehydes,
T is carbon included in Ar 1 ,
T and nitrogen are bonded to each other to form a substituted or unsubstituted 5 to 7 membered ring (H) optionally containing at least one heteroatom,
When the ring (H) is a substituted ring, the ring (H) is a deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, or at least one substituent including at least one heteroatom. substituted or unsubstituted C 2 -C 10 heteroalkyl, C 2 -C 10 alkenyl substituted or unsubstituted with at least one substituent, C 2 -C 10 alkynyl substituted or unsubstituted with at least one substituent, at least C 2 -C 10 alkoxy optionally substituted with one substituent, C 6 -C 24 aryloxy optionally substituted with at least one substituent, C 1 -C 10 halo optionally substituted with one substituent Alkyl, halogen, cyano, hydroxy, amino substituted or unsubstituted with at least one substituent, amide substituted or unsubstituted with at least one substituent, carbamate, sulfhydryl, nitro, carboxyl, carboxylate, at least C 6 -C 24 aryl unsubstituted or substituted with one substituent, C 5 -C 23 heteroaryl unsubstituted or substituted with at least one substituent containing at least one heteroatom, substituted or unsubstituted with at least one substituent substituted with at least one selected from cyclic C 7 -C 34 aralkyl, quaternary ammonium, phosphoric acid, phosphoric acid salt, ketone, aldehyde, ester, acyl chloride, sulfonic acid, sulfonic acid salt and -LX functional group;
n is an integer from 1 to 4;
two adjacent R 2 are bonded to each other to form a 4- to 6-membered hydrocarbon ring optionally containing at least one heteroatom;
When R 1 is C 1 -C 10 alkyl substituted with sulfonic acid or sulfonate, C 2 -C 10 heteroalkyl substituted with sulfonic acid or sulfonate, or polyalkylene oxide, the compound has at least one -LX functional group. Including,
The aryl is a single ring or an unsaturated aromatic ring including 2 to 4 rings connected to each other by bonding or covalent bonds,
The heteroaryl is an unsaturated aromatic ring in which one or more carbon atoms in the aryl are substituted with a hetero atom,
The hetero atom is selected from non-carbon atoms including nitrogen (N), oxygen (O), sulfur (S), selenium (Se) and silicon (Si),
The substituents are selected from sulfonic acids, sulfonates, ketones, aldehydes, carboxylic acids, carboxylic acid salts, phosphoric acid, phosphoric acid salts, acyl chlorides, hydroxyl, polyalkylene oxides, quaternary ammonium salts, C 6 -C 24 aryls, esters and amides; , wherein the polyalkylene oxide is terminated with methyl ether and contains ethylene glycol as a repeating unit.
상기 고리(H)에 치환된 작용기 및 상기 작용기와 인접한 임의의 작용기가 서로 결합하여 방향족성 고리를 형성하거나,
상기 고리(H)에 치환된 인접한 두 작용기가 서로 결합하여 방향족성 고리를 형성하는,
시아닌계 화합물.
According to claim 1 or 2,
The functional group substituted on the ring (H) and any functional group adjacent to the functional group bond to each other to form an aromatic ring,
Two adjacent functional groups substituted on the ring (H) bond to each other to form an aromatic ring,
Cyanine-based compounds.
인접한 두 R2가 서로 결합하여 형성된 고리는 중수소, 적어도 하나의 치환기로 치환 또는 비치환된 C1-C10 알킬, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C2-C10 헤테로알킬, 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, 카바메이트, 설프하이드릴, 나이트로, 카복실, 카복실산염, 적어도 하나의 치환기로 치환 또는 비치환된 C6-C24 아릴, 적어도 하나의 헤테로 원자를 포함하는 적어도 하나의 치환기로 치환 또는 비치환된 C5-C23 헤테로아릴, 적어도 하나의 치환기로 치환 또는 비치환된 C7-C34 아르알킬, 4차 암모늄, 인산, 인산염, 케톤, 알데하이드, 에스터, 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 claim 2,
A ring formed by combining two adjacent R 2 groups is deuterium, C 1 -C 10 alkyl substituted or unsubstituted with at least one substituent, or C 2 unsubstituted or substituted with at least one substituent containing at least one heteroatom. -C 10 heteroalkyl, C 2 -C 10 alkenyl substituted or unsubstituted with at least one substituent, C 2 -C 10 alkynyl substituted or unsubstituted with at least one substituent, substituted or unsubstituted with at least one substituent cyclic C 2 -C 10 alkoxy, C 6 -C 24 aryloxy unsubstituted or substituted with at least one substituent, C 1 -C 10 haloalkyl unsubstituted or substituted 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, carbamate, sulfhydryl, nitro, carboxyl, carboxylate, substituted or unsubstituted with at least one substituent cyclic C 6 -C 24 aryl, C 5 -C 23 heteroaryl optionally substituted with at least one substituent containing at least one heteroatom, C 7 -C 34 optionally substituted with at least one substituent substituted with at least one selected from aralkyl, quaternary ammonium, phosphoric acid, phosphate salt, ketone, aldehyde, ester, acylchloride, sulfonic acid, sulfonate and -LX functional groups;
The substituents are selected from sulfonic acids, sulfonates, ketones, aldehydes, carboxylic acids, carboxylic acid salts, phosphoric acid, phosphoric acid salts, acyl chlorides, hydroxyl, polyalkylene oxides, quaternary ammonium salts, C 6 -C 24 aryls, esters and amides; , wherein the polyalkylene oxide is terminated with methyl ether and contains ethylene glycol as a repeating unit.
Cyanine-based compounds.
R1이 설폰산 또는 설폰산염으로 치환된 C1-C10 알킬, 설폰산 또는 설폰산염으로 치환된 C2-C10 헤테로알킬 또는 폴리알킬렌 옥사이드인 경우, R2, R3 또는 R4가 -L-X 작용기이거나, Ar1 및 Ar2 중 적어도 하나는 -L-X 작용기로 치환된,
시아닌계 화합물.
According to claim 1 or 2,
When R 1 is a sulfonic acid or a C 1 -C 10 alkyl substituted with a sulfonate, a C 2 -C 10 heteroalkyl substituted with a sulfonic acid or sulfonate, or a polyalkylene oxide, then R 2 , R 3 or R 4 is -LX functional group, or at least one of Ar 1 and Ar 2 is substituted with -LX functional group,
Cyanine-based compounds.
A dye for labeling biomolecules comprising 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 claim 6,
The biomolecule is at least one selected from antibodies, lipids, proteins, peptides, carbohydrates and nucleic acids,
Dyes for labeling biomolecules.
A kit for labeling biomolecules comprising the dye for labeling biomolecules according to claim 6.
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