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WO2015064939A1 - Procédé de synthèse de banque de nouvelles sondes fluorescentes à échafaudage dansylique et procédé d'imagerie de cellules vivantes à l'aide de cette dernière - Google Patents

Procédé de synthèse de banque de nouvelles sondes fluorescentes à échafaudage dansylique et procédé d'imagerie de cellules vivantes à l'aide de cette dernière Download PDF

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Publication number
WO2015064939A1
WO2015064939A1 PCT/KR2014/009806 KR2014009806W WO2015064939A1 WO 2015064939 A1 WO2015064939 A1 WO 2015064939A1 KR 2014009806 W KR2014009806 W KR 2014009806W WO 2015064939 A1 WO2015064939 A1 WO 2015064939A1
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Prior art keywords
substituted
unsubstituted
compound
formula
dansyl
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PCT/KR2014/009806
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English (en)
Inventor
Jun Seok Lee
Chang No Yoon
Won Young Kim
Jin Kak Lee
Won Seok Han
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Korea Institute of Science and Technology KIST
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Korea Institute of Science and Technology KIST
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Publication of WO2015064939A1 publication Critical patent/WO2015064939A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/40—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms

Definitions

  • One or more aspects of the present invention relate to a method of synthesizing a noble compound by using a dansyl compound and a method of imaging cells by using the synthesized compound.
  • a fluorescent compound is used in an assay method for measuring the activity of biological enzymes of various types.
  • a method of producing signals for measuring the activity of the biological enzymes may include a method of measuring a difference of the color or intensity of a substrate of the enzyme with fluorescence, or a fluorescence resonance energy transfer (FRET) method using ambient another fluorescent material.
  • FRET fluorescence resonance energy transfer
  • a fluorescence scaffold for producing fluorescent signals is not much off from conventionally known structures.
  • a compound producing signals through an interaction with a specific bioactive material as a fluorescent compound is known as a chemosensor, or as a fluorescent probe in terms of detecting a biomaterial. Since early 2000, the development of a fluorescent probe using a structure of a fluorescent compound has accelerated, and in the early stage of development, for example, an approaching method of connecting the fluorescent compound and a metal chelator by direct covalent bond may be used (J. Am. Chem. Soc., 2005, 127, 10124-0125). However, the method is limited to a type of molecules that may be a target.
  • a suggested method is an approaching method using combination chemicals which was named diversity-oriented fluorescence library approach (DOFLA) by the NYU research team.
  • DOFLA diversity-oriented fluorescence library approach
  • the team developed a sensor compound that synthesizes a library of fluorescent compounds and recognizes a specific biomolecule depending on a structure variety (Mol. BioSyst. 5, 411-421 (2009), J Am Chem Soc 131, 10077-10082 (2009), and Angew Chem Int Edit 43, 6331-6335 (2004)).
  • libraries related to structures of coumarin, dapoxyl, styryl, rosamine, hemicyanine bodipy etc. have been developed, and a compound that interacts with specific protein or lipid therefrom has been developed.
  • the present invention provides a dansyl derivative compound.
  • the present invention also provides a composition for imaging cells by using a dansyl derivative.
  • the present invention also provides a method of imaging cells by using a dansyl derivative.
  • the present invention also provides a method of synthesizing a dansyl derivative compound.
  • a compound represented by Formula 1, or its hydrate or its solvate are provided.
  • R is one selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 30 alkyl, substituted or unsubstituted C 1 -C 30 alkenyl, substituted or unsubstituted C 1 -C 30 alkynyl, substituted or unsubstituted C 1 -C 30 cycloalkyl, substituted or unsubstituted C 5 -C 30 aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkenyl, substituted or unsubstituted arylalkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalky
  • halogen such as flourine, chlorine
  • alkyl may refer to a linear or branched aliphatic hydrocarbon group having any number of carbon atoms.
  • alkyl group include, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and heptyl.
  • halogen may refer to one selected from the group consisting of flourine, chlorine, bromine, and iodine, but not limited thereto.
  • alkoxy may refer to one selected from, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and t-butoxy.
  • alkenyl may refer to one selected from the group consisting of ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2-butenyl, but not limited thereto.
  • alkynyl may refer to one selected from the group consisting of ethynyl, propynyl, and butynyl, but not limited thereto.
  • cycloalkyl may refer to one selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, perhydronaphthyl, adamantyl, cross-linked cyclic groups, and spirobicyclic groups, but not limited thereto.
  • heterocycloalkyl or heteroaryl may refer to one selected from the group consisting of azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzopuranyl, carbazolyl, cinnolinyl, dioxolanyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, pyrrolyl, piperonyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, decahydro
  • aryl may refer to one selected from the group consisting of phenyl, naphthyl, anthracenyl, indanyl, and biphenyl, but not limited thereto.
  • hydroxy alkyl may refer to hydroxymethyl or hydroxyethyl, but not limited thereto.
  • amide may refer to one selected from the group consisting of substituted or unsubstituted C 1 -C 30 alkylamide, substituted or unsubstituted C 1 -C 30 benzylamide, substituted or unsubstituted C 1 -C 30 halobenzylamide, substituted or unsubstituted C 1 -C 30 phenylamide, or substituted or unsubstituted C 1 -C 30 phenylalkylamide, wherein at least one hydrogen atom of the phenyl may be independently and selectively substituted with at least one of alkyl, cycloalkyl, alkoxy, cyano, halogen, alkylsulfonyl, alkylthio, -CO 2 -alkyl, -COOH, -CONH 2 , -CHO, -CH 2 OH, hydroxyl, haloalkyl, amino, and nitro, but not limited thereto.
  • heterocyclylalkyl may refer to one selected from the group consisting of, oxadiazole, oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, and morphonyl, but not limited thereto.
  • heteroarylalkenyl may refer to one selected from the group consisting of pyridinylethenyl, thienylethenyl, and triazolylethenyl, but not limited thereto.
  • heteroarylalkynyl may refer to pyridinylethynyl or thienylethynyl, but not limited thereto.
  • R may be one selected from the group consisting of hydrogen, substituted or unsubstituted carboxylic acid methylester, substituted or unsubstituted carboxylic acid, substituted or unsubstituted hydroxy methyl, substituted or unsubstituted amino, substituted or unsubstituted N,N-dimethylamide, substituted or unsubstituted methylamide, substituted or unsubstituted benzylamide, chloro, substituted or unsubstituted 4-chlorobenzylamide, substituted or unsubstituted phenylamide, substituted or unsubstituted phenyl penethylamide, fluoride, substituted or unsubstituted benzylcarbamoyl, substituted or unsubstituted isopropylamide, substituted or unsubstituted 3-methylbutoxy, substituted or unsubstituted methoxy, substituted or unsubstituted 5-methyl-[1,
  • An example of Formula 1 may be one selected from Formula 2 to Formula 4. Also, a compound represented by one selected from Formula 2 to Formula 4 may exist as a hydrate or a solvate thereof:
  • a composition for imaging a cell wherein the composition includes the compound.
  • the cell may be a live cell.
  • the cell may be an eukaryotic cell or prokaryotic cell.
  • the cells may be a single cell, multicellular cells, or a tissue cell separated from tissue.
  • a composition for imaging cells refers to a material that allows the composition to be attached on a surface of a cell by having the cell as a target object or to penetrate into the cell, and make the cell be visibly recognizable.
  • the cell may be visibly recognizable by fluorescence.
  • the composition for imaging cells may penetrate into a cell. Particularly, the composition may be located in cytoplasm.
  • the compound may absorb light at a certain wavelength and may emit the absorbed light back. The cell may be imaged by detecting a wavelength of the emitted light.
  • a method of imaging cells includes contacting a cell with the compound. Also, the method may further include irradiating light for fluorescent excitation and detecting fluorescence emitted by the light.
  • the method may include contacting a cell with the compound.
  • the compound may be a compound having a structure of Formula 1.
  • the compound may be a compound represented by one selected from Formula 2 to Formula 4.
  • a concentration of the compound may be in a range of 0.1 ⁇ M to 1,000 ⁇ M, for example, 1 ⁇ M to 500 ⁇ M, or 1 ⁇ M to 100 ⁇ M.
  • the method may further include irradiating light for fluorescence excitation.
  • a wavelength of the light irradiated on the compound for fluorescence excitation may be in a range of 300 nm to 500 nm, for example, 315 nm to 400 nm, or 330 nm to 350 nm.
  • a wavelength of the light may be in a range of 338 nm to 341 nm.
  • the light may be any light emitted from a light source for fluorescence excitation.
  • the light source may be a laser light source.
  • the method may further include detecting emitted fluorescence.
  • a wavelength of the emitted fluorescence may be in a range of 500 nm to 560 nm, for example, 510 nm to 555 nm, or 520 nm to 550 nm.
  • a wavelength of the emitted fluorescence may be in a range of 531 nm to 546 nm.
  • a method of preparing a dansyl derivative includes heatinga dansyl-halogen and a primary amine in the presence of tetrahydrofuran to produce the dansyl derivative.
  • the preparing process may be performed in the same manner shown in Reaction scheme 1.
  • the dansyl derivative may be a compound represented by Formula 1.
  • the dansyl derivative may be a compound represented by one of Formula 2 to Formula 4.
  • dansyl derivatives may be synthesized in the same manner shown in Reaction scheme 1.
  • a fluorescence compound library including dansyl derivatives of various structures may be synthesized.
  • R is as defined in the present specification.
  • the halogen may be chlorine.
  • a fluorescent dansyl compound may be prepared by using a substitution reaction of a dansyl chloride and a primary amine.
  • the substitution may be performed by heating. That is, when 5-(dimethylamino)naphthalene-1-sulfonyl chloride compound represented by a dansyl-chloride and a primary amine are dissolved in THF and heated, a product of Formula 1 may be prepared. Also, the product may be purified by column chromatography.
  • Developing a cell imaging technique is an on-going process, but various fluorescence materials still need to be developed.
  • various types of dansyl derivatives may be used as a novel fluorescent composition for imaging cells, and thus it enabled variation of types of fluorescent materials.
  • the molecules enable imaging of live cells and thus have a high possibility in being used for various researches and industrial purposes.
  • a preparation method capable of parallel synthesizing a derivative of 5-(dimethylamino)naphthalene-1-sulfonamide , which is a dansyl derivative that is produced by a preparation process of Reaction scheme 1 from 5-(dimethylamino)naphthalene-1-sulfonyl chloride, i.e., a compound represented by Formula 1; and a real-time molecule imaging method using the compound.
  • the synthesis method and the molecule imaging method may be applied to development of molecule imaging and assaying methods of a novel fluorescent compound.
  • FIG. 1 illustrates a dye of FITC channel of Formula 4 (Dansyl-3 dye);
  • FIG. 2 illustrates a dye of DAPI channel of Formula 4 (Hoechst dye);
  • FIG. 3 illustrates a dye of FITC channel of Formula 3 (Dansyl-2 dye);
  • FIG. 4 illustrates a dye of DAPI channel of Formula 3 (Hoechst dye).
  • FIG. 5 illustrates a dye of FITC channel of Formula 2 (Dansyl-1 dye).
  • FIG. 6 illustrates a dye of DAPI channel of Formula 2 (Hoechst dye)
  • a real-time fluorescent dye method of live cells uses HEK293 cells and cultures the cells on a culture dish in an 5% CO 2 incubator by following a protocol provided from ATCC.
  • HEK293 cells used Dulbecco's Modified Eagle Medium (DMEM) and 10% Fetal Bovine Serum (FBS), 1X Pen/Strep as a culture media.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • 1X Pen/Strep 1X Pen/Strep
  • Live cells contained in each of the cell culturing media were treated with 100 ⁇ M (DMSO 1%) Dansyl compound and 1x Hoechst and incubated in a 37°C incubator for 15 minutes.
  • a filter capable of detecting DAPI dye and a filter capable of detecting FITC dye from a fluorescence microscope were used to obtain a fluorescent image.
  • the dansyl compound is transmitted through living cells, and thus fluorescent imaging was made possible (see FIG. 1 to FIG. 6)

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  • Biophysics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur une nouvelle utilisation d'un dérivé dansylique et, en particulier, sur un dérivé dansylique qui peut être efficacement utilisé en imagerie de cellules vivantes. Un procédé de préparation selon la présente invention et divers types de dérivés dansyliques préparés à l'aide du procédé peuvent être efficacement utilisés en imagerie de cellules puisque les dérivés dansyliques sont situés dans des cellules lorsque les dérivés dansyliques sont en contact avec les cellules. Ainsi, les dérivés dansyliques permettent l'imagerie de cellules vivantes et donc peuvent être utilisés dans diverses études et divers domaines industriels.
PCT/KR2014/009806 2013-10-31 2014-10-17 Procédé de synthèse de banque de nouvelles sondes fluorescentes à échafaudage dansylique et procédé d'imagerie de cellules vivantes à l'aide de cette dernière Ceased WO2015064939A1 (fr)

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KR1020130131502A KR101752473B1 (ko) 2013-10-31 2013-10-31 신규 단실 형광 화합물 라이브러리의 합성 방법과 이를 이용한 살아있는 세포 이미징 방법
KR10-2013-0131502 2013-10-31

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Publication number Priority date Publication date Assignee Title
KR101953313B1 (ko) * 2017-07-25 2019-03-04 한국과학기술연구원 프로게스테론 검출용 형광 프로브
WO2021096263A1 (fr) * 2019-11-12 2021-05-20 이화여자대학교 산학협력단 Composition d'imagerie cellulaire et méthode d'imagerie de matière cellulaire utilisant cette dernière

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378500A (en) * 1981-03-10 1983-03-29 Varian Associates, Inc. Fluorescence enhancement of dansyl derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4378500A (en) * 1981-03-10 1983-03-29 Varian Associates, Inc. Fluorescence enhancement of dansyl derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY CHEMICAL ABSTRACTS SERVICE; 12 April 2009 (2009-04-12), accession no. 136429-73-6 *
DATABASE REGISTRY CHEMICAL ABSTRACTS SERVICE; 18 May 2008 (2008-05-18), accession no. 023170-23-1 *
HOENES, G. ET AL.: "Dynamic total fluorescence and anisotropy decay study of the dansyl fluorophor in model compounds and enzymens", PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 43, no. 2, 1986, pages 133 - 137 *

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