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WO2013039307A2 - High efficiency fluorescent compound and method for preparing the same - Google Patents

High efficiency fluorescent compound and method for preparing the same Download PDF

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Publication number
WO2013039307A2
WO2013039307A2 PCT/KR2012/007133 KR2012007133W WO2013039307A2 WO 2013039307 A2 WO2013039307 A2 WO 2013039307A2 KR 2012007133 W KR2012007133 W KR 2012007133W WO 2013039307 A2 WO2013039307 A2 WO 2013039307A2
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group
heteroatom
formula
alkoxy
alkyl
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WO2013039307A3 (en
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Seong Keun Kim
Seung Bum Park
Il Seung Yang
Eun Ha Kim
Jun Hee Kang
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SNU R&DB Foundation
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SNU R&DB Foundation
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Priority claimed from KR1020120083374A external-priority patent/KR101294993B1/en
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Priority to US14/344,585 priority Critical patent/US10787607B2/en
Publication of WO2013039307A2 publication Critical patent/WO2013039307A2/en
Publication of WO2013039307A3 publication Critical patent/WO2013039307A3/en
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K85/00—Organic materials used in the body or electrodes of devices covered by this subclass
    • H10K85/60—Organic compounds having low molecular weight
    • H10K85/615—Polycyclic condensed aromatic hydrocarbons, e.g. anthracene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1003—Carbocyclic compounds
    • C09K2211/1011—Condensed systems
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K50/00—Organic light-emitting devices
    • H10K50/10—OLEDs or polymer light-emitting diodes [PLED]
    • H10K50/11—OLEDs or polymer light-emitting diodes [PLED] characterised by the electroluminescent [EL] layers

Definitions

  • the present invention relates to a new fluorescent compound having high efficiency, a method for preparing the same, and its use.
  • Luminescence means the emission of light having a wavelength which correspond to the energy difference when a substance is converted to a stable state having low energy from an unstable state having high energy.
  • Various sources of energy such as light, chemical reactions, heat, electricity, cathode-emitted electron or the like may be used. Said difference sources of energy produce different types of light emission such as photo-, chemi-, thermo-, electro-, cathodo-luminecence, or the like.
  • Luminescence can be classified as fluorescence and phosphorescence. Fluorescence refers to the phenomenon that a substance emits light only when the substance is irradiated, and phosphorescence refers to the phenomenon that a substance continuously emits a light even after the irradiation to the substance is ended.
  • a substance emitting fluorescence is referred to as a fluorescent element or a fluorescent substance.
  • Such fluorescent substance can be divided into a single-photon absorption fluorescent substance which absorbs only one photon under a strong laser to emit the fluorescence and a multi-photon absorption fluorescent substance which absorbs a plurality of photons to emit the fluorescence.
  • the present invention relates to a new fluorescent compound simultaneously having a single-photon absorption fluorescent feature as well as a multi-photon absorption fluorescent feature, in particular, 2-photon absorption fluorescent feature.
  • the present invention was completed by finding a new fluorescent compound of ( E )-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one (hereinafter, referred to as resveratrone ) having a high single-photon absorptive efficiency and/or 2-photon absorptive efficiency after a photochemical reaction of a conventionally known resveratrol which is frequently found in peanuts, grapes, berries and the like.
  • resveratrone a new fluorescent compound of ( E )-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one
  • the purpose of the present invention is to provide a new fluorescent compound with high efficiency having single-photon absorptive characteristics and/or two-photon absorptive characteristics.
  • the purpose of the present invention is to provide a method of preparing the above fluorescent compound.
  • the purpose of the present invention is to provide the use of the fluorescent compound having single-photon absorptive characteristics and/or two-photon absorptive characteristics.
  • the present invention provides resveratrone [(E)-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one] and its derivatives as a new fluorescent compound and a method for preparing the same by a photochemical reaction of resveratrol and its derivatives which are not fluorescent.
  • R is naphthyl group ( ), anthracenyl group ( ) or phenalenyl group ( ),
  • naphthyl, anthracenyl or phenalenyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C 1 -C 10 alkyl; C 3 -C 6 cycloalkyl; straight-chain or branched C 1 -C 6 alkoxy; C 2 -C 6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 1 -C 10 alkoxy group, C 3 -C 6 cyclaoalkyl group, C 2 -C 6 heterocycloalkyl group comprising N, O or S as heteroatom, C 6 -C 16 aryl group, and C
  • each of R 1 is independently hydrogen atom; halogen, straight-chain or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, straight-chain or branched C 1 -C 6 alkoxy; C 2 -C 6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 1 -C 10 alkoxy group, C 3 -C 6 cyclaoalkyl group, C 2 -C 6 heterocycloalkyl group comprising N, O or S as heteroatom, C 6 -C 16 aryl group, and C 5 -C 15 heteroaryl group comprising N, O and/or S as heteroatom;
  • R 4 is substituted or unsubstituted phenyl group ( ) or substituted or unsubstituted naphthyl group ( ),
  • said phenyl or naphthyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C 1 -C 10 alkyl; C 3 -C 6 cycloalkyl; straight-chain or branched C 1 -C 6 alkoxy; C 2 -C 6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 1 -C 10 alkoxy group, C 3 -C 6 cyclaoalkyl group, C 2 -C 6 heterocycloalkyl group comprising N, O or S as heteroatom, C 6 -C 16 aryl group, and C 5 -C 15 heteroaryl
  • a display element comprising the organic fluorescent compound of (3).
  • the new fluorescent compound of the present invention has single-photon absorptive characteristics and/or two-photon absorptive characteristics as well as no or little toxicity according to a cytotoxicity test.
  • Fig. 1 is a graph showing emission spectra of the reactant compounds and the fluorescent compound finally produced of the present invention (wherein the highly fluorescent species is denoted by X).
  • Fig. 2 is a graph showing a single-photon emission spectrum (left) and a two-photon emission spectrum (right) of the fluorescent compound of the present invention.
  • Fig. 3 is graph showing a change of single-photon emission spectra of the fluorescent compound finally of the present invention.
  • Fig. 4 is a photograph showing two-photon emission of the fluorescent compound of the present invention.
  • Fig. 5 is a HPLC graph for the reaction products obtained after different durations of exposure to UV irradiation (wherein the highly fluorescent species is denoted by X).
  • Fig. 6 is a graph showing the comparison of the intensity versus wavelength of the fluorescent compounds which have been produced in the presence of ascorbic acid and in the absence of ascorbic acid, respectively.
  • Fig. 7 is a graph showing the comparison of the intensity versus wavelength of the fluorescent compounds which have been produced under N 2 atmosphere (N 2 purging) and not, respectively.
  • Fig. 8 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 10 of the present invention.
  • Fig. 9 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 11 of the present invention.
  • Fig. 10 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 12 of the present invention.
  • Fig. 11 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 13 of the present invention.
  • Fig. 12 is the photo images showing the result of Cytomorphology Test for a blank test (Control), a fluorescent compound of the present invention (Resveratrone) and a comparative compound(a commercial anticancer agent, Etoposide ).
  • Fig. 13 is a graph showing the result of Blue Exclusion Test for a blank test (Control), a fluorescent compound of the present invention (Resveratrone) and a comparative compound ( Etoposide ).
  • Fig. 14 is a graph showing the result of Western Blotting Test for a blank test (Control), a fluorescent compound of the present invention (Resveratrone) and a comparative compound ( Etoposide ).
  • the present invention provides a new fluorescent compound represented by the following formula 1:
  • R is naphthyl group ( ), anthracenyl group ( ) or phenalenyl group ( ),
  • naphthyl, anthracenyl or phenalenyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C 1 -C 10 alkyl; C 3 -C 6 cycloalkyl; straight-chain or branched C 1 -C 6 alkoxy; C 2 -C 6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 1 -C 10 alkoxy group, C 3 -C 6 cyclaoalkyl group, C 2 -C 6 heterocycloalkyl group comprising N, O or S as heteroatom, C 6 -C 16 aryl group, and C
  • each of R 1 is independently hydrogen atom; halogen, straight-chain or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, straight-chain or branched C 1 -C 6 alkoxy; C 2 -C 6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 1 -C 10 alkoxy group, C 3 -C 6 cyclaoalkyl group, C 2 -C 6 heterocycloalkyl group comprising N, O or S as heteroatom, C 6 -C 16 aryl group, and C 5 -C 15 heteroaryl group comprising N, O and/or S as heteroatom; preferably, selected from the group consisting of hydrogen
  • the present invention provides a fluorescent compound represented by any one of the following formulae 2 ⁇ 6:
  • R 2 and R 3 are each independently selected from a group consisting of hydrogen atom; hydroxy; halogen; straight-chain or branched C 1 -C 10 alkyl; C 3 -C 6 cycloalkyl; straight-chain or branched C 1 -C 6 alkoxy; C 2 -C 6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 1 -C 10 alkoxy group, C 3 -C 6 cyclaoalkyl group, C 2 -C 6 heterocycloalkyl group comprising N, O or S as heteroatom, C 6 -C 16 aryl group, and C 5 -C 15 heteroaryl group comprising N, O and/or S as heteroatom
  • the present invention provides a method of preparing a fluorescent compound represented by formula 1 above.
  • a fluorescent compound represented by formula 1 above is prepared via a method comprises a step of dissolving a compound represented by the following Formula 7, a compound represented by the following Formula 8 or a mixture thereof in water, an organic solvent or mixture thereof and a step of subjecting to a UV irradiation:
  • R 4 is substituted or unsubstituted phenyl group ( ) or substituted or unsubstituted naphthyl group ( ),
  • said phenyl or naphthyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C 1 -C 10 alkyl; C 3 -C 6 cycloalkyl; straight-chain or branched C 1 -C 6 alkoxy; C 2 -C 6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 1 -C 10 alkoxy group, C 3 -C 6 cyclaoalkyl group, C 2 -C 6 heterocycloalkyl group comprising N, O or S as heteroatom, C 6 -C 16 aryl group, and C 5 -C 15 heteroaryl
  • organic solvent which can be used in the present invention
  • protic solvents such as ethanol, methanol, n-propanol, iso-propanol, n-butanol, DMSO (dimethyl sulfoxide), EA (ethyl ester), THF (tetrahydrofuran) and the like, which can be used alone or as a mixture thereof.
  • Ethanol, methanol, n-propanol, iso-propanol, n-butanol or DMSO are preferable, and DMSO is most preferable.
  • the reaction mixture can additionally include an antioxidant such as, for example, ascorbic acid, polyphenols, glutathione, N-acetylcystein, -tocopherol, butylated hydroxyanisole (BHA), catechin, quercetin, uric acid, bilirubin, glucose, flavonoid or the like, which can be added alone or as mixture thereof, after dissolving a compound represented by Formula 7, a compound represented by Formula 8 or a mixture thereof in water or an organic solvent, and before subjecting to an UV irradiation.
  • an antioxidant such as, for example, ascorbic acid, polyphenols, glutathione, N-acetylcystein, -tocopherol, butylated hydroxyanisole (BHA), catechin, quercetin, uric acid, bilirubin, glucose, flavonoid or the like, which can be added alone or as mixture thereof, after dissolving a compound represented by Formula 7, a compound represented by Formula 8 or a mixture thereof
  • the reaction in order to improve the yield of the product, the reaction can be conducted under N 2 atmosphere (N 2 purging).
  • the reaction temperature at the photochemical reaction can be selected from -10 ⁇ 100 °C, particularly 0 and 60 °C, preferably between 10 and 40 °C, and more preferably between 20 and 30 °C.
  • the wavelength of UV ray to be irradiated can be selected from 100 ⁇ 500 nm, preferably 200 ⁇ 400 nm, and more preferably 250 ⁇ 450 nm.
  • the irradiation time can be selected from 5 second ⁇ 50 minutes, particularly 6 second ⁇ 40 minutes, preferably 8 seconds ⁇ 30 minutes, and more preferably 10 seconds ⁇ 20 minutes.
  • the reaction temperature, UV wavelength and irradiation time is not strictly limited to the above ranges and can be easily modified according to the purpose.
  • the fluorescent compound of the present invention prepared by the above method has high efficiency single-photon absorptive characteristics and/or two-photon absorptive characteristics ( see Figs. 2 ⁇ 4).
  • the fluorescent compound of the present invention can be utilized in an organic fluorescent element including a fluorescent compound as well as in a display element including an organic fluorescent elements.
  • the display element can be a plasma display panel, a cathode-ray tube (CRT), a lamp, or the like.
  • the fluorescent compound according to the present invention does not have toxicity to a cell which can be verified by a cytotoxicity test ( see Figs. 12 ⁇ 14 and Test Examples 1 ⁇ 3). Thus, it can be used as an organic fluorescent element directed to a specific target in cells.
  • the fluorescent compound according to the present invention can be usefully utilized in the field of a spectrometer, a two-photon absorptive storing device, a laser micro processing apparatus, a photo dynamic therapy apparatus or the like.
  • HRMS high-resolution mass spectrometry
  • LTQ orbitrab high-resolution mass spectrometry
  • HRMS analysis is conducted using a High-Resolution Liquid Chromatography/Tandem Mass Analysis equipment located at the National Instrumentation Center for Environmental Management of Seoul National University.
  • UV absorption of the final fluorescent compound is determined by using a UV-VISIBLE spectrophotometer (Perkin Elmer, USA). Maximum values of excitation and emission are determined by using a fluorescent spectrophotometer (PTI, USA).
  • the absolute quantum yield is determined by using an absolute PL quantum yield measurement system (QE-1000, Otsuka Electronics, Japan).
  • the relative quantum yield is determined by measuring the absorbance and emission intensity for each five concentrations for one solvent, determining the slope of said measured values, and comparing the slope with that of rhodamin 6G (the quantum yield of rhodamin 6G in ethanol is 0.95).
  • trans -Resveratrol and trans -pterostilbene are commercially available (from sigma-Aldlich and TCI, respectively). Other solvents and organic samples are purchased in the market and used without any additional purification unless there is any other description. Distilled water is completed by ion exchange and filtration.
  • the fluorescent compound is obtained from trans -resveratrol in the same manner as Example 1. Quantum yields of each organic solvent are shown in Table 1.
  • the fluorescent compound is obtained from trans -resveratrol in the same manner as Example 1.
  • the emission spectra of the obtained compound is shown in Fig. 3, wherein the time of 0 min, 2 min and 4 min means the UV irradiation, thus the spectrum at 0 min is for the reactant ( trans -pterostilbene).
  • the final compound prepared from a non-fluorescent compound of trans -pterostilbene is a fluorescent compound.
  • the fluorescent compound is obtained from trans -resveratrol in the same manner as Example 1.
  • Fig. 6 shows each graph of intensity versus wavelength of the final product obtained with adding ascorbic acid and the final product obtained without adding ascorbic acid. As can be seen in Fig. 6, it can be understood that the intensity of the final product obtained with adding ascorbic acid is higher than that obtained without adding ascorbic acid.
  • the fluorescent compound is obtained from trans -resveratrol in the same manner as Example 1.
  • Fig. 7 shows each graph of intensity versus wavelength of the final product obtained with conducting under N 2 atmosphere and the final product obtained without conducting under N 2 atmosphere. As can be seen in Fig. 7, it can be understood that the intensity of the final product obtained with conducting under N 2 atmosphere is higher than that obtained without conducting under N 2 atmosphere.
  • a cell line is cultured for a certain period of time (about 72 hours) and then a cytotoxicity test is conducted.
  • a cytotoxicity test is conducted as a control group.
  • a blank test is conducted in the same manner as above without adding any compound including the test compound and the comparative compound.
  • a test compound Resveratrone, the fluorescent compound obtained in Example 1
  • a comparative compound Etoposide , a commercial anticancer agent
  • Fig. 12 shows each microscopic photo image of the resulting breast epithelial cells after cultured in a blank test (control group, left) and in the presence of the test fluorescent compound ( Resveratrone, center) or the comparative compound ( Etoposide , right), respectively.
  • the comparative compound ( Etoposide ) results to a remarkable reduction in the number of cells in comparison with the control group, while the test compound ( Resveratrone ) has no significant difference from the control group.
  • test compound ( Resveratrone ) of the present invention has no or little cell toxicity and very high stability in comparison with the commercial anticancer agent ( Etoposide ).
  • Fig. 13 is a graph showing the result of Blue Exclusion Test for the control group (blank), the test compound (resveratrone) and the comparative compound (etoposide), respectively.
  • the test compound (left side) results to a number of cells similar to that of the control group in both test concentrations (1 ⁇ M and 10 ⁇ M), while the comparative compound (right side) results to a remarkably reduced number of cells in both test concentrations (1 ⁇ M and 10 ⁇ M).
  • test compound ( Resveratrone ) of the present invention has no or little cell toxicity and a very high stability in comparison with the commercial anticancer agent ( Etoposide ).
  • a breast epithelial cell line is cultured in a blank test (control group) and in the presence of a test compound ( Resveratrone ), respectively, and an osteosarcoma cell line (U2OS) is cultured in the presence of a comparative compound ( Etoposide ).
  • the degree of cell extinction is evaluated by examining the degree of expression of extinction and damage of a specific factor by using Western Blotting Test and the result is shown in Fig. 14.
  • the blank test left side, Control group , concentration of 0 ⁇ M
  • the test compound center side, Resveratrone , three concentrations of 1, 10 and 100 ⁇ M
  • the comparative compound (right side, Etoposide , concentration of 10 ⁇ M) shows a significantly remarkable peak at 17kDa, 19kDa and 89kDa positions which result from cell extinction and damage, by which it can be understood that a lot of cells are extinguished and/or damaged.
  • test compound ( Resveratrone ) of the present invention has no or little cell toxicity.
  • the new fluorescent compound of the present invention can be usefully utilized in the field of organic fluorescent element, display element, spectrometer, two-photon absorptive storing device, laser micro processing apparatus, photo dynamic therapy apparatus and the like.

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Abstract

The present invention provides a fluorescent resveratrone [(E)-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one] and its derivatives having Formula 1 and a method for preparing the same by a photochemical reaction of resveratrol and its derivatives which are not fluorescent having Formula 7 or Formula 8. The new fluorescent compounds of the present invention has single-photon absorptive characteristics and/or two-photon absorptive characteristics as well as no or little toxicity according to a cytotoxicity test and can be usefully utilized in the field of organic fluorescent element, display element, spectrometer, two-photon absorptive storing device, laser micro processing apparatus, photo dynamic therapy apparatus and the like.

Description

HIGH EFFICIENCY FLUORESCENT COMPOUND AND METHOD FOR PREPARING THE SAME
The present invention relates to a new fluorescent compound having high efficiency, a method for preparing the same, and its use.
There are cases where light is emitted from a substance at a low temperature at which the substance can not emit any visible ray by thermal radiation. Such lighting phenomenon is referred to as luminescence. Luminescence means the emission of light having a wavelength which correspond to the energy difference when a substance is converted to a stable state having low energy from an unstable state having high energy. Thus, in order to make a substance emit such light, it is necessary to make the substance to an unstable excited state having high energy. Various sources of energy such as light, chemical reactions, heat, electricity, cathode-emitted electron or the like may be used. Said difference sources of energy produce different types of light emission such as photo-, chemi-, thermo-, electro-, cathodo-luminecence, or the like.
Luminescence can be classified as fluorescence and phosphorescence. Fluorescence refers to the phenomenon that a substance emits light only when the substance is irradiated, and phosphorescence refers to the phenomenon that a substance continuously emits a light even after the irradiation to the substance is ended.
In this regard, a substance emitting fluorescence is referred to as a fluorescent element or a fluorescent substance. Such fluorescent substance can be divided into a single-photon absorption fluorescent substance which absorbs only one photon under a strong laser to emit the fluorescence and a multi-photon absorption fluorescent substance which absorbs a plurality of photons to emit the fluorescence. The present invention relates to a new fluorescent compound simultaneously having a single-photon absorption fluorescent feature as well as a multi-photon absorption fluorescent feature, in particular, 2-photon absorption fluorescent feature.
In more particular, the present invention was completed by finding a new fluorescent compound of (E)-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one (hereinafter, referred to as resveratrone ) having a high single-photon absorptive efficiency and/or 2-photon absorptive efficiency after a photochemical reaction of a conventionally known resveratrol which is frequently found in peanuts, grapes, berries and the like.
The purpose of the present invention is to provide a new fluorescent compound with high efficiency having single-photon absorptive characteristics and/or two-photon absorptive characteristics.
Also, the purpose of the present invention is to provide a method of preparing the above fluorescent compound.
In addition, the purpose of the present invention is to provide the use of the fluorescent compound having single-photon absorptive characteristics and/or two-photon absorptive characteristics.
In order to achieve the above purposes, the present invention provides resveratrone [(E)-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one] and its derivatives as a new fluorescent compound and a method for preparing the same by a photochemical reaction of resveratrol and its derivatives which are not fluorescent.
(1) A fluorescent compound represented by the following formula 1:
[Formula 1]
Figure PCTKR2012007133-appb-I000001
[wherein, R is naphthyl group (
Figure PCTKR2012007133-appb-I000002
), anthracenyl group (
Figure PCTKR2012007133-appb-I000003
) or phenalenyl group (
Figure PCTKR2012007133-appb-I000004
),
wherein said naphthyl, anthracenyl or phenalenyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy;
each of R1 is independently hydrogen atom; halogen, straight-chain or branched C1-C6 alkyl, C3-C6 cycloalkyl, straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom;
n is 0, 1, 2 or 3 (wherein, n=0 means that the carbon ring is open)].
(2) A method of preparing a fluorescent compound represented by the following Formula 1, characterized in that it comprises a step of dissolving a compound represented by Formula 7, a compound represented by Formula 8 or a mixture thereof in water or an organic solvent, and a step of subjecting to an UV irradiation:
[Formula 1]
Figure PCTKR2012007133-appb-I000005
;
[Formula 7]
Figure PCTKR2012007133-appb-I000006
;
[Formula 8]
Figure PCTKR2012007133-appb-I000007
[wherein, R1 and n are the same as defined in above (1),
R4 is substituted or unsubstituted phenyl group (
Figure PCTKR2012007133-appb-I000008
) or substituted or unsubstituted naphthyl group (
Figure PCTKR2012007133-appb-I000009
),
wherein, said phenyl or naphthyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy].
(3) An organic fluorescent element comprising the fluorescent compound of (1).
(4) A display element comprising the organic fluorescent compound of (3).
(5) A spectrometer, a two-photon absorptive storing device, a laser micro processing apparatus, or a photo dynamic therapy apparatus, comprising the organic fluorescent element of (3).
The new fluorescent compound of the present invention has single-photon absorptive characteristics and/or two-photon absorptive characteristics as well as no or little toxicity according to a cytotoxicity test.
Fig. 1 is a graph showing emission spectra of the reactant compounds and the fluorescent compound finally produced of the present invention (wherein the highly fluorescent species is denoted by X).
Fig. 2 is a graph showing a single-photon emission spectrum (left) and a two-photon emission spectrum (right) of the fluorescent compound of the present invention.
Fig. 3 is graph showing a change of single-photon emission spectra of the fluorescent compound finally of the present invention.
Fig. 4 is a photograph showing two-photon emission of the fluorescent compound of the present invention.
Fig. 5 is a HPLC graph for the reaction products obtained after different durations of exposure to UV irradiation (wherein the highly fluorescent species is denoted by X).
Fig. 6 is a graph showing the comparison of the intensity versus wavelength of the fluorescent compounds which have been produced in the presence of ascorbic acid and in the absence of ascorbic acid, respectively.
Fig. 7 is a graph showing the comparison of the intensity versus wavelength of the fluorescent compounds which have been produced under N2 atmosphere (N2 purging) and not, respectively.
Fig. 8 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 10 of the present invention.
Fig. 9 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 11 of the present invention.
Fig. 10 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 12 of the present invention.
Fig. 11 is a graph showing an excitation spectrum of the reactant compound and an emission spectrum of the fluorescent compound finally produced in Example 13 of the present invention.
Fig. 12 is the photo images showing the result of Cytomorphology Test for a blank test (Control), a fluorescent compound of the present invention (Resveratrone) and a comparative compound(a commercial anticancer agent, Etoposide).
Fig. 13 is a graph showing the result of Blue Exclusion Test for a blank test (Control), a fluorescent compound of the present invention (Resveratrone) and a comparative compound (Etoposide).
Fig. 14 is a graph showing the result of Western Blotting Test for a blank test (Control), a fluorescent compound of the present invention (Resveratrone) and a comparative compound (Etoposide).
Hereinafter, the present invention will be explained in more detail in the term of construction and effect.
The present invention provides a new fluorescent compound represented by the following formula 1:
[Formula 1]
Figure PCTKR2012007133-appb-I000010
[Wherein, R is naphthyl group (
Figure PCTKR2012007133-appb-I000011
), anthracenyl group (
Figure PCTKR2012007133-appb-I000012
) or phenalenyl group (
Figure PCTKR2012007133-appb-I000013
),
wherein said naphthyl, anthracenyl or phenalenyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy; preferably, independently substituted with hydroxyl, halogen, straight-chain or branched C1-C10 alkyl, C3-C6 cycloalkyl, straight-chain or branched C1-C6 alkoxy or C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; more preferably, independently substituted with hydroxyl, halogen or straight-chain or branched C1-C10 alkyl;
each of R1 is independently hydrogen atom; halogen, straight-chain or branched C1-C6 alkyl, C3-C6 cycloalkyl, straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; preferably, selected from the group consisting of hydrogen atom, hydroxyl, halogen, straight-chain or branched C1-C10 alkyl, C3-C6 cycloalkyl, straight-chain or branched C1-C6 alkoxy or C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; more preferably, selected from the group consisting of hydrogen atom, hydroxyl, halogen or straight-chain or branched C1-C10 alkyl;
n is 0, 1, 2 or 3, preferably 0 or 1, more preferably 0 (wherein, n=0 means that the carbon ring is open)].
Also, the present invention provides a fluorescent compound represented by any one of the following formulae 2~6:
[Formula 2]
Figure PCTKR2012007133-appb-I000014
[Formula 3]
Figure PCTKR2012007133-appb-I000015
[Formula 4]
Figure PCTKR2012007133-appb-I000016
[Formula 5]
Figure PCTKR2012007133-appb-I000017
[Formula 6]
Figure PCTKR2012007133-appb-I000018
[wherein, R, R1 and n are the same as defined in the above, and
R2 and R3 are each independently selected from a group consisting of hydrogen atom; hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy; preferably, independently selected from the group consisting of hydrogen atom, hydroxyl, halogen, straight-chain or branched C1-C10 alkyl, C3-C6 cycloalkyl, straight-chain or branched C1-C6 alkoxy or C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; more preferably, independently selected from the group consisting of hydrogen atom, hydroxyl, halogen or straight-chain or branched C1-C10 alkyl.]
Also, the present invention provides a method of preparing a fluorescent compound represented by formula 1 above.
In particular, a fluorescent compound represented by formula 1 above is prepared via a method comprises a step of dissolving a compound represented by the following Formula 7, a compound represented by the following Formula 8 or a mixture thereof in water, an organic solvent or mixture thereof and a step of subjecting to a UV irradiation:
[Formula 7]
Figure PCTKR2012007133-appb-I000019
;
[Formula 8]
Figure PCTKR2012007133-appb-I000020
[wherein, R1 and n are the same as defined as above,
R4 is substituted or unsubstituted phenyl group (
Figure PCTKR2012007133-appb-I000021
) or substituted or unsubstituted naphthyl group (
Figure PCTKR2012007133-appb-I000022
),
wherein, said phenyl or naphthyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy; preferably, independently substituted with hydroxyl, halogen, straight-chain or branched C1-C10 alkyl, C3-C6 cycloalkyl, straight-chain or branched C1-C6 alkoxy or C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; more preferably, independently substituted with hydroxyl, halogen or straight-chain or branched C1-C10 alkyl.]
A method of preparing (E)-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one (resveratrone) corresponding to the above Formula 1 by photochemical reaction of trans- and/or cis-resveratrol corresponding to the above Formula 7 can be exemplified by the following reaction formula 1.
[Reaction Formula 1]
Figure PCTKR2012007133-appb-I000023
Also, the above Reaction formula 1 can be schematized as follows:
[Reaction Formula 2]
Figure PCTKR2012007133-appb-I000024
As to the organic solvent which can be used in the present invention, it is possible to mention protic solvents such as ethanol, methanol, n-propanol, iso-propanol, n-butanol, DMSO (dimethyl sulfoxide), EA (ethyl ester), THF (tetrahydrofuran) and the like, which can be used alone or as a mixture thereof. Ethanol, methanol, n-propanol, iso-propanol, n-butanol or DMSO are preferable, and DMSO is most preferable.
According to a preferred embodiment of the present invention, in order to improve the yield of the product, the reaction mixture can additionally include an antioxidant such as, for example, ascorbic acid, polyphenols, glutathione, N-acetylcystein, -tocopherol, butylated hydroxyanisole (BHA), catechin, quercetin, uric acid, bilirubin, glucose, flavonoid or the like, which can be added alone or as mixture thereof, after dissolving a compound represented by Formula 7, a compound represented by Formula 8 or a mixture thereof in water or an organic solvent, and before subjecting to an UV irradiation. Among them, ascorbic acid or polyphenol is preferable.
According to a preferred embodiment of the present invention, in order to improve the yield of the product, the reaction can be conducted under N2 atmosphere (N2 purging).
The reaction temperature at the photochemical reaction can be selected from -10~100 ℃, particularly 0 and 60 ℃, preferably between 10 and 40 ℃, and more preferably between 20 and 30 ℃. The wavelength of UV ray to be irradiated can be selected from 100~500 nm, preferably 200~400 nm, and more preferably 250~450 nm. The irradiation time can be selected from 5 second ~ 50 minutes, particularly 6 second ~ 40 minutes, preferably 8 seconds ~ 30 minutes, and more preferably 10 seconds ~ 20 minutes. In addition, the reaction temperature, UV wavelength and irradiation time is not strictly limited to the above ranges and can be easily modified according to the purpose.
The fluorescent compound of the present invention prepared by the above method has high efficiency single-photon absorptive characteristics and/or two-photon absorptive characteristics (see Figs. 2~4). Thus, the fluorescent compound of the present invention can be utilized in an organic fluorescent element including a fluorescent compound as well as in a display element including an organic fluorescent elements. The display element can be a plasma display panel, a cathode-ray tube (CRT), a lamp, or the like.
Further, the fluorescent compound according to the present invention does not have toxicity to a cell which can be verified by a cytotoxicity test (see Figs. 12~14 and Test Examples 1~3). Thus, it can be used as an organic fluorescent element directed to a specific target in cells.
In addition, the fluorescent compound according to the present invention can be usefully utilized in the field of a spectrometer, a two-photon absorptive storing device, a laser micro processing apparatus, a photo dynamic therapy apparatus or the like.
Hereinafter, the present invention is explained in more detail with reference to the examples. However, the following examples are merely to exemplify the present invention and the present invention is not limited to the following examples and various corrections and modifications can be made.
Examples
In general
1H NMR and 13C NMR spectra are recorded on Bruker Avance 600 (Bruker Biospin, Germany) and Varian Inova-500 (Varian Assoc.,Palo Alto, USA), wherein data are reported in the following order: chemical shift (δ) in ppm; multiplicities are indicated bs (broadened singlet), s (singlet), d (doublet), m (multiplet), dd (doublet of doubled); coupling constants (J) are in Hertz (Hz).
Identification of the desired fluorescent compound is confirmed by high-resolution mass spectrometry (HRMS; LTQ orbitrab). HRMS analysis is conducted using a High-Resolution Liquid Chromatography/Tandem Mass Analysis equipment located at the National Instrumentation Center for Environmental Management of Seoul National University.
UV absorption of the final fluorescent compound is determined by using a UV-VISIBLE spectrophotometer (Perkin Elmer, USA). Maximum values of excitation and emission are determined by using a fluorescent spectrophotometer (PTI, USA).
The absolute quantum yield is determined by using an absolute PL quantum yield measurement system (QE-1000, Otsuka Electronics, Japan). The relative quantum yield is determined by measuring the absorbance and emission intensity for each five concentrations for one solvent, determining the slope of said measured values, and comparing the slope with that of rhodamin 6G (the quantum yield of rhodamin 6G in ethanol is 0.95).
trans-Resveratrol and trans-pterostilbene are commercially available (from sigma-Aldlich and TCI, respectively). Other solvents and organic samples are purchased in the market and used without any additional purification unless there is any other description. Distilled water is completed by ion exchange and filtration.
Preparation of the fluorescent compound of the present invention
Example 1: Preparation of (E)-4-(6,8-dihydroxynaphthalen-2-yl)but-3-en-2-one
A solution of trans-resveratrone (R5010, sigma-Aldlich; 125μM) in 300 mL of methanol is subjected to a UV irradiation at 295 K for 90 seconds by using a UV lamp (λmax = 305nm) of 6-watt to give the titled compound of the following Formula 6.
[Formula 6]
Figure PCTKR2012007133-appb-I000025
1H NMR (600 MHz, MeOD) δ: 8.21 (s, 1H), 7.69 (d, J = 16.2 Hz, 1H), 7.56 (dd, J = 8.7, 1.1 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 16.2 Hz, 1H), 6.63 (d, J = 1.7 Hz, 1H), 6.50 (d, J = 1.9 Hz, 1H), 2.35 (s, 3H); 13C NMR (125 MHz, MeOD) 201.6, 159.1, 156.9, 147.1 138.6, 128.9, 127.8, 127.1, 125.5, 125.1, 121.2, 102.1, 27.1; HRMS (ESI): m/z calcd for C14H11O3 [M]- 227.0714, found 227.0742.
Examples 2~6
Except for conducting the photochemical reaction in the presence of an organic solvent such as ethanol (Example 2), n-propanol (Example 3), iso-propanol (Example 4), n-butanol (Example 5) or DMSO (Example 6), respectively, the fluorescent compound is obtained from trans-resveratrol in the same manner as Example 1. Quantum yields of each organic solvent are shown in Table 1.
Table 1
Solvent Excitation(nm) Emission(nm) Relative quantum yield Absolute quantum yield
Example 1 Methanol 390 547 0.035 0.058
Example 2 Ethanol 390 540 0.103 0.145
Example 3 n-Propanol 390 534 0.155 0.212
Example 4 iso-Propanol 390 525 0.247 0.311
Example 5 n-Butanol 390 536 0.200 0.254
Example 6 DMSO 390 497 0.523 0.439
Example 7
Except for using trans-pterostilbene as the reactant compound, the fluorescent compound is obtained from trans-resveratrol in the same manner as Example 1.
The emission spectra of the obtained compound is shown in Fig. 3, wherein the time of 0 min, 2 min and 4 min means the UV irradiation, thus the spectrum at 0 min is for the reactant (trans-pterostilbene). As can be seen in Fig. 3, it can be confirmed that the final compound prepared from a non-fluorescent compound of trans-pterostilbene is a fluorescent compound.
Example 8
Except for additionally adding ascorbic acid (50 μM, 40 μL) to a solution (125 μM) of trans-resveratrone (R5010, sigma-Aldlich; 8.559mg) in 300 mL of methanol before subjecting to an UV irradiation, the fluorescent compound is obtained from trans-resveratrol in the same manner as Example 1.
Fig. 6 shows each graph of intensity versus wavelength of the final product obtained with adding ascorbic acid and the final product obtained without adding ascorbic acid. As can be seen in Fig. 6, it can be understood that the intensity of the final product obtained with adding ascorbic acid is higher than that obtained without adding ascorbic acid.
Example 9
Except for conducting the photochemical reaction under N2 atmosphere or with N2 purging), the fluorescent compound is obtained from trans-resveratrol in the same manner as Example 1.
Fig. 7 shows each graph of intensity versus wavelength of the final product obtained with conducting under N2 atmosphere and the final product obtained without conducting under N2 atmosphere. As can be seen in Fig. 7, it can be understood that the intensity of the final product obtained with conducting under N2 atmosphere is higher than that obtained without conducting under N2 atmosphere.
Example 10: Preparation of ( Z )-4-(6,8-dihydroxynaphthalen-2-yl)-4-hydroxybut-3-en-2-one
A solution of oxyresveratrol (9.159 mg) [O0373, SejinCI Company; 2,3',4,5'-Tetrahydroxy-trans-stilbene] in 300 mL of methanol is subjected to a UV irradiation at 295 K for 2 minutes by using a UV lamp (λmax = 305nm) of 6-watt to give the titled compound represented by following Formula 9. The excitation spectrum of the reactant compound and the emission spectrum of the final fluorescent compound are shown in Fig. 8.
[Formula 9]
Figure PCTKR2012007133-appb-I000026
Example 11: Preparation of ( E )-4-(5,7-dimethoxynaphthalen-3-yl)but-3-en-2-one
A solution of pterostilbene (9.611 mg) [P1928, SejinCI Company; trans-1-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)ethylene] in 300 mL of methanol is subjected to a UV irradiation at 295 K for 5 minutes 30 seconds by using a UV lamp (λmax = 305nm) of 6-watt to give the titled compound represented by following Formula 10. The excitation spectrum of the reactant compound and the emission spectrum of the final fluorescent compound are shown in Fig. 9.
[Formula 10]
Figure PCTKR2012007133-appb-I000027
Example 12: Preparation of ( E )-4-(6,8-dihydroxynaphthalen-2-yl)methoxybut-3-en-2-one
A solution of isorhapontigenin (9.685 mg) [I0804, SejinCI Company; 3,4',5-Trihydroxy-3'-methoxy-trans-stilbene] in 300 mL of methanol is subjected to a UV irradiation at 295 K for 7 minutes by using a UV lamp (λmax = 305nm) of 6-watt to give the titled compound represented by following Formula 11. The excitation spectrum of the reactant compound and the emission spectrum of the final fluorescent compound are shown in Fig. 10.
[Formula 11]
Figure PCTKR2012007133-appb-I000028
Example 13: Preparation of (E)-4-(8-hydroxy-6-methoxynaphthalen-2-yl)but-3-en-2-one
A solution of pinostilbene hydrate (9.085mg) (SML0098, sigma-Aldlich; 3,4'-Dihydroxy-5-methoxy-trans-stilbene) in 300 mL of methanol is subjected to a UV irradiation at 295 K for 4 minutes 30 seconds by using a UV lamp (λmax = 305nm) of 6-watt to give the titled compound represented by following Formula 12. The excitation spectrum of the reactant compound and the emission spectrum of the final fluorescent compound are shown in Fig. 11.
[Formula 12]
Figure PCTKR2012007133-appb-I000029
Test Example: Cytotoxicity test
In the presence of a test compound or a comparative compound, a cell line is cultured for a certain period of time (about 72 hours) and then a cytotoxicity test is conducted. As a control group, a blank test is conducted in the same manner as above without adding any compound including the test compound and the comparative compound.
Test Example 1: Cytomorphology test
A breast epithelial cell line cultured in the presence of a test compound (Resveratrone, the fluorescent compound obtained in Example 1) and a comparative compound (Etoposide, a commercial anticancer agent), respectively, and a microscopic examination is conducted to evaluate the cytomorphology and number change of the cultured cell.
Fig. 12 shows each microscopic photo image of the resulting breast epithelial cells after cultured in a blank test (control group, left) and in the presence of the test fluorescent compound (Resveratrone, center) or the comparative compound (Etoposide, right), respectively. In Fig. 12, it can be confirmed that the comparative compound (Etoposide) results to a remarkable reduction in the number of cells in comparison with the control group, while the test compound (Resveratrone) has no significant difference from the control group.
Therefore, it can be understood from Fig. 12 that the test compound (Resveratrone) of the present invention has no or little cell toxicity and very high stability in comparison with the commercial anticancer agent (Etoposide).
Test Example 2: Trypan Blue Exclusion Test
To the each resulting breast epithelial cell cultured and microscopically examined in Test Example 1, a trypan blue test solution which does not dye cells alive is added and the number of cells alive is counted to evaluate the cell toxicity of the test compound and the comparative compound by comparing with the control group.
Fig. 13 is a graph showing the result of Blue Exclusion Test for the control group (blank), the test compound (resveratrone) and the comparative compound (etoposide), respectively. In Fig. 13, the test compound (left side) results to a number of cells similar to that of the control group in both test concentrations (1μM and 10 μM), while the comparative compound (right side) results to a remarkably reduced number of cells in both test concentrations (1μM and 10 μM).
Therefore, it can be understood from Fig. 13 that the test compound (Resveratrone) of the present invention has no or little cell toxicity and a very high stability in comparison with the commercial anticancer agent (Etoposide).
Test Example 3. Western Blotting Test
A breast epithelial cell line is cultured in a blank test (control group) and in the presence of a test compound (Resveratrone), respectively, and an osteosarcoma cell line (U2OS) is cultured in the presence of a comparative compound (Etoposide).
After a certain period of time, the degree of cell extinction is evaluated by examining the degree of expression of extinction and damage of a specific factor by using Western Blotting Test and the result is shown in Fig. 14.
In Fig. 14, the blank test (left side, Control group, concentration of 0 μM) and the test compound (center side, Resveratrone, three concentrations of 1, 10 and 100 μM) show only a peak at 45kDa position and no peak at 17kDa, 19kDa and 89kDa positions which result from cell extinction and damage. Therefore, it can be understood that the test compound does not give any significant level of cell extinction and damage.
Further, the comparative compound (right side, Etoposide, concentration of 10μM) shows a significantly remarkable peak at 17kDa, 19kDa and 89kDa positions which result from cell extinction and damage, by which it can be understood that a lot of cells are extinguished and/or damaged.
As a result, it can be understood from Fig. 14 that the test compound ( Resveratrone ) of the present invention has no or little cell toxicity.
The terms used in Fig. 14 have the following meanings:
- Caspase-3: one of proteins found when cells die
- PARP: one of proteins found when cells die
- Actin: a procedure for confirming whether the current Western Blotting System is normally operating (control group)
- Osteosarcoma cells (U2OS): one of cancer cell lines
- Etoposide: one of commercial anticancer agents
In the result using osteosarcoma cells (U2OS) in the presence of a comparative compound (etoposide), the expression of the above specific proteins means that the Western Blotting System is normally operating.
The new fluorescent compound of the present invention can be usefully utilized in the field of organic fluorescent element, display element, spectrometer, two-photon absorptive storing device, laser micro processing apparatus, photo dynamic therapy apparatus and the like.

Claims (12)

1. A fluorescent compound represented by the following formula 1:
[Formula 1]
Figure PCTKR2012007133-appb-I000030
[Wherein R is naphthyl group (
Figure PCTKR2012007133-appb-I000031
), anthracenyl group (
Figure PCTKR2012007133-appb-I000032
) or phenalenyl group (
Figure PCTKR2012007133-appb-I000033
),
wherein said naphthyl, anthracenyl or phenalenyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy;
each of R1 is independently hydrogen atom; halogen, straight-chain or branched C1-C6 alkyl, C3-C6 cycloalkyl, straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom;
n is 0, 1, 2 or 3 (wherein, n=0 means that the carbon ring is open)].
The fluorescent compound according to claim 1, wherein n is 0 and the compound is represented by the following formula 2:
[Formula 2]
Figure PCTKR2012007133-appb-I000034
[wherein, R and R1 are the same as defined in claim 1].
The fluorescent compound according to claim 1, wherein R is substituted or unsubstituted naphthalene and the compound is represented by the following formula 3:
[Formula 3]
Figure PCTKR2012007133-appb-I000035
[wherein, R1 and n are the same as defined in claim 1, and
R2 and R3 are each independently selected from a group consisting of hydrogen atom; hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy].
The fluorescent compound according to claim 3, wherein n is 0 and the compound is represented by the following formula 4:
[Formula 4]
Figure PCTKR2012007133-appb-I000036
[wherein, R1, R2 and R3 are the same as defined in claim 3.]
The fluorescent compound according to claim 4, wherein the compound is represented by the following formula 5:
[Formula 5]
Figure PCTKR2012007133-appb-I000037
[wherein, R1, R2 and R3 are the same as defined in claim 3.]
The fluorescent compound according to claim 5, wherein the compound is represented by the following formula 6:
[Formula 6]
Figure PCTKR2012007133-appb-I000038
.
A method of preparing a fluorescent compound represented by the following Formula 1, characterized in that it comprises a step of dissolving a compound represented by Formula 7, a compound represented by Formula 8 or a mixture thereof in water or an organic solvent, and a step of subjecting to an UV irradiation:
[Formula 1]
Figure PCTKR2012007133-appb-I000039
;
[Formula 7]
Figure PCTKR2012007133-appb-I000040
;
[Formula 8]
Figure PCTKR2012007133-appb-I000041
[wherein, R1 and n are the same as defined in claim 1, and
R4 is substituted or unsubstituted phenyl group (
Figure PCTKR2012007133-appb-I000042
) or substituted or unsubstituted naphthyl group (
Figure PCTKR2012007133-appb-I000043
),
wherein, said phenyl or naphthyl group can be each independently substituted with at least one substituent selected from the group consisting of hydroxy; halogen; straight-chain or branched C1-C10 alkyl; C3-C6 cycloalkyl; straight-chain or branched C1-C6 alkoxy; C2-C6 heterocycloalkyl comprising N, O and/or S as heteroatom; phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O or S as heteroatom, C6-C16 aryl group, and C5-C15 heteroaryl group comprising N, O and/or S as heteroatom; benzyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atom, amino group, nitrile group, nitro group, C1-C10 alkyl group, C2-C10 alkenyl group, C1-C10 alkoxy group, C3-C6 cyclaoalkyl group, C2-C6 heterocycloalkyl group comprising N, O and/or S as heteroatom, C6-C30 aryl group and C5-C30 heteroaryl group comprising N, O and/or S as heteroatom; benzoyl; C1-C10 alkylamino; di(C1-C10 alkyl)amino; and C1-C10 alkoxy].
The method according to claim 7, characterized in that it comprises additionally adding ascorbic acid, polyphenol or a mixture thereof after dissolving a compound represented by Formula 7, a compound represented by Formula 8 or a mixture thereof in water or an organic solvent, and before subjecting to an UV irradiation.
The method according to claim 7, characterized in that it is conducted under N2 atmosphere or N2 purging.
An organic fluorescent element comprising fluorescent compounds according to any one claim among claims 1 to 6.
A display element comprising organic fluorescent elements according to claim 10.
A spectrometer, a two-photon absorptive storing device, a laser micro processing apparatus, or a photo dynamic therapy apparatus, comprising organic fluorescent elements according to claim 10.
PCT/KR2012/007133 2011-09-16 2012-09-05 High efficiency fluorescent compound and method for preparing the same Ceased WO2013039307A2 (en)

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