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FLUORESCENT COMPOUND RESPONDING TO MITOCHONDRIAL MEMBRANE POTENTIAL

外国特許コード F190009864
整理番号 (S2018-0102-N0)
掲載日 2019年7月26日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2018JP041417
国際公開番号 WO 2019093400
国際出願日 平成30年11月8日(2018.11.8)
国際公開日 令和元年5月16日(2019.5.16)
優先権データ
  • 特願2017-216664 (2017.11.9) JP
発明の名称 (英語) FLUORESCENT COMPOUND RESPONDING TO MITOCHONDRIAL MEMBRANE POTENTIAL
発明の概要(英語) The present invention addresses the problem of providing a compound that is a pigment capable of staining cells, is water-soluble, shows a high light emission efficiency, translocates from mitochondria to nucleus depending on mitochondrial membrane potential and exhibits light emission in the red color region. The compound according to the present invention is expressed by formula (1) [in formula (1): X is represented by formula (2) (in formula (2), R1 represents a C1-C10 alkyl group, and Z- represents a counter anion to a pyridinium cation); k and m are an integer of 0-3 and l and n are an integer of 0-2, provided that k, l, m and n do not simultaneously represent 0; X's may be the same or different; R2 represents an electron-donating group or an electron-withdrawing group; a and c are an integer of 0-3 and b and d are an integer of 0-2; R2's may be either the same or different and attached to a carbon atom which is not substituted by X; and the wavy line represents a geometric isomer E or Z].
従来技術、競合技術の概要(英語) BACKGROUND ART
Mitochondria, while producing energy for the cell involved in the control of apoptosis, cell viability of the cells involved in a small organ. In addition, due to the fault in mitochondrial function, diabetes, stroke, myocardial infarction such as metabolic diseases, neurodegenerative diseases such as Alzheimer's or Parkinson's disease, cancer and the onset of a pointed out. Therefore, these diseases and elucidate the mechanism, also for the development of the method, to observe the change of the mitochondria is important.
Mitochondrial membrane potential is generated along with the energy production, the potential difference between the inside and outside of the mitochondria means, the vitality of the mitochondrial itself (active). That is, when the membrane potential energy are produced, mitochondrial vigor is in a high state. On the other hand, when the membrane potential is lost, not to produce energy, vitality is at a low state. Also, the mitochondrial membrane potential, the state of health of the cells, when the membrane potential of a normal cell, membrane potential and when there is no abnormal cells.
Changes in mitochondrial membrane potential, and the health of the cells due to varying in order to distinguish, on the membrane potential to change the light emission behavior in accordance with the stained mitochondria by the dye, the light emission behavior of a method to observe a change. Mitochondrial membrane potential dye related art in response to, the three types of 2. Is one, the light emission intensity in accordance with the mitochondrial membrane potential change of the dye type, the other one is, to change the emission color of the dye. However, a change in the emission intensity of the dye, and a change in emission intensity caused by mitochondrial membrane potential, a change in emission intensity by photo-bleaching of the dye itself occurs at the same time, change of the fluorescence intensity caused by changes in the membrane potential, due to photo-bleaching of the dye makes it difficult to distinguish, in the membrane potential is not necessarily suitable for the detection of the change.
In addition, the emission color of the other changes in the dye type, due to the change in membrane potential dye in order to observe the color of the emitted light, the fluorescent excitation light source and the detector is also reduced depending on the emission color are to be provided and the system 2, and the excitation light source and the real-time fluorescence detector may need to be adjusted, and the cost of the device, experimental operations becomes extremely complicated. Further, one type of dye can be, from the low solubility of the staining, cells that are harmful to the organic solvent is also a problem that must be used.
The inventors of the present invention, in accordance with the mitochondrial membrane potential, nuclear mitochondrial localization is shifted to the location of the following compounds have the nature of the BP has been found, can be used for the staining of cells and has already been reported (Non-Patent Document 1).
In accordance with the mitochondrial membrane potential, localized in the nucleus compound BP from mitochondria where the properties of the transfer, since it is not a change in fluorescence intensity, its own BP of the photo-bleaching compound without being affected by the changes in the membrane potential to be detected. In addition, since there is no change in the fluorescence color, fluorescence excitation light source and a special device is not required, generally the film by the fluorescent microscope to allow detection of a change of potential. In addition, the water-soluble compound BP is high, the cell without using a harmful organic solvent and is capable of staining of the cells. Therefore, the organic solvent which does not cause cell death, living cells over more than 24 time and can be observed.
However, in the BP compound, the absorption (excitation) by the number of photons absorbed by the compound and the number of photons emitted by fluorescence quantum yield (φ) is a ratio as low as 0.14, may be the luminescence efficiency is not, high sensitivity to detect the fluorescent light emitting efficiency of the compound may have been required.
Therefore, the inventors of the present invention, high quantum yields of light emission efficiency may be further proposed a compound (Patent Document 1 and 2). However, Patent Document 1 and this compound was proposed in 2, light emission of blue or green light and is generated in a region, red region emitting compound was not obtained. A red region of the biological light emission of a high permeability and therefore can be easily identified, has a response to the mitochondrial membrane potential, and the transmission of the biological compounds for emitting light in the red color has been demanded.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • YAMAGUCHI UNIVERSITY
  • KOCHI UNIVERSITY
  • 発明者(英語)
  • KAWAMATA, Jun
  • SUZUKI, Yasutaka
  • ASAMURA, Naoya
  • NIKO, Yosuke
  • SEKI, Hitomi
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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