WO2020044213A1 - Composés à base de diphénylamino-méthylène malononitrile en tant que sondes de fluorescence - Google Patents

Composés à base de diphénylamino-méthylène malononitrile en tant que sondes de fluorescence Download PDF

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WO2020044213A1
WO2020044213A1 PCT/IB2019/057180 IB2019057180W WO2020044213A1 WO 2020044213 A1 WO2020044213 A1 WO 2020044213A1 IB 2019057180 W IB2019057180 W IB 2019057180W WO 2020044213 A1 WO2020044213 A1 WO 2020044213A1
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compound
formula
ring
heteroaryl
aryl
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PCT/IB2019/057180
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Balamurugan RENGARAJAN
Tamilarasan DURAIYARASU
Bramanandam MANAVATHI
Lokesh Reddy
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University Of Hyderabad
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages

Definitions

  • the present invention relates to diphenylamino-methylene malononitrile based compounds, a process for preparing thereof and their use as photodynamic therapy agents in biological, biochemical and industrial applications such as in photodynamic therapeutics, diagnostics and as fluorescence probes for cell imaging applications.
  • Tubulin is a protein that polymerize in to dynamic microtubules in eukaryotic cells.
  • Tubulin involves in various functions such as cell integrity, cell division, cell signalling, intracellular vesicles and organelle transport and locomotion.
  • the minute changes of tubulin in microtubules is associated with different cancers.
  • the control of these trace changes in tubulins has become new target of cancer therapy research. Therefore, the visualization of microtubules is critical to understand their intracellular function.
  • imaging techniques have been developed to visualize and study specific organelles in living cell, such as electron microscopy, silver staining and fluorescence imaging.
  • fluorescence probes with confocal microscopy present an exciting opportunity for the selective imaging of tubulin, microtubules and relevant events in living cells which has potential application in the cancer therapy research.
  • the existing probes generally have shortcomings such as difficult to modify, possess high cytotoxicity, photo-instability, low sensitivity, poor selectivity and so on.
  • ring A is aryl, heteroaryl or is absent; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and -CORi;
  • ring B is aryl or heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and - CORi;
  • Ri is hydroxy or alkoxy
  • the present disclosure also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or formula (II).
  • the present disclosure discloses preparation of compounds of formula (I) or formula (II).
  • the present disclosure discloses a method of detecting the tubulin in a subject using the compound of formula (I) or (II).
  • FIG. 1 illustrates effect of compounds of formula (I) and formula (II) on viability of
  • FIG. 2 illustrates co-localization of Example 1 in Hela cells
  • FIG. 3 illustrates co-localization of Example 2 in Hela cells
  • FIG. 4 illustrates co-localization of Example 6 in Hela cells
  • FIG. 5 illustrates co -localization of Example 3, Example 4 and Example 5 in Hela cells DETAILED DESCRIPTION
  • the present disclosure discloses a compound of formula (I) or formula (II).
  • the compound is useful as fluorescent probe for detecting the presence or absence of tubulin in a subject. These probes are easy to modify, possess low cytotoxicity, high photo stability, high sensitivity and site specific thereby good option for monitoring dynamic changes of tubulins in living biological samples.
  • the probes of the present disclosure possess superior properties, such as accessibility to living cells, specificity for tubulin, and super-resolution imaging, compared to existing probes.
  • the present disclosure discloses a compound of formula (I) or (II):
  • ring A is aryl, heteroaryl or is absent; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and -CORi;
  • ring B is aryl or heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and - CORi;
  • Ri is hydroxy or alkoxy
  • ring A in formula (I), is monocyclic aryl. In further embodiments, ring A is phenyl.
  • ring A in formula (I), is absent and ring B is phenyl.
  • the compound of formula (I) is a compound of formula (III):
  • ring A is aryl, heteroaryl or is absent; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and -CORi;
  • ring B is aryl or heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and - CORi; and
  • Ri is hydroxy or alkoxy.
  • ring A, in formula (III) is monocyclic aryl. In further embodiments, ring A is phenyl. In certain embodiments, ring A, in formula (III), is monocyclic heteroaryl. In further embodiments, ring A is thiophenyl.
  • ring A is absent and ring B is phenyl.
  • the compound of formula (III) is a compound of formula (IIIA):
  • ring A is aryl or heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and - CORi; and
  • Ri is hydroxy or alkoxy.
  • ring A in formula (IIIA), is monocyclic aryl. In further embodiments, ring A is phenyl.
  • ring A in formula (IIIA), is monocyclic heteroaryl. In further embodiments, ring A is thiophenyl.
  • the compound of formula (II) is a compound of formula (IV):
  • ring A is aryl, heteroaryl or is absent; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and -CORi;
  • ring B is aryl or heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and - CORi; and
  • Ri is hydroxy or alkoxy.
  • ring A, in formula (IV) is monocyclic aryl. In further embodiments, ring A is phenyl.
  • ring A, in formula (IV) is monocyclic heteroaryl. In further embodiments, ring A is thiophenyl.
  • ring A is absent and ring B is phenyl.
  • the compound of formula (IV) is a compound of formula
  • ring A is aryl or heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, cyano, nitro and - CORi; and
  • Ri is hydroxy or alkoxy.
  • ring A, in formula (IVA) is monocyclic aryl. In further embodiments, ring A is phenyl.
  • ring A, in formula (IVA) is monocyclic heteroaryl. In further embodiments, ring A is thiophenyl. In certain embodiments, the compounds of formula (I), formula (III) and formula (IIIA) are selected from:
  • the compounds of formula (II), formula (IV) and formula (IVA) are selected from:
  • the present disclosure provides a pharmaceutical composition comprising a compound as disclosed herein.
  • the compounds of the formula (I) and (II) may be useful in photodynamic therapy as fluorescent probe for the diagnosis of tubulin and its associated diseases like cancer.
  • the present disclosure provides compounds of formula (I) and/or formula (II) for use both in vitro and in vivo photodynamic therapeutic treatment.
  • compounds of the formula (I) and/or formula (II) can be used as cellular components in fixed or live cell imaging applications.
  • the compound of formula (I) and/or formula (II) are tubulin specific fluorescent compounds.
  • the compounds have low cytotoxicity, specifically binds to tubulins and emitting green fluorescence. Therefore, the compounds are useful for fluorescence imaging, observing and detecting trace changes of tubulin in microtubules during cancer therapy.
  • the present disclosure provides a method of detecting tubulin in a sample, wherein the method comprises contacting the compound of formula (I) or (II) with the sample and detecting the fluorescence generated due to the reaction of the compound with the sample. In certain embodiments, this method is further characterized by the fact that the fluorescence detection is visualized using fluorescent imaging means. In certain embodiments, the amount of the compound of formula (I) or (II) (fluorescent probe) is not particularly restricted and the amount of compound can be selected as appropriate by one skilled in the art.
  • the sample is selected from a group comprising cells, biological fluids and chemical mixture.
  • the disclosure provides a kit for detecting tubulin in a sample, wherein the kit comprises a compound of formula (I) or formula (II).
  • the kit may also comprise instructions for carrying out a method of detecting the tubulin in the sample.
  • This kit may also include other reagents and the like as needed. For example, dissolution auxiliaries, buffers, isotonifying agents, pH adjusters and other such additives, and the amounts compounded can be selected as appropriate by one skilled in the art.
  • an element means one element or more than one element.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as the event or circumstance where the alkyl is not substituted.
  • alkyl refers to a straight chain or branched saturated hydrocarbon group containing no unsaturation. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, Ci -6 alkyl which includes alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkyl examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec -butyl, tert-butyl, l-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, l-hexyl, 2-hexyl, 3-hexyl, l-heptyl, 2- heptyl, 3-heptyl, 4-heptyl, l-octyl, 2-octyl, 3-octyl and 4-octyl.
  • the "alkyl” group may be optionally substituted.
  • alkoxy refers to a straight or branched, saturated aliphatic hydrocarbon radical bonded to an oxygen atom that is attached to a core structure. Alkoxy groups may have one to six carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy.
  • Aryl refers to monocyclic or fused bicyclic or polycyclic ring system having the well-known characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron system.
  • aryl groups contain 6 to 20 carbon atoms ("C 6 -C 20 aryl”) as ring members, preferably 6 to 14 carbon atoms (“C 6 -C 14 aryl”) or more preferably, 6 to 12 carbon atoms (“C 6 -C 12 aryl”).
  • Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl or heteroaryl ring or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided the point of attachment to the base molecule on such fused ring systems is an atom of the aromatic portion of the ring system.
  • aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, indanyl, indenyl, phenanthrenyl, and tetrahydronaphthyl.
  • cyano refers to -CN group.
  • halo or“halogen” refers to fluoro (fluorine), chloro (chlorine), bromo (bromine) and iodo (iodine).
  • haloalkyl means alkyl substituted with one or more halogen atoms, wherein the term“halo” and“alkyl” are as defined above.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
  • Heteroaryl or “heteroaromatic” refer to monocyclic or fused bicyclic or polycyclic ring systems having the well-known characteristics of aromaticity that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in an aromatic ring. The inclusion of a heteroatom permits aromaticity in 5- membered rings as well as 6-membered rings.
  • heteroaryl groups contain 5 to 20 ring atoms (“5-20 membered heteroaryl”), preferably 5 to 14 ring atoms (“5-14 membered heteroaryl”), and more preferably 5 to 12 ring atoms ("5-12 membered heteroaryl”).
  • Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained.
  • 6-membered heteroaryl rings may be attached to the base molecule via a ring C atom
  • 5-membered heteroaryl rings may be attached to the base molecule via a ring C or N atom.
  • Heteroaryl groups may also be fused to another aryl or heteroaryl ring or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided the point of attachment to the base molecule on such fused ring systems is an atom of the heteroaromatic portion of the ring system.
  • unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthryidine and carbazole.
  • 5- or 6-membered heteroaryl groups are selected from the group consisting of thiophenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl and pyrimidinyl, pyrazinyl and pyridazinyl rings.
  • hydroxy or "hydroxyl” refers to -OH group.
  • nitro refers to -N0 2 group.
  • stereoisomer or “stereoisomers” refers to any enantiomers, diastereomers or geometrical isomers of the compounds of formula (I) or (II), wherever they are chiral or when they bear one or more double bond.
  • compounds of the formula (I) or (II) and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as -isomers and /-isomers and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the present disclosure may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti,
  • Mechanism E and sixteen (Z) isomers as well as the appropriate mixtures thereof.
  • Another embodiment of the present disclosure provides process for preparation of the compounds of general formula (I) and formula (II) are set forth in the below examples and generalized scheme.
  • scheme can be adapted to produce the compounds of general structure (I) and structure (II) and their pharmaceutically acceptable salts or stereo isomers according to the present disclosure.
  • UV-Vis spectra were recorded on a Shimadzu UV-3600. Fluorescence spectra were recorded on Fluoromax-4 spectrometer at room temperature. High-resolution mass spectra (HRMS) were recorded on micro mass ESI-TOF MS. The progress of the reaction was monitored by TLC and visualized under UV and/or Iodine chamber. Column chromatography was performed on silica gel (100-200 mesh size), using ethyl acetate and hexanes mixture as eluent.
  • Ring A and Ring B independently represents all the possible substitutions as disclosed in compound of formula (I) and formula (II).
  • Compounds of formula (II) can be obtained by treating compound of formula (I) with BF 3 OEt 2 in presence of suitable solvent like DCM at room temperature.
  • UV-Vis spectra were recorded on a Shimadzu UV-3600. Fluorescence spectra were recorded on Fluoromax-4 spectrometer at room temperature. High-resolution mass spectra (HRMS) were recorded on micro mass ESI-TOF MS. The progress of the reaction was monitored by TLC and visualized under UV and/or Iodine chamber. Column chromatography was performed on silica gel (100-200 mesh size), using ethyl acetate and hexanes mixture as eluent.
  • Methyl 4-(diphenylamino)benzoate 3 (0.5 g, 1.65 mmol) was added to a stirred solution of NaH (0.2g, 8.24 mmol) in dry toluene (20 mL) at room temperature for 0.5 h.
  • l-(5- bromothiophen-2-yl)ethan-l-one (0.34 g, 1.66 mmol) was added to the reaction mixture and was stirred at reflux condition under atmosphere of nitrogen for 21 h.
  • the reaction mixture was allowed to cool to room temperature then neutralized with dil. HC1 and extracted with EtOAc (2 x 20 mL). The organic phase was combined and dried with anhydrous sodium sulphate.
  • HeLa (human cervical cancer) cell line was obtained from the National Centre for Cellular Sciences (NCCS), Pune, India. Cells were cultured in DMEM media, supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1 mM NaHC0 3 , 2 mM -glutamine, 100 units/mL penicillin and 100 pg/mL streptomycin. All cell lines were maintained in culture at 37 °C in an atmosphere of 5% C0 2 .
  • FBS heat-inactivated fetal bovine serum
  • FBS heat-inactivated fetal bovine serum
  • 1 mM NaHC0 3 1 mM NaHC0 3
  • 2 mM -glutamine 100 units/mL penicillin and 100 pg/mL streptomycin. All cell lines were maintained in culture at 37 °C in an atmosphere of 5% C0 2 .
  • DMSO dimethyl sulfoxide
  • Exactly 20 pL of stock was diluted to 1 mL in culture medium to obtain experimental stock concentration of 200 pg/mL. This solution was further serially diluted with media to generate a dilution series of O.OOlpg to 100 pg/ml.
  • Exactly 100 pL of each diluent was added to 100 pL of cell suspension (total assay volume of 200 pL) and incubated for 24 h at 37 °C in 5% C0 2 . Respected volume of DMSO used as a control.
  • Cytotoxicty was measured using the MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay, according to the known method (Mosmann T, J Immunol Methods. 1983 Dec 16; 65(l-2):55-63). Briefly, the cells (3 x 10 3 ) were seeded in each well containing 0.1 mL of medium in 96 well plates. After overnight incubation at 37 °C in 5% C0 2 , the cells were treated with 100 pL of different test concentrations of test compounds at identical conditions with five replicates each. The final test concentrations were equivalent to 0.001 to 100 pg/mL or 0.001 to 100 ppm.
  • the cell viability was assessed after 24 h, by adding 10 pL of MTT (5 mg/mL) per well. The plates were incubated at 37 °C for additional three hours. The medium was discarded and the formazan blue, which formed in the cells, was dissolved with 100 pL of DMSO. The rate of color formation was measured at 570 nm in a spectrophotometer (Bio-rad). The percent inhibition of cell viability was determined with reference to the control values (without test compound). The data were subjected to linear regression analysis and the regression lines were plotted for the best straight-line fit. The IC50 (inhibition of cell viability) concentrations were calculated using the respective regression equation. IC50 values of the test compounds for 24 h on HeLa cell line were calculated and depicted in Table 2 below.
  • Exponentially growing cells were treated with different concentrations of compounds ( Examples 1-6) for 24h and cell growth inhibition was analyzed through MTT assay.
  • the values represent the mean ⁇ SE of three individual observations.
  • hDoxorubicin was employed as positive control.
  • NA indicates that the derivatives are not active at 100 pg/mL concentration.
  • HeLa cells were cultured on cover slips in the 6-well plates to 70 % confluence and treated with 10 pg of compounds (Examples 1-6) in complete cell culture media for up to 12 h.
  • a corresponding DMSO control was run in parallel for 12 h.
  • HeLa cells were washed with PBS for three times and fixed with 4% paraformaldehyde for 20 min, mounted using with DAPI for visualization of nuclei, and incubated for 1 h in the dark. After incubation cells were visualized and captured by fluorescence microscopy (Olympus, USA) using excitation wavelengths between 400-418 for DAPI and 478-495 for compounds.
  • HeLa cells were cultured on cover slips in the 6-well plates to 70 % confluence washed with PBS for three times and fixed with 4% paraformaldehyde for 20 min, permeabilized with cold methanol for another 10 min. After that, the cells were blocked with 5% BSA for 1 h. Subsequently, the cells were washed with PBS, and incubated with anti-tubulin antibody in 3% BSA (1:200, Sigma.) overnight at 4 °C. After being washed with PBS for three times, each cover slip was added 200 pL of Alexa Fluor 546 anti-mouse secondary antibody in 3% BSA (1:500, Molecular probes.) and incubated at room temperature for 1 h. At last, HeLa cells was stained with 20 pL of DAPI for 1 h and observed under confocal microscope (Olympus, USA).

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Abstract

La présente invention concerne des composés de formule (I) et de formule (II), ou un sel pharmaceutiquement acceptable ou un stéréoisomère de ceux-ci ; le cycle A et le cycle B ayant les significations données dans la description. Les composés de la présente invention sont utiles en tant que sonde de fluorescence dans la détection de la tubuline dans un échantillon et par conséquent utiles pour le diagnostic de la tubuline et de ses maladies associées comme le cancer chez un sujet.
PCT/IB2019/057180 2018-08-27 2019-08-27 Composés à base de diphénylamino-méthylène malononitrile en tant que sondes de fluorescence WO2020044213A1 (fr)

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FR3118036A1 (fr) * 2020-12-22 2022-06-24 Oberthur Fiduciaire Sas Composé mécanochromique et mécanofluorochromique, composition et document fiduciaire qui en font usage
CN116514857A (zh) * 2023-04-14 2023-08-01 大连理工大学 一类二羰基氟硼荧光染料及合成方法和应用

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CN102851370A (zh) * 2012-09-10 2013-01-02 广州达健生物科技有限公司 微管蛋白基因表达荧光定量pcr检测试剂盒
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WO2013173396A2 (fr) * 2012-05-15 2013-11-21 Plextronics, Inc. Matériaux de transport de trou y compris pour les applications à oled
CN102851370A (zh) * 2012-09-10 2013-01-02 广州达健生物科技有限公司 微管蛋白基因表达荧光定量pcr检测试剂盒

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3118036A1 (fr) * 2020-12-22 2022-06-24 Oberthur Fiduciaire Sas Composé mécanochromique et mécanofluorochromique, composition et document fiduciaire qui en font usage
WO2022135913A1 (fr) 2020-12-22 2022-06-30 Oberthur Fiduciaire Sas Composé mécanochromique et mécanofluorochromique, composition et document fiduciaire qui en font usage
CN116514857A (zh) * 2023-04-14 2023-08-01 大连理工大学 一类二羰基氟硼荧光染料及合成方法和应用

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