WO2019238121A1 - Nir-ii emissive luminogens - Google Patents

Nir-ii emissive luminogens Download PDF

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WO2019238121A1
WO2019238121A1 PCT/CN2019/091281 CN2019091281W WO2019238121A1 WO 2019238121 A1 WO2019238121 A1 WO 2019238121A1 CN 2019091281 W CN2019091281 W CN 2019091281W WO 2019238121 A1 WO2019238121 A1 WO 2019238121A1
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compound
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cancer cell
imaging
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Benzhong Tang
Pengfei Zhang
Jen-Shyang Ni
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Hong Kong University of Science and Technology
HKUST Shenzhen Research Institute
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Hong Kong University of Science and Technology
HKUST Shenzhen Research Institute
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Priority to US17/251,961 priority patent/US12023387B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
    • C09B23/005—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being a COOH and/or a functional derivative thereof
    • C09B23/0058—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being a COOH and/or a functional derivative thereof the substituent being CN
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/14—Styryl dyes
    • C09B23/141—Bis styryl dyes containing two radicals C6H5-CH=CH-
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks

Definitions

  • the present subject matter relates generally to a series of compounds capable of aggregation-induced emission in the spectrum range of 900 nm-1700 nm and their application in in vivo imaging.
  • NIR fluorescence imaging is a biocompatible imaging technology that can realize noninvasive, high resolution, and real time visualization as well as dynamic tracking of a living organism at the cellular level. As such, NIR fluorescence imaging shows great potential in early detection and accurate diagnosis of disease.
  • fluorescence imaging In comparison with other imaging techniques, such as computed tomography (CT) , magnetic resonance imaging (MRI) , and positron emission tomography (PET) , fluorescence imaging has the advantages of low cost, high resolution, and real-time monitoring ability. Due to minimal photon scattering and negligible tissue auto-fluorescence in the spectrum range of 1000-1700 nm (the second near-infrared widow, “NIR-II” ) , NIR-II fluorescence imaging provides improved imaging performance with higher image contrast at much greater penetration depth compared to conventional fluorescence imaging using NIR-I fluorescent light (first near-infrared window within a spectrum range of 650-900 nm) .
  • CT computed tomography
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • fluorescent materials including natural polymers, organic small molecular dyes, inorganic quantum dots, and organic fluorescent nanoparticles have been investigated for fluorescence imaging and sensing.
  • fluorescent nanoparticles based on organic dyes have been a research focus due to their tunable size, low cytotoxicity, good photostability, and surface functionalization feasibility.
  • Organic emitters are rich in variety.
  • the traditional planar organic dyes provide weakened or even quenched emission in aggregate, known as the notorious aggregation-caused quenching (ACQ) .
  • ACQ aggregation-caused quenching
  • NIR near-infrared red
  • D-A donor-acceptor
  • AIE aggregation-induced emission
  • RIM intramolecular motion
  • NIR fluorophores are toxic, however.
  • many existing NIR-II fluorophores are emissive in both the separate and aggregate states. The “always-on” feature of these NIR-II fluorophores provide limited responsive ability to fluctuations of microenvironments in vivo.
  • twisted structures of some fluorophores cause emission of D-A type AIEgens to suffer from the influence of twisted intramolecular charge transfer (TICT) , which has been proposed as one of the major non-radiative decay pathways for D-A type fluorophores.
  • TCT twisted intramolecular charge transfer
  • expanding the ⁇ -conjugation of D-A structures likely results in the ACQ problem, due to the strong intermolecular ⁇ - ⁇ interaction.
  • organic luminogens having a D-A structure which nevertheless overcome these challenges are highly desirable.
  • the present subject matter contemplates small molecule compounds having aggregation-induced emission (AIE) characteristics.
  • the present compounds include donor-acceptor (D-A) structural NIR fluorophores based on 1, 3-bis (dicyanomethylene) indan (BDCI) , a strong and steric electron-deficient acceptor.
  • D-A donor-acceptor
  • BDCI 1, 3-bis (dicyanomethylene) indan
  • TQDB twisted quasi- double bond
  • the compounds can provide emission in the second near-infrared window (NIR-II) and, thereby, serve as NIR-II activated fluorescent probes.
  • the compounds are non-toxic and can be used as NIR-II fluorescent dyes for in vivo imaging.
  • the compounds can conjugate with bioactive molecules, such as peptides, sugars, aptamers and antibodies, to provide specific and active NIR-II fluorescent probes.
  • the compounds can serve as active NIR-II fluorescent probes in many applications, such as, cancer cell-targeted imaging, accurate diagnosis of disease, and image-guided phototherapy. Since the present compounds are useful for imaging in the NIR-II window, they can be used for deep-tissue, high resolution optical imaging in vivo.
  • the compounds can have the following backbone structural formula:
  • R 1 and R 2 are independently selected from the group consisting of
  • each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • n is an integer selected from 1, 2, 3, 4, and R.
  • each of R 1 and R 2 can be any of R 1 and R 2.
  • each of R 3 , R 4 , R 5 , and R 6 can be hydrogen.
  • n 1
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Fig. 1 depicts the 1H NMR spectra of TSPCI.
  • Fig. 2 depicts the 13C NMR spectra of TSPCI.
  • Fig. 3 depicts a high resolution mass spectrum (MALDI-TOF) of TSPCI.
  • Fig. 4 depicts (A) an image of TSPCI powder in daylight; (B) the UV-vis absorption spectrum of TSPCI; (C) the photoluminescence (PL) spectra of TSPCI in THF and THF/water mixtures with different water fractions (f w ) ; and (D) the plot of relative PL intensities at 950 nm versus the f w (concentration: 10 ⁇ M; excitation wavelength: 808 nm) .
  • Fig. 5 depicts full width at half maximum (FWHM) curves analysis of a TSPCI-drawn panel (NIR-II fluorescence) with (A) no paper layer covering; (B) one paper layer (64 ⁇ m) ; (C) two paper layers (128 ⁇ m) ; (D) three paper layers (192 ⁇ m) ; (E) four paper layers (256 ⁇ m) ; (F) five paper layers (320 ⁇ m) ; (G) six paper layers (384 ⁇ m) ; (H) seven paper layers (448 ⁇ m) ; (I) eight paper layers (512 ⁇ m) ; and (J) nine paper layers (576 ⁇ m) .
  • the inset in each figure shows gray-scaled fluorescence images of the panels taken using an InGaAs-based NIR-II camera.
  • Fig. 6 depicts the spatial resolution anlaysis, in order, of each of the NIR-II fluorescence images provided in Figs. 5A-5J.
  • Fig. 7 depicts time course NIR-II fluorescence images of a nude mouse (A) before intravenous injection of TSPCI solution; (B) one second after injection of TSPCI solution; (C) two seconds after injection of TSPCI solution; (D) three seconds after injection of TSPCI solution; (E) four seconds after injection of TSPCI solution; and (F) five seconds after injection of TSPCI solution.
  • ⁇ ex refers to excitation wavelength
  • aggregation caused quenching or “ACQ” as used herein refers to the phenomenon wherein the aggregation of ⁇ -conjugated fluorophores significantly decreases the fluorescence intensity of the fluorophores.
  • the aggregate formation is said to “quench” light emission of the fluorophores.
  • AIE aggregation induced emission
  • Emission intensity refers to the magnitude of fluorescence/phosphorescence normally obtained from a fluorescence spectrometer or fluorescence microscopy measurement
  • fluorophore or “fluorogen” as used herein refer to a molecule which exhibits fluorescence
  • luminogen or “luminophore” as used herein refer to a molecule which exhibits luminescence
  • AIEgen as used herein refers to a molecule exhibiting AIE characteristics.
  • halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • alkyl groups include methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and z′-propyl) , butyl (e.g., n-butyl, z′-butyl, sec-butyl, tert-butyl) , pentyl groups (e.g., n-pentyl, z′-pentyl, -pentyl) , hexyl groups, and the like.
  • an alkyl group can have 1 to 40 carbon atoms (i.e., C1-40 alkyl group) , for example, 1-30 carbon atoms (i.e., C1-30 alkyl group) .
  • an alkyl group can have 1 to 6 carbon atoms, and can be referred to as a “lower alkyl group” .
  • lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and z′-propyl) , and butyl groups (e.g., n-butyl, z′-butyl, sec-butyl, tert-butyl) .
  • alkyl groups can be substituted as described herein.
  • An alkyl group is generally not substituted with another alkyl group, an alkenyl group, or an alkynyl group.
  • alkenyl refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds.
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like.
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene) .
  • an alkenyl group can have 2 to 40 carbon atoms (i.e., C2-40 alkenyl group) , for example, 2 to 20 carbon atoms (i.e., C2-20 alkenyl group) .
  • alkenyl groups can be substituted as described herein.
  • An alkenyl group is generally not substituted with another alkenyl group, an alkyl group, or an alkynyl group.
  • heteroatom refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, silicon, sulfur, phosphorus, and selenium.
  • aryl refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system in which two or more aromatic hydrocarbon rings are fused (i.e., having a bond in common with) together or at least one aromatic monocyclic hydrocarbon ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings.
  • An aryl group can have 6 to 24 carbon atoms in its ring system (e.g., C6-24 aryl group) , which can include multiple fused rings.
  • a polycyclic aryl group can have 8 to 24 carbon atoms. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure.
  • aryl groups having only aromatic carbocyclic ring include phenyl, 1-naphthyl (bicyclic) , 2-naphthyl (bicyclic) , anthracenyl (tricyclic) , phenanthrenyl (tricyclic) , pentacenyl (pentacyclic) , and like groups.
  • polycyclic ring systems in which at least one aromatic carbocyclic ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5, 6-bicyclic cycloalkyl/aromatic ring system) , cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6, 6-bicyclic cycloalkyl/aromatic ring system) , imidazoline (i.e., a benzimidazolinyl group, which is a 5, 6-bicyclic cycloheteroalkyl/aromatic ring system) , and pyran (i.e., a chromenyl group, which is a 6, 6-bicyclic cycloheteroalkyl/aromatic ring system) .
  • aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like.
  • aryl groups can be substituted as described herein.
  • an aryl group can have one or more halogen substituents, and can be referred to as a “haloaryl” group.
  • Perhaloaryl groups i.e., aryl groups where all of the hydrogen atoms are replaced with halogen atoms (e.g., -C 6 F 5 ) , are included within the definition of “haloaryl” .
  • an aryl group is substituted with another aryl group and can be referred to as a biaryl group. Each of the aryl groups in the biaryl group can be substituted as disclosed herein.
  • heteroaryl refers to an aromatic monocyclic ring system containing at least one ring heteroatom selected from oxygen (O) , nitrogen (N) , sulfur (S) , silicon (Si) , and selenium (Se) or a polycyclic ring system where at least one of the rings present in the ring system is aromatic and contains at least one ring heteroatom.
  • Polycyclic heteroaryl groups include those having two or more heteroaryl rings fused together, as well as those having at least one monocyclic heteroaryl ring fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, and/or non-aromatic cycloheteroalkyl rings.
  • a heteroaryl group as a whole, can have, for example, 5 to 24 ring atoms and contain 1-5 ring heteroatoms (i.e., 5-20 membered heteroaryl group) .
  • the heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain O-O, S-S, or S-0 bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide thiophene S-oxide, thiophene S, S-dioxide) .
  • heteroaryl groups include, for example, the 5-or 6-membered monocyclic and 5-6 bicyclic ring systems shown below: where T is O, S, NH, N-alkyl, N-aryl, N- (arylalkyl) (e.g., N-benzyl) , SiH 2 , SiH(alkyl) , Si (alkyl) 2 , SiH (arylalkyl) , Si (arylalkyl) 2 , or Si (alkyl) (arylalkyl) .
  • T is O, S, NH, N-alkyl, N-aryl, N- (arylalkyl) (e.g., N-benzyl) , SiH 2 , SiH(alkyl) , Si (alkyl) 2 , SiH (arylalkyl) , Si (arylalkyl) 2 , or Si (alkyl) (arylalkyl) .
  • heteroaryl rings examples include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, lH-indazolyl, 2H-indazo
  • heteroaryl groups include 4, 5, 6, 7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuropyridinyl groups, and the like.
  • heteroaryl groups can be substituted as described herein.
  • a "donor” material refers to an organic material, for example, an organic nanoparticle material, having holes as the majority current or charge carriers.
  • an "acceptor" material refers to an organic material, for example, an organic nanoparticle material, having electrons as the majority current or charge carriers.
  • the present compounds can include a donor-acceptor (D-A) structure in which a twisted quasi-double bond (TQDB) links an electron-deficient acceptor group to an electron donor group.
  • D-A donor-acceptor
  • TQDB twisted quasi-double bond
  • An exemplary electron-deficient acceptor can include 1, 3-bis (dicyanomethylene) indan (BDCI) based compounds, having the following structural formula
  • An exemplary electron donor can include at least one compound selected from
  • R 1 and R 2 are independently selected from the group consisting of
  • each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • n is an integer selected from 1, 2, 3, 4, and 5.
  • an exemplary electron donor can have the following backbone structural formula
  • R 1 and R 2 are independently selected from the group consisting of
  • each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • n is an integer selected from 1, 2, 3, 4, and 5.
  • the present subject matter relates to compounds having the following backbone structural formula
  • R 1 and R 2 are independently selected from
  • each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • n is an integer selected from 1, 2, 3, 4, and 5.
  • each of R 1 and R 2 can be any of R 1 and R 2.
  • each of R 3 , R 4 , R 5 , and R 6 can be hydrogen.
  • n can be 1.
  • the compound is “TSPCI, ” having the following structure
  • the present compounds have fluorescent properties when in a solid state.
  • the present compounds can provide ⁇ 35-fold higher signal enhancement from solution state to aggregate state and wide absorption (500 nm-850 nm) .
  • the present compounds can be used as a probe in imaging methods.
  • the imaging methods can include, for example, fluorescence imaging in the near infrared spectral range of 900 nm to 1700 nm.
  • the compounds can exhibit bright emission in the NIR-II spectral range of 1000 nm to 1700 nm, or in certain more limited ranges therein, such as 1000 nm to 1300 nm.
  • a fluorescence imaging method can include contacting a target cell with one or more of the present compounds and conducting fluorescence imaging of the contacted target cell in the near infrared spectral region.
  • the present compounds can exhibit excellent AIE properties and can be easily synthesized from commercially available raw materials.
  • the present compounds can be used in cellular imaging methods to detect the presence or absence of a target of interest in a target cell.
  • a target cell can be contacted with one or more of the present compounds.
  • the presence or absence of the target of interest can be detected using an imaging method.
  • the target of interest can include at least one of a peptide, a sugar, an aptamer, and an antibody.
  • the target cell can be a cancer cell, for example.
  • a method of killing a target cancer cell can include contacting the target cancer cell with one or more of the present compounds, imaging the target cancer cell while the compound contacts the target cancer cell, irradiating the target cancer cell with light while the compound is contacting the target cancer cell to kill the target cancer cell.
  • the present compounds can have various applications, including cancer cell targeted imaging, disease diagnosis and image-guided phototherapy.
  • the present compounds can be useful in technologies relating to the military, energy, and the environment.
  • the present compounds can have applications in night vision, solar energy, and desalination technologies.
  • the present subject matter contemplates organic compounds having aggregation-induced emission (AIE) characteristics.
  • the compounds can possess fluorescence properties in the solid or aggregate state. In the solution state, the compounds are less emissive.
  • TSPCI An exemplary compound according to the present teachings is TSPCI.
  • TSPCI is less emissive in the solution state. In the aggregate state, however, the emission of this compound is induced or rejuvenated by the restriction of intramolecular motions (RIM)
  • the present compounds can be synthesized using a two-step process: 1) reacting 1, 3-bis(dicyanomethylene) indan (BDCI) with 2, 6-dimethyl-4-pyrone (1) in acetic anhydride to yield an intermediate (SPCI) ; and 2) condensing the intermediate (SPCI) to provide the present compounds.
  • the present subject matter relates to a method of synthesizing a fluorescent compound with a twisted quasi-double bond bridging an electron-deficient acceptor and an electron donor, the method comprising:
  • SPCI 1, 3-bis (dicyanomethylene) indan with 2, 6-dimethyl-4-pyrone
  • R 1 and R 2 are independently selected from the group consisting of
  • each of R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; andn is an integer selected from 1, 2, 3, 4, and 5.
  • the UV-vis spectrum measured in THF solution (10 ⁇ M) showed the maximal absorption wavelength at 682 nm with a relatively high molar extinction coefficient (up to 6.67 ⁇ 104 M -1 cm -1 ) (Fig. 4B) .
  • the AIE property of TSPCI was investigated by varying the water fractions (fw) in tetrahydrofuran (THF) /water mixtures (Fig. 4C) . Upon the increase of fw, a significant fluorescence enhancement was observed clearly, whereas no emission was observed in the pure THF solution.
  • NIR-I fluorescence imaging was performed using the Maestro in vivo imaging system (CRI, Inc. ) .
  • CTI, Inc. the Maestro in vivo imaging system
  • NIR-I AIEgen TTD
  • a 605 nm ( ⁇ 25 nm) bandpass filter and a 645 nm longpass filter were selected as the excitation filter and the emission filter, respectively.
  • NIR-II imaging was performed using the home-built NIR-II in vivo imaging system. The excitation light was provided by an 808 nm diode laser.
  • the emitted light from the TSPCI was filtered through a 1000 nm long-pass filter, which was coupled with a two-dimensional InGaAs array camera (with spectral response range of 900-1700 nm, Photonic Science) for NIR-II fluorescence signal collection.
  • the excitation power density at the imaging plane was 6.4 mW/cm 2 , much lower than the safe exposure limit of 330 mW/cm 2 at 808 nm determined by the International Commission on Nonionizing Radiation Protection.
  • the exposure time for all images was 100 ms.
  • Fig. 5A depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with no paper layer covering.
  • Fig. 5B depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with one paper layer (64 ⁇ m) .
  • Fig. 5A depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with one paper layer (64 ⁇ m) .
  • FIG. 5C depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with two paper layers (128 ⁇ m) .
  • Fig. 5D depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with three paper layers (192 ⁇ m) . ) .
  • Fig. 5E depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with four paper layers (256 ⁇ m) .
  • FIG. 5F depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with five paper layers (320 ⁇ m) .
  • Fig. 5G depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with six paper layers (384 ⁇ m) .
  • Fig. 5H depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with seven paper layers (448 ⁇ m) .
  • FIG. 5I depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with eight paper layers (512 ⁇ m) .
  • Fig. 5J depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with nine paper layers (576 ⁇ m) .
  • Fig. 6 depicts the spatial resolution anlaysis, in order, of each of the NIR-II fluorescence images provided in Figs. 5A-5J.
  • FIG. 7A depicts an NIR-II fluorescence image of the nude mouse before intravenous injection of TSPCI solution.
  • Fig. 7B depicts an NIR-II fluorescence image of the nude mouse one second after injection of TSPCI solution.
  • Fig. 7C depicts an NIR-II fluorescence image of the nude mouse two seconds after injection of TSPCI solution.
  • Fig. 7D depicts an NIR-II fluorescence image of the nude mouse three seconds after injection of TSPCI solution.
  • FIG. 7E depicts an NIR-II fluorescence image of the nude mouse four seconds after injection of TSPCI solution.
  • Fig. 7F depicts an NIR-II fluorescence image of the nude mouse five seconds after injection of TSPCI solution.
  • Figs. 7A-7F confirmed that TSPCI achieves high contrast and penetration depth for in vivo dynamic NIR-II imaging.

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Abstract

Disclosed herein are small molecule compounds having aggregation-induced emission (AIE) characteristics include donor-acceptor (D-A) structural NIR fluorophores based on 1, 3-bis (dicyanomethylene) indan (BDCI), The compounds function as NIR-II fluorescent dyes for in vivo imaging.

Description

NIR-II Emissive Luminogens FIELD
The present subject matter relates generally to a series of compounds capable of aggregation-induced emission in the spectrum range of 900 nm-1700 nm and their application in in vivo imaging.
BACKGROUND
Organic dyes with NIR emission are favorable in many fields, such as organic light-emitting diode (OLED) , fluorescent imaging, and anti-counterfeit technology. Near-infrared (NIR) fluorescence imaging is a biocompatible imaging technology that can realize noninvasive, high resolution, and real time visualization as well as dynamic tracking of a living organism at the cellular level. As such, NIR fluorescence imaging shows great potential in early detection and accurate diagnosis of disease.
In comparison with other imaging techniques, such as computed tomography (CT) , magnetic resonance imaging (MRI) , and positron emission tomography (PET) , fluorescence imaging has the advantages of low cost, high resolution, and real-time monitoring ability. Due to minimal photon scattering and negligible tissue auto-fluorescence in the spectrum range of 1000-1700 nm (the second near-infrared widow, “NIR-II” ) , NIR-II fluorescence imaging provides improved imaging performance with higher image contrast at much greater penetration depth compared to conventional fluorescence imaging using NIR-I fluorescent light (first near-infrared window within a spectrum range of 650-900 nm) .
A large variety of fluorescent materials including natural polymers, organic small molecular dyes, inorganic quantum dots, and organic fluorescent nanoparticles have been investigated for fluorescence imaging and sensing. Among them, fluorescent nanoparticles based on organic dyes have been a research focus due to their tunable size, low cytotoxicity, good photostability, and surface functionalization feasibility.
Organic emitters are rich in variety. The traditional planar organic dyes, however, provide weakened or even quenched emission in aggregate, known as the notorious aggregation-caused quenching (ACQ) . As such, application of the traditional planar organic dyes is greatly restricted. The ACQ phenomenon is particularly significant for dyes with red or near-infrared red (NIR) emission, since their elongated π-conjugation or strong donor-acceptor (D-A) interaction favor  strong π-π interaction to quench the emission. In contrast to the ACQ system, a novel class of molecular rotors discovered by Tang et al. exhibit aggregation-induced emission (AIE) , which means they exhibit little or no emission in dilute solution, but enhanced fluorescence in the aggregate through restriction of intramolecular motion (RIM) . The unique emission property of AIE luminogens (AIEgens) paved the way for preparation of highly emissive organic fluorescence nanoparticles.
Organic dyes with NIR absorbance and emission are more favorable compared to other traditional visible-light emissive dyes in bio-application due to their lower cellular or tissue auto-fluorescence interference and anti-photo bleaching ability. Many NIR fluorophores are toxic, however. In addition, many existing NIR-II fluorophores are emissive in both the separate and aggregate states. The “always-on” feature of these NIR-II fluorophores provide limited responsive ability to fluctuations of microenvironments in vivo.
Synthesis of existing NIR fluorophores is often complex. A rational design and synthesis method for NIR-II emissive AIEgens with NIR absorbance was previously difficult to achieve. First, because most AIEgens have highly twisted structures, it is very difficult to effectively red-shift the emission by merely expanding the electron delocalization of π-system due to the poor π-conjugation of the molecular backbone. Second, excessively large π-conjugation through fused rings or double bonds likely leads to poor solubility, increased instability of the AIEgens, and/or the ACQ problem. Constructing D-A (donor-acceptor) structures is a very efficient strategy for affording red emitters. However, the twisted structures of some fluorophores cause emission of D-A type AIEgens to suffer from the influence of twisted intramolecular charge transfer (TICT) , which has been proposed as one of the major non-radiative decay pathways for D-A type fluorophores. Additionally, expanding the π-conjugation of D-A structures likely results in the ACQ problem, due to the strong intermolecular π-π interaction.
Accordingly, organic luminogens having a D-A structure which nevertheless overcome these challenges are highly desirable.
SUMMARY
The present subject matter contemplates small molecule compounds having aggregation-induced emission (AIE) characteristics. The present compounds include donor-acceptor (D-A) structural NIR fluorophores based on 1, 3-bis (dicyanomethylene) indan (BDCI) , a strong and steric electron-deficient acceptor. An electron donor is linked to the acceptor by a twisted quasi- double bond (TQDB) . It is believed that the AIE characteristics of the present compounds stem, at least partially, from the presence of the twisted quasi-double bonds.
The compounds can provide emission in the second near-infrared window (NIR-II) and, thereby, serve as NIR-II activated fluorescent probes. The compounds are non-toxic and can be used as NIR-II fluorescent dyes for in vivo imaging. The compounds can conjugate with bioactive molecules, such as peptides, sugars, aptamers and antibodies, to provide specific and active NIR-II fluorescent probes. The compounds can serve as active NIR-II fluorescent probes in many applications, such as, cancer cell-targeted imaging, accurate diagnosis of disease, and image-guided phototherapy. Since the present compounds are useful for imaging in the NIR-II window, they can be used for deep-tissue, high resolution optical imaging in vivo.
In an embodiment, the compounds can have the following backbone structural formula:
Figure PCTCN2019091281-appb-000001
wherein each of R 1 and R 2 is independently selected from the group consisting of 
Figure PCTCN2019091281-appb-000002
Figure PCTCN2019091281-appb-000003
Figure PCTCN2019091281-appb-000004
Figure PCTCN2019091281-appb-000005
wherein each of R 3, R 4, R 5, and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
wherein R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; and
wherein n is an integer selected from 1, 2, 3, 4, and R.
In an embodiment, each of R 1 and R 2 can be
Figure PCTCN2019091281-appb-000006
In an embodiment, each of R 3, R 4, R 5, and R 6 can be hydrogen.
In an embodiment, n is 1.
In a further embodiment, the compound is
Figure PCTCN2019091281-appb-000007
BRIEF DESCRIPTION OF DRAWINGS
Various embodiments will now be described in detail with reference to the accompanying  drawings.
Fig. 1 depicts the 1H NMR spectra of TSPCI.
Fig. 2 depicts the 13C NMR spectra of TSPCI.
Fig. 3 depicts a high resolution mass spectrum (MALDI-TOF) of TSPCI.
Fig. 4 depicts (A) an image of TSPCI powder in daylight; (B) the UV-vis absorption spectrum of TSPCI; (C) the photoluminescence (PL) spectra of TSPCI in THF and THF/water mixtures with different water fractions (f w) ; and (D) the plot of relative PL intensities at 950 nm versus the f w (concentration: 10 μM; excitation wavelength: 808 nm) . The inset of Fig. 4D shows fluorescence photographs of TSPCI in THF (f w = 0 vol%) (left) and water/THF mixture (f w = 90 vol%) (right) in 1.5 mL centrifuge tubes under laser illumination of 808 nm wavelength, which were collected using an InGaAs camera (1000-1600 nm) .
Fig. 5 depicts full width at half maximum (FWHM) curves analysis of a TSPCI-drawn panel (NIR-II fluorescence) with (A) no paper layer covering; (B) one paper layer (64 μm) ; (C) two paper layers (128 μm) ; (D) three paper layers (192 μm) ; (E) four paper layers (256 μm) ; (F) five paper layers (320 μm) ; (G) six paper layers (384 μm) ; (H) seven paper layers (448 μm) ; (I) eight paper layers (512 μm) ; and (J) nine paper layers (576 μm) . The inset in each figure shows gray-scaled fluorescence images of the panels taken using an InGaAs-based NIR-II camera.
Fig. 6 depicts the spatial resolution anlaysis, in order, of each of the NIR-II fluorescence images provided in Figs. 5A-5J.
Fig. 7 depicts time course NIR-II fluorescence images of a nude mouse (A) before intravenous injection of TSPCI solution; (B) one second after injection of TSPCI solution; (C) two seconds after injection of TSPCI solution; (D) three seconds after injection of TSPCI solution; (E) four seconds after injection of TSPCI solution; and (F) five seconds after injection of TSPCI solution.
DETAILED DESCRIPTION
Definitions
The following definitions are provided for the purpose of understanding the present subject matter and for constructing the appended patent claims.
It is noted that, as used in this specification and the appended claims, the singular forms “a”, “an” , and “the” include plural references unless the context clearly dictates otherwise.
The term “λ ex” as used herein refers to excitation wavelength.
The phrase “aggregation caused quenching” or “ACQ” as used herein refers to the phenomenon wherein the aggregation of π-conjugated fluorophores significantly decreases the fluorescence intensity of the fluorophores. The aggregate formation is said to “quench” light emission of the fluorophores.
The phrase “aggregation induced emission” or “AIE” as used herein refers to the phenomenon manifested by compounds exhibiting significant enhancement of light-emission upon aggregation in the amorphous or crystalline (solid) states whereas they exhibit weak or almost no emission in dilute solutions.
“Emission intensity” as used herein refers to the magnitude of fluorescence/phosphorescence normally obtained from a fluorescence spectrometer or fluorescence microscopy measurement; “fluorophore” or “fluorogen” as used herein refer to a molecule which exhibits fluorescence; “luminogen” or “luminophore” as used herein refer to a molecule which exhibits luminescence; and “AIEgen” as used herein refers to a molecule exhibiting AIE characteristics.
As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.
As used herein, “alkyl” refers to a straight-chain or branched saturated hydrocarbon group. Examples of alkyl groups include methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and z′-propyl) , butyl (e.g., n-butyl, z′-butyl, sec-butyl, tert-butyl) , pentyl groups (e.g., n-pentyl, z′-pentyl, -pentyl) , hexyl groups, and the like. In various embodiments, an alkyl group can have 1 to 40 carbon atoms (i.e., C1-40 alkyl group) , for example, 1-30 carbon atoms (i.e., C1-30 alkyl group) . In some embodiments, an alkyl group can have 1 to 6 carbon atoms, and can be referred to as a “lower alkyl group” . Examples of lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and z′-propyl) , and butyl groups (e.g., n-butyl, z′-butyl, sec-butyl, tert-butyl) . In some embodiments, alkyl groups can be substituted as described herein. An alkyl group is generally not substituted with another alkyl group, an alkenyl group, or an alkynyl group.
As used herein, “alkenyl” refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene) . In various embodiments, an alkenyl group can have 2 to 40 carbon atoms (i.e., C2-40  alkenyl group) , for example, 2 to 20 carbon atoms (i.e., C2-20 alkenyl group) . In some embodiments, alkenyl groups can be substituted as described herein. An alkenyl group is generally not substituted with another alkenyl group, an alkyl group, or an alkynyl group.
As used herein, “heteroatom” refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, silicon, sulfur, phosphorus, and selenium.
As used herein, “aryl” refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system in which two or more aromatic hydrocarbon rings are fused (i.e., having a bond in common with) together or at least one aromatic monocyclic hydrocarbon ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings. An aryl group can have 6 to 24 carbon atoms in its ring system (e.g., C6-24 aryl group) , which can include multiple fused rings. In some embodiments, a polycyclic aryl group can have 8 to 24 carbon atoms. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure. Examples of aryl groups having only aromatic carbocyclic ring (s) include phenyl, 1-naphthyl (bicyclic) , 2-naphthyl (bicyclic) , anthracenyl (tricyclic) , phenanthrenyl (tricyclic) , pentacenyl (pentacyclic) , and like groups. Examples of polycyclic ring systems in which at least one aromatic carbocyclic ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5, 6-bicyclic cycloalkyl/aromatic ring system) , cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6, 6-bicyclic cycloalkyl/aromatic ring system) , imidazoline (i.e., a benzimidazolinyl group, which is a 5, 6-bicyclic cycloheteroalkyl/aromatic ring system) , and pyran (i.e., a chromenyl group, which is a 6, 6-bicyclic cycloheteroalkyl/aromatic ring system) . Other examples of aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like. In some embodiments, aryl groups can be substituted as described herein. In some embodiments, an aryl group can have one or more halogen substituents, and can be referred to as a “haloaryl” group. Perhaloaryl groups, i.e., aryl groups where all of the hydrogen atoms are replaced with halogen atoms (e.g., -C 6F 5) , are included within the definition of “haloaryl” . In certain embodiments, an aryl group is substituted with another aryl group and can be referred to as a biaryl group. Each of the aryl groups in the biaryl group can be substituted as disclosed herein.
As used herein, “heteroaryl” refers to an aromatic monocyclic ring system containing at least one ring heteroatom selected from oxygen (O) , nitrogen (N) , sulfur (S) , silicon (Si) , and selenium (Se) or a polycyclic ring system where at least one of the rings present in the ring  system is aromatic and contains at least one ring heteroatom. Polycyclic heteroaryl groups include those having two or more heteroaryl rings fused together, as well as those having at least one monocyclic heteroaryl ring fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, and/or non-aromatic cycloheteroalkyl rings. A heteroaryl group, as a whole, can have, for example, 5 to 24 ring atoms and contain 1-5 ring heteroatoms (i.e., 5-20 membered heteroaryl group) . The heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain O-O, S-S, or S-0 bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide thiophene S-oxide, thiophene S, S-dioxide) . Examples of heteroaryl groups include, for example, the 5-or 6-membered monocyclic and 5-6 bicyclic ring systems shown below: where T is O, S, NH, N-alkyl, N-aryl, N- (arylalkyl) (e.g., N-benzyl) , SiH 2, SiH(alkyl) , Si (alkyl)  2, SiH (arylalkyl) , Si (arylalkyl)  2, or Si (alkyl) (arylalkyl) . Examples of such heteroaryl rings include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, lH-indazolyl, 2H-indazolyl, indolizinyl, isobenzofuyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl groups, and the like. Further examples of heteroaryl groups include 4, 5, 6, 7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuropyridinyl groups, and the like. In some embodiments, heteroaryl groups can be substituted as described herein.
As used herein, a "donor" material refers to an organic material, for example, an organic nanoparticle material, having holes as the majority current or charge carriers.
As used herein, an "acceptor" material refers to an organic material, for example, an organic nanoparticle material, having electrons as the majority current or charge carriers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently described subject matter pertains.
Where a range of values is provided, for example, concentration ranges, percentage  ranges, or ratio ranges, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the described subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and such embodiments are also encompassed within the described subject matter, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the described subject matter.
Throughout the application, descriptions of various embodiments use “comprising” language. However, it will be understood by one of skill in the art, that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of” or “consisting of” .
For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about” . Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Compounds
The present compounds can include a donor-acceptor (D-A) structure in which a twisted quasi-double bond (TQDB) links an electron-deficient acceptor group to an electron donor group.
An exemplary electron-deficient acceptor can include 1, 3-bis (dicyanomethylene) indan (BDCI) based compounds, having the following structural formula
Figure PCTCN2019091281-appb-000008
An exemplary electron donor can include at least one compound selected from
Figure PCTCN2019091281-appb-000009
wherein each of R 1 and R 2 is independently selected from the group consisting of
Figure PCTCN2019091281-appb-000010
Figure PCTCN2019091281-appb-000011
Figure PCTCN2019091281-appb-000012
Figure PCTCN2019091281-appb-000013
wherein each of R 3, R 4, R 5, and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
wherein R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; and
n is an integer selected from 1, 2, 3, 4, and 5.
In an embodiment, an exemplary electron donor can have the following backbone structural formula
Figure PCTCN2019091281-appb-000014
wherein each of R 1 and R 2 is independently selected from the group consisting of
Figure PCTCN2019091281-appb-000015
Figure PCTCN2019091281-appb-000016
Figure PCTCN2019091281-appb-000017
Figure PCTCN2019091281-appb-000018
wherein each of R 3, R 4, R 5, and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
wherein R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; and
n is an integer selected from 1, 2, 3, 4, and 5.
According to an embodiment, the present subject matter relates to compounds having the following backbone structural formula
Figure PCTCN2019091281-appb-000019
wherein each of R 1 and R 2 is independently selected from 
Figure PCTCN2019091281-appb-000020
Figure PCTCN2019091281-appb-000021
Figure PCTCN2019091281-appb-000022
Figure PCTCN2019091281-appb-000023
wherein each of R 3, R 4, R 5, and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
wherein R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; and
n is an integer selected from 1, 2, 3, 4, and 5.
In an embodiment, each of R 1 and R 2 can be
Figure PCTCN2019091281-appb-000024
In an embodiment, each of R 3, R 4, R 5, and R 6 can be hydrogen.
In an embodiment, n can be 1.
In a further embodiment, the compound is “TSPCI, ” having the following structure
Figure PCTCN2019091281-appb-000025
Compound Properties
The present compounds have fluorescent properties when in a solid state. For example,  the present compounds can provide ～35-fold higher signal enhancement from solution state to aggregate state and wide absorption (500 nm-850 nm) .
The present compounds can be used as a probe in imaging methods. The imaging methods can include, for example, fluorescence imaging in the near infrared spectral range of 900 nm to 1700 nm. For example, the compounds can exhibit bright emission in the NIR-II spectral range of 1000 nm to 1700 nm, or in certain more limited ranges therein, such as 1000 nm to 1300 nm. By virtue of their emission in the NIR-II spectrum, the present compounds provide a high signal to noise ratio. A fluorescence imaging method can include contacting a target cell with one or more of the present compounds and conducting fluorescence imaging of the contacted target cell in the near infrared spectral region.
The present compounds can exhibit excellent AIE properties and can be easily synthesized from commercially available raw materials. The present compounds can be used in cellular imaging methods to detect the presence or absence of a target of interest in a target cell. A target cell can be contacted with one or more of the present compounds. The presence or absence of the target of interest can be detected using an imaging method. The target of interest can include at least one of a peptide, a sugar, an aptamer, and an antibody. The target cell can be a cancer cell, for example.
In an embodiment, a method of killing a target cancer cell can include contacting the target cancer cell with one or more of the present compounds, imaging the target cancer cell while the compound contacts the target cancer cell, irradiating the target cancer cell with light while the compound is contacting the target cancer cell to kill the target cancer cell.
Accordingly, the present compounds can have various applications, including cancer cell targeted imaging, disease diagnosis and image-guided phototherapy. According to an embodiment, the present compounds can be useful in technologies relating to the military, energy, and the environment. For example, the present compounds can have applications in night vision, solar energy, and desalination technologies.
AIE activity
The present subject matter contemplates organic compounds having aggregation-induced emission (AIE) characteristics. The compounds can possess fluorescence properties in the solid or aggregate state. In the solution state, the compounds are less emissive.
An exemplary compound according to the present teachings is TSPCI. As described in  detail herein, TSPCI is less emissive in the solution state. In the aggregate state, however, the emission of this compound is induced or rejuvenated by the restriction of intramolecular motions (RIM)
Method of Synthesis
The present compounds can be synthesized using a two-step process: 1) reacting 1, 3-bis(dicyanomethylene) indan (BDCI) with 2, 6-dimethyl-4-pyrone (1) in acetic anhydride to yield an intermediate (SPCI) ; and 2) condensing the intermediate (SPCI) to provide the present compounds. An exemplary reaction scheme is provided below:
Figure PCTCN2019091281-appb-000026
According to an embodiment, the present subject matter relates to a method of synthesizing a fluorescent compound with a twisted quasi-double bond bridging an electron-deficient acceptor and an electron donor, the method comprising:
reacting 1, 3-bis (dicyanomethylene) indan with 2, 6-dimethyl-4-pyrone to provide an intermediate compound (SPCI) having the following structural formula
Figure PCTCN2019091281-appb-000027
reacting the intermediate compound with
Figure PCTCN2019091281-appb-000028
to provide the fluorescent compound,
wherein each of R 1 and R 2 is independently selected from the group consisting of
Figure PCTCN2019091281-appb-000029
Figure PCTCN2019091281-appb-000030
Figure PCTCN2019091281-appb-000031
wherein each of R 3, R 4, R 5, and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,  carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
wherein R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; andn is an integer selected from 1, 2, 3, 4, and 5.
The present teachings are illustrated by the following examples.
EXAMPLES
Example 1
Synthesis and Characterization of SPCI
In a 50 mL two-necked flask, a mixture of 1 (2, 6-disubstituted y-pyrones, 300 mg, 2.41 mmole) , BDCI (1, 3-bis (dicyanomethylene) indan) (648 mg, 2.63 mmole) , and acetic anhydride (10 ml, 97.8 mmole) was refluxed overnight. Then, the solution was cooled to room temperature and filtered to obtain the crude product, which was purified by silica column chromatography (eluent solvent, dichloromethane: hexane = 1: 1, V/V) to obtain compound SPCI as a purple powder (626 mg) , yield 74%.  1H NMR (400 MHz, DMSO-d 6) δ: 8.34 (br, 2H) , 7.87 (s, 2H) , 7.68 (br, 2H) , 2.81 (s, 6H) .  13C NMR (100 MHz, CDCl 3) δ: 169.03, 158.11, 154.08, 137.53, 131.73, 123.57, 120.11, 115.56, 115.53, 110.58, 61.14, 20.49. HRMS (MALDI-TOF) , m/z: [M] + calculated: 348.1011, found: 348.1037.
Example 2
Synthesis and Characterization of TSPCI
An exemplary reaction scheme for preparing TSPCI is as provided below:
Figure PCTCN2019091281-appb-000032
1, 3-bis (dicyanomethylene) indan (BDCI) was reacted with 2, 6-dimethyl-4-pyrone (1) in acetic anhydride at 120 ℃ to yield the intermediate, SPCI. In a 50 mL two-necked flask, SPCI (168 mg, 0.48 mmol) and 4 (4- (N, N-Diphenylamino) benzaldehyde (329 mg, 1.21 mmol) were  dissolved in anhydrous toluene (15 mL) to provide a mixture. Then, piperidine (1.0 mL) and acetic acid (0.5 mL) were added to the aforementioned mixture. The solution was stirred and heated at 120℃ for 8 h, while the solution color changed from purple to dark blue. Then, the solution was cooled to room temperature and filtered to obtain the crude product, which was purified by silica column chromatography (eluent solvent, dichloromethane: methanol = 100: 1, V/V) to obtain TSPCI as a black powder (46.5 mg) (Fig. 4A) , yield 4%.  1H NMR (400 MHz, THF-d8) δ: 8.44 (dd, J=3.2 Hz, J=6.0 Hz, 2H) , 8.02 (d, J=16.0 Hz, 2H) , 7.63 (d, J=8.8 Hz, 8H) , 7.51 (dd, J=3.2 Hz, J=5.6 Hz, 2H) , 7.35-7.31 (m, 8H) , 7.22-7.12 (m, 14H) , 6.99 (d, J=8.4 Hz, 2H) .  13C NMR (100 MHz, CDCl 3) δ: 163.72, 156.25, 153.49, 150.87, 145.48, 142.14, 137.50, 130.93, 129.88, 129.10, 126.04, 125.50, 124.47, 123.14, 119.79, 116.78, 116.21, 113.83, 110.69, 57.29. HRMS (MALDI-TOF) , m/z: [M] + calculated: 858.3107, found: 858.3108.
Example 3
Photophysical properties of TSPCI
The UV-vis spectrum measured in THF solution (10 μM) showed the maximal absorption wavelength at 682 nm with a relatively high molar extinction coefficient (up to 6.67 × 104 M -1cm -1) (Fig. 4B) . The AIE property of TSPCI was investigated by varying the water fractions (fw) in tetrahydrofuran (THF) /water mixtures (Fig. 4C) . Upon the increase of fw, a significant fluorescence enhancement was observed clearly, whereas no emission was observed in the pure THF solution. The strongest emission intensity at a950 nm reached its maximum value at 90 vol%water content, which was ～35-fold higher than that in the pure THF due to the restriction of intramolecular rotation (Fig. 5D) . TSPCI in aggregate state showed bright emission in a broad NIR-II spectrum range of 1000-1700 nm.
Example 4
In vivo and Ex vivo imaging study
NIR-I fluorescence imaging was performed using the Maestro in vivo imaging system (CRI, Inc. ) . To acquire fluorescence of an NIR-I AIEgen (TTD) , a 605 nm (±25 nm) bandpass filter and a 645 nm longpass filter were selected as the excitation filter and the emission filter, respectively. NIR-II imaging was performed using the home-built NIR-II in vivo imaging system. The excitation light was provided by an 808 nm diode laser. The emitted light from the TSPCI was filtered through a 1000 nm long-pass filter, which was coupled with a two-dimensional InGaAs array camera (with spectral response range of 900-1700 nm, Photonic  Science) for NIR-II fluorescence signal collection. The excitation power density at the imaging plane was 6.4 mW/cm 2, much lower than the safe exposure limit of 330 mW/cm 2 at 808 nm determined by the International Commission on Nonionizing Radiation Protection. The exposure time for all images was 100 ms.
TSCPI was used to draw letters on two panels for imaging. NIR-II fluorescence imaging of the panels uncovered and with different layers of paper covering was then performed using an InGaAs-based NIR-II camera. Fig. 5A depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with no paper layer covering. Fig. 5B depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with one paper layer (64 μm) . Fig. 5C depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with two paper layers (128 μm) . Fig. 5D depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with three paper layers (192 μm) . ) . Fig. 5E depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with four paper layers (256 μm) . Fig. 5F depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with five paper layers (320 μm) . Fig. 5G depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with six paper layers (384 μm) . Fig. 5H depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with seven paper layers (448 μm) . Fig. 5I depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with eight paper layers (512 μm) . Fig. 5J depicts the full width at half maximum (FWHM) curve analysis and the corresponding NIR-II fluorescence image (inset) of the TSPCI-drawn panel with nine paper layers (576 μm) . Fig. 6 depicts the spatial resolution anlaysis, in order, of each of the NIR-II fluorescence images provided in Figs. 5A-5J.
TSPCI was added to water under sonication to provide a TSPCI solution. The TSPCI solution was administered to a mouse by intravenous injection. Fig. 7A depicts an NIR-II fluorescence image of the nude mouse before intravenous injection of TSPCI solution. Fig. 7B  depicts an NIR-II fluorescence image of the nude mouse one second after injection of TSPCI solution. Fig. 7C depicts an NIR-II fluorescence image of the nude mouse two seconds after injection of TSPCI solution. Fig. 7D depicts an NIR-II fluorescence image of the nude mouse three seconds after injection of TSPCI solution. Fig. 7E depicts an NIR-II fluorescence image of the nude mouse four seconds after injection of TSPCI solution. Fig. 7F depicts an NIR-II fluorescence image of the nude mouse five seconds after injection of TSPCI solution. Figs. 7A-7F confirmed that TSPCI achieves high contrast and penetration depth for in vivo dynamic NIR-II imaging.
The present subject matter being thus described, it will be apparent that the same may be modified or varied in many ways. Such modifications and variations are not to be regarded as a departure from the spirit and scope of the present subject matter, and all such modifications and variations are intended to be included within the scope of the following claims.

Claims (20)

  1. A compound having the following backbone structural formula:
    Figure PCTCN2019091281-appb-100001
    wherein each of R 1 and R 2 is independently selected from the group consisting of
    Figure PCTCN2019091281-appb-100002
    Figure PCTCN2019091281-appb-100003
    Figure PCTCN2019091281-appb-100004
    wherein each of R 3, R 4, R 5, and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
    wherein R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; and
    n is an integer selected from 1, 2, 3, 4, and 5.
  2. The compound according to claim 1, wherein the compound is:
    Figure PCTCN2019091281-appb-100005
  3. The compound of claim 1, wherein the compound provides emission in a spectral range of 1000 nm to 1700 nm.
  4. The compound of claim 3, wherein the compound provides emission in a spectral range of 1000 nm to 1300 nm.
  5. The compound of claim 1, wherein the compound has fluorescent properties when in a solid state.
  6. The compound of claim 1, wherein the compound comprises a donor group and an acceptor group.
  7. A fluorescence imaging method, comprising:
    contacting a target cell with the compound of claim 1 to obtain a contacted target cell; and
    conducting fluorescence imaging of the contacted target cell in the near infrared spectral region.
  8. A method of cellular imaging comprising:
    contacting a target cell with the compound according to claim 1; and
    detecting a presence or absence of a target of interest in the target cell using an imaging method.
  9. The method of claim 8, wherein the target of interest in the target cell comprises at least one of a peptide, a sugar, an aptamer, and an antibody.
  10. The method of claim 8, wherein the target cell is a cancer cell.
  11. A method of killing a cancer cell, comprising:
    contacting a target cancer cell with the compound according to claim 1;
    imaging the target cancer cell while the compound contacts the target cancer cell using an imaging method; and
    irradiating the target cancer cell with light while the compound is contacting the target cancer cell to kill the target cancer cell.
  12. A method of synthesizing a fluorescent compound with a twisted quasi-double bond bridging an electron-deficient acceptor and an electron donor, the method comprising:
    reacting 1, 3-bis (dicyanomethylene) indan with 2, 6-dimethyl-4-pyrone to provide an intermediate compound having the following structural formula
    Figure PCTCN2019091281-appb-100006
    reacting the intermediate compound with
    Figure PCTCN2019091281-appb-100007
    to provide the fluorescent compound,
    wherein each of R 1 and R 2 is independently selected from the group consisting of
    Figure PCTCN2019091281-appb-100008
    Figure PCTCN2019091281-appb-100009
    Figure PCTCN2019091281-appb-100010
    Figure PCTCN2019091281-appb-100011
    wherein each of R 3, R 4, R 5, and R 6 is independently selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group;
    wherein R 7 is selected from the group consisting of H, F, Cl, Br, I, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl group, amino group, sulfonic group, alkylthio, and alkoxy group; and
    n is an integer selected from 1, 2, 3, 4, and 5.
  13. A compound having the following structural formula:
    Figure PCTCN2019091281-appb-100012
  14. The compound of claim 13, wherein the compound provides emission in a spectral range of 900 nm to 1700 nm.
  15. The compound of claim 13, wherein the compound provides emission in a spectral range of 900 nm to 1300 nm.
  16. The compound of claim 13, wherein the compound has fluorescent properties when in a solid state.
  17. A method of killing a cancer cell, comprising:
    contacting a target cancer cell with the compound according to claim 13;
    imaging the target cancer cell while the compound contacts the target cancer cell using an imaging method; and
    irradiating the target cancer cell with light while the compound is contacting the target cancer cell to kill the target cancer cell.
  18. A fluorescence imaging method, comprising:
    contacting a target cell with the compound of claim 13 to obtain a contacted target cell; and
    conducting fluorescence imaging of the contacted target cell in the near infrared spectral region.
  19. A method of cellular imaging comprising:
    contacting a target cell with the compound according to claim 13; and
    detecting a presence or absence of a target of interest in the target cell using an imaging method.
  20. The method of claim 19, wherein the target of interest in the target cell comprises at least one of a peptide, a sugar, an aptamer, and an antibody.
PCT/CN2019/091281 2018-06-15 2019-06-14 Nir-ii emissive luminogens Ceased WO2019238121A1 (en)

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