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WO2014111906A1 - Imagerie par bioluminescence de biomolécules de petite taille - Google Patents

Imagerie par bioluminescence de biomolécules de petite taille Download PDF

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Publication number
WO2014111906A1
WO2014111906A1 PCT/IB2014/058440 IB2014058440W WO2014111906A1 WO 2014111906 A1 WO2014111906 A1 WO 2014111906A1 IB 2014058440 W IB2014058440 W IB 2014058440W WO 2014111906 A1 WO2014111906 A1 WO 2014111906A1
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azido
living
compound
group
modified
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Inventor
Riccardo SINISI
Elena Dubikovskaya
Ghyslain BUDIN
Grigory KARATEEV
Jens FRIGELL
Aleksandra KONOVALOVA
Aurélien GODINAT
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Ecole Polytechnique Federale de Lausanne EPFL
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Ecole Polytechnique Federale de Lausanne EPFL
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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1003—Carbocyclic compounds
    • C09K2211/1011—Condensed systems
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1003—Carbocyclic compounds
    • C09K2211/1014—Carbocyclic compounds bridged by heteroatoms, e.g. N, P, Si or B
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
    • C09K2211/1037—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom with sulfur

Definitions

  • the invention relates to a technique to detect small molecules using Bioluminescence imaging (BLI) to image and quantify non-invasively, in vitro and in vivo, intracellular metabolite fluxes and which can be applied to azido-modified compounds, such as azido-modified biomolecules.
  • BLI Bioluminescence imaging
  • Bioluminescence imaging is a relatively recent technique that has been widely applicable for monitoring cells and biomolecular processes in living subjects, including pathogen detection, tumor growth, and responses to therapy patterns of gene regulation, measurements of protein-protein interactions and ADMET.
  • BLI is a natural process that has been found in various living organisms such as the North American firefly (Photinus pyralis) and is based on the oxidation of D-luciferin catalyzed by the enzyme Luciferase. Upon oxidation of D-luciferin, a photon of light is released. The intensity of the light output is closely related to the amount of D-luciferin available for the enzyme and therefore it is possible to quantify the amount of luciferin by measuring the amount of emitted light with a CCD camera. As a non-invasive imaging method, BLI is comparable to other in vitro and in vivo techniques but has the advantage of high sensitivity, convenience and ease of use.
  • Luciferase An example of the high specificity of Luciferase is that the substrate is required to have the 6- hydroxy group unsubstituted. Therefore, modification of D-luciferin might prohibit its recognition by luciferase, and cause quenching of the bioluminescent emission.
  • Caged luciferins are luciferins that have a cleavable group covalently bound to the 6-hydroxy position. These probes produce luminescence when becoming 'uncaged' followed by Luciferase oxidation.
  • a large variety of methods to uncage luciferin have been reported and in particular the bioorthogonal Staudinger ligation is one of the most used.
  • Bioorthogonal reactions are a very useful set of chemical reactions that in living systems can be used to assemble two components through ligation without interference from the inherent biological moieties.
  • Reaction of two components bearing biologically orthogonal groups such as an aldehyde with an hydrazine or aminoxy derivative or tetracysteine motifs with biarsenicals have been described in the literature but they have shortcomings.
  • the arsenicals are toxic whereas the aldehydes do form stable products guanidine plus are prone to oxidation.
  • US patent application 2008/0274057 A discloses the release or activation of a drug and/or imaging agent which is triggered by the Staudinger reaction, and each of the components of the invention comprise a reaction partner for the Staudinger ligation i.e. a phosphine or an azide group. These components are of use in medical imaging and therapy and in methods where a pre-localized prodrug/pro-imaging probe or activator is used.
  • WO 2010/133851 Al discloses a process for producing labelled compounds through the Staudinger ligation where a detectable moiety is incorporated.
  • phosphine derivatives suitable for azide specific bio orthogonal labelling through the Staudinger ligation have been reported including phosphine derivatives of the affinity reagent biotin, and fluorescent probes such as fluorescein, coumarin, rhodamines and cyanines.
  • Staudinger ligation in combination with other imaging methods has been used to label modified proteins, unnatural amino acids, unnatural nucleic acids and DNA. Moreover, it has been used to profile prenylation and proteolipids in vitro.
  • the present invention provides a phosphine compound according to the Formula I useful in Bioluminescence imaging (BLI)
  • X and Y are each independently selected from the group comprising oxygen, sulfur, carb group.
  • Z is selected from the roup comprising
  • R.4 is selected from the group comprising -(C y FFj, aromatic six-membered aryl and aromatic six-membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, oxygen; wherein a is an integer from 1-50.
  • V and W are each independently selected from the group comprising aromatic six-membered aryl and aromatic six-membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, oxygen.
  • Ri is selected from the group comprising -(CH2) a CH3, aromatic six-membered aryl and aromatic six-membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, oxygen; wherein a is an integer from 1-50;
  • the present invention further provides use of the phosphine compound of the invention for detection of azido-modified compounds in living cells, living plants or subjects by Bioluminescence imaging (BLI).
  • BLI Bioluminescence imaging
  • the present invention further provides a kit for Bioluminescence imaging of metabolic fluxes and biomolecules in living cells, living plants or subjects, said kit comprising at least one phosphine compound of the present invention and at least one azido-modified compound.
  • the present invention also provides a method for Bioluminescence imaging of metabolic fluxes and biomolecules in living cells, living plant or a subject, said method comprising the steps of: either
  • Figure 1 shows chemical reaction in which a phosphine or phosphite react with an azide to produce an iminophosphorane intermediate which upon hydrolysis leads to the formation of an amine/amide bond and a phosphine oxide derivative.
  • B The scheme shows the general mechanism of metabolites-azide uptake imaging.
  • Figure 2 shows light output from the Staudinger ligation in cell-free assay with Lip-CLP and Azido-NR. Error bars are ⁇ SD. * - statistically significant difference between signal from NR Az R+Lip-CLP versus Lip-CLP.
  • Figure 3 shows total amount of light from reaction of AzNR with LipCLP in MDA-MB-231 Luc cells.
  • Regular NR was used as a control and no difference were obtained between wells with NR+LipCLP versus wells with LipCLP. Error bars are ⁇ SD. * - statistically significant difference between signal from NR/AzNR+Lip-CLP versus Lip-CLP (p ⁇ 0.05). Error bars are ⁇ SD.
  • Figure 4 shows total photon flux for Staudinger Ligation between GAz 1, 2, 3, 5, 6 and LipCLP. Error bars are ⁇ SD. * -represents statistically significant difference between signal-to-noise ratio. Numbers represent the difference in signal between GAz + LipCLP versus LipCLP.
  • Figure 5 shows normalized total photon flux after 12 hours incubation of caged luciferin probe with azido-sugars in cell lysates. Error bars are ⁇ SD. Normalized total photon flux 24 hours. Error bars are ⁇ SD. * - statistically significant difference between signal from GAz + CLP versus CLP. Numbers represent the difference in signal between GAz + CLP versus CLP.
  • Black dots Background signal from mouse injected with normal glucose and Lip-CLP, black square: Signal from mouse treated with GAzl and Lip-CLP.
  • aromatic or “aromatic group” refers to six membered carbocyclic rings (aryl rings).
  • heteromatic denotes six-membered carbocyclic rings (aryl rings) containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably containing 1 to 4 heteroatoms selected from nitrogen, sulphur, oxygen, preferably containing nitrogen, either alone or in combination with sulfur or oxygen atom in the aromatic ring.
  • the present invention relates to a phosphine compound according to the Formula I useful in Bioluminescence imaging (BLI)
  • X and Y are each independently selected from the group comprising oxygen, sulfur, carb group.
  • Z is selected from the group comprising
  • R4 is selected from the group comprising -(CH2) a CH3, aromatic six-membered aryl and aromatic six-membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, oxygen; wherein a is an integer from 1-50.
  • V and W are each independently selected from the group comprising aromatic six-membered aryl and aromatic six-membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, oxygen.
  • Ri is selected from the group comprising -(CH2) a CH3, aromatic six-membered aryl and aromatic six-membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, oxygen; wherein a is an integer from 1-50;
  • the phosphine compound of the present invention comprises (i) a substrate for the luciferase, which, upon enzymatic reaction with the luciferase yields a detectable chemiluminescent signal, and (ii) phosphine-containing moiety.
  • the substrate for luciferase is preferably luciferin or a luciferin derivative.
  • Luciferin can be selected from the group comprising luciferin (e.g., a firefly luciferin), dihydroluciferin, luciferin 6' methylether.
  • the phosphine compound of the present invention is the compound of formula II:
  • the use of the phosphine compounds of the present invention is based on the use of the Staudinger Ligation in order to image metabolites-derivatives or biomolecules using bioluminescence imaging.
  • Metabolite derivatives or biomolecules bearing an azido group can be imaged using the phosphine-luciferin compounds of the present invention.
  • the free D-luciferin as a substrate of firefly luciferase, is oxidized by the enzyme and leads to conversion of luciferin to oxyluciferin, which is accompanied by production of light during this bioluminescent reaction and the light can be detected using CCD camera.
  • the present invention provides combinations of components of biologically active moieties which are functionalized so as to (re-) assemble into an intact biologically active molecule or a compound having essentially the same activity as the biologically active molecule based on either the traceless and non-traceless Staudinger ligation.
  • cells, plant or animal are first incubated/injected with azido-modified compounds (azido analogues of glucose, lactate, pyruvate, nicotinamide riboside, nicotinamide). Sufficient time is then given to allow internalization of said azido-modified compounds. Then, in a second step, cells, plant or animal are incubated/injected with the modified phosphine-luciferin compound, and luminescent emission is acquired over the time. Alternatively, cells, plant or animal are first incubated/injected with the modified phosphine-luciferin compound (the compound of the invention).
  • azido-modified compounds azido analogues of glucose, lactate, pyruvate, nicotinamide riboside, nicotinamide.
  • azido-modified compounds (azido analogues of glucose, lactate, pyruvate, nicotinamide riboside, nicotinamide) are incubated/injected and luminescent emission is acquired over the time.
  • the time for internalization is typically in the range of 5 minutes up to 5 hours, depending on used compounds, cells, plants and/or organs.
  • the present invention also provides a method for Bioluminescence imaging of metabolic fluxes and biomolecules in living cells, living plant or a subject, said method comprising the steps of:
  • metabolite or biomolecule uptake in particular tissues, organs or domains can be determined and imaged by bioluminescence.
  • Cellular uptake of different azido-modified compounds (metabolites) such as azido-glucose, lactate-azide, azido pyruvate, azido nicotinamide riboside, azido nicotinamide can also be quantified using this fast, cheap and convenient technology to understand metabolite behavior in important diseases such as cancer, diabetes and Alzheimer.
  • Metabolic flux is analysis related to examination of production and consumption rates of metabolites or biomolecules in biological systems, such as living organisms.
  • Living organisms include living cells (such as bacterial cells, prokaryotic cells, eukaryotic cells, plant cells), living plants, living tissues, living organs or subjects.
  • the method of the present invention can be carried out in-vivo, in-vitro and/or ex-vivo.
  • biomolecule is any molecule that is produced by a living organism, including large macromolecules such as proteins, polysaccharides, lipids and nucleic acids, as well as small molecules such as primary metabolites, secondary metabolites and natural products.
  • said biomolecules bear at least one azido group, preferably one azido group, in order to be imaged according to the method of the present invention.
  • said biomolecules are small molecules of biological relevance or biomolecules.
  • the term "subject" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human.
  • the subject is a subject in need of treatment or a subject with a disease or disorder, such as cancer, diabetes or Alzheimer.
  • a disease or disorder such as cancer, diabetes or Alzheimer.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.
  • Detecting luminescent emission can be done by any appropriate detection means, such as ultrasensitive CCD camera or photon-counting video camera.
  • cell permeable or cell-permeable and releasable phosphine-luciferin compounds of the invention are suitable for intracellular measurements and phosphine-luciferin conjugates for extracellular imaging.
  • the azido-modified compound can be any compound, preferably any biomolecule, modified to contain an azido group.
  • Unnatural azide-compounds can be easily synthesized or selected from a group of commercially available compounds, such as:
  • L is selected from an aliphatic group or water soluble linker.
  • aliphatic group can be linear, branched or cyclic (C3 ⁇ 4)n, n is an integer from 1 to 50.
  • the water soluble linker can be hydrophilic spacer linkers formed primarily from carbon, hydrogen, and oxygen, and have a carbon/oxygen ratio of about 3 : 1 or less, or of about 2: 1 or less.
  • soluble hydrophilic linkers include a plurality of ether and/or hydroxyl functional
  • linkers include polyhydroxyl compounds such as carbohydrates, polyether compounds such as polyethylene glycol units, and acid groups such as carboxyl and alkyl sulfuric acids and oligoamide spacers formed from amino acids.
  • the linkers can also be derived from acids, to carry a negative charge include carboxylic acids, such as aspartic acid, glutamic acid, and longer chain carboxylic acid groups, and sulfuric acid esters, such as alkyl esters of sulfuric acid.
  • the linkers can also carry a positive charge through protonation of amino groups, such as polyaminoalkylenes including ethylene diamines, propylene diamines, butylene diamines and/or heterocycles including pyrollidines, piperidines, piperazines, and other amino groups, each of which is optionally substituted.
  • the regions of the linkers that are neutral include poly hydroxyl groups, such as sugars, carbohydrates, saccharides, inositols, and the like, and/or polyether groups, such as polyoxyalkylene groups including polyoxyethylene, polyoxypropylene,
  • the present invention further provides the use of the phosphine compound of the invention for detection of azido-modified compounds, such as azido-modified biomolecules in living cells, living plants or subjects by Bioluminescence imaging (BLI).
  • the phosphine compounds of the present invention can be used in Bioluminescence imaging (BLI) able to image and quantify non-invasively, in vitro and in vivo, intracellular metabolite fluxes and which can be applied to any kind of azido-modified compounds, such as azido-modified biomolecules; for example azido-glucose, lactate-azide, azido-pyruvate, azido nicotinamide riboside, azido nicotinamide, or any other azido-modified biomolecule as long as the azido-modified compounds have similar properties and behavior as unmodified (native, natural) compounds, for example divers metabolites or biomolecules.
  • Detection of azido-modified compounds includes assaying, imaging, monitoring or otherwise establishing presence, production, evolution, uptake and/or consumption of the azido- modified compounds in living cells, living plants or subjects.
  • the present invention also provides a kit for Bioluminescence imaging of metabolic fluxes and biomolecules in living cells, living plants or subjects, said kit comprising at least one phosphine compound of the present invention and at least one azido-modified compound.
  • the kit can further contain separate containers, dividers or compartments for the reagents, administration / injection devices and informational material.
  • the informational material of the kits is not limited in its form.
  • the informational material e.g., instructions
  • the informational material is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet.
  • the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording.
  • the informational material can also be provided in any combination of formats.
  • MDA-MB-231 Luc cell line which is stably expresses luciferase were plated in 96 well-plate and grown to confluency. Cells were pretreated for 1 hour with Lip-CLP (10 ⁇ ), washed (3x) with PBS followed by addition of solutions of AzNR or NR as control (100, 10 ⁇ ). Bioluminescent signal was acquired using a charge coupled device camera and Living Image software (IVIS spectrum, Xenogen Corp.) for up to 120 min. During this experiment, we obtained 32-times difference between signal from Staudinger ligation between AzNR (100 ⁇ ) and Lip-CLP versus Lip-CLP and 13 -times in case of 10 ⁇ AzNR ( Figure 3).
  • Example 5 Synthesis of Azido-glucose derivatives
  • Diacetone glucose (36 mg, 0.139 mmol) was dissolved in DMF (1 mL) and NaH (95%, 4.9 mg, 0.192 mmol) was added at 0 °C.
  • the reaction was allowed to reach room temperature over 15 min, after which 5-azido-pentyl-tosylate (30 mg, 0.107 mmol) dissolved in DMF (1 mL) was added. After 30 min, the reaction was put at 50 °C and left overnight.
  • TLC hexane:EtOAc 2: 1 showed formation of a main product (Rf 0.7) and disappearance of diacetone glucose (Rf 0.4). After 18 h, the reaction was quenched by the addition of MeOH at 0 °C.
  • 3-azido-pyridine was synthesized following the protocol described in Colombano, G., et al., Journal of medicinal chemistry, 2010. 53(2): p. 616-23.
  • SKOV3- Luc D3 cells (human ovarian cancer cell line) were plated in 96 well-plate and grown to confluency in complete DMEM media. Cells were first washed twice with PBS and incubated with 500 ⁇ GAz 5, 6, and 7 in glucose depleted DMEM media for 0.1, 0.3, 1, 10, 30, 60 min. The cells were then washed with glucose depleted DMEM media (2x) and lysed by using freezing/thawing method. Resulting ly sates were treated with CLP (final concentration 100 ⁇ ) for 12 hours and corresponding bioluminescent signal was measured for 2 hours (Figure 5).
  • Example 8 ADG imaging in nu/nu mice with subcutaneous SKOV3-Luc-D3 tumor xenografts.
  • mice were injected with the Lip-CLP probe (Img/mice from a 25 mg/mL stock solution) and imaging was performed over lh (auto exposure, imaged every min) (Figure 6).
  • Lip-CLP probe Img/mice from a 25 mg/mL stock solution

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Abstract

La présente invention concerne une technique permettant de détecter des molécules de petite taille au moyen de l'imagerie par bioluminescence (IBL) afin d'obtenir des images et de quantifier de manière non invasive des flux de métabolites in vitro et in vivo, laquelle technique peut être appliquée à des composés azido-modifiés, tels que des biomolécules azido-modifiées.
PCT/IB2014/058440 2013-01-21 2014-01-21 Imagerie par bioluminescence de biomolécules de petite taille Ceased WO2014111906A1 (fr)

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CN104610355A (zh) * 2015-01-27 2015-05-13 华东师范大学 基于吲哚骨架的中心手性亚磺酰胺类单膦配体及制备方法
CN104804006A (zh) * 2014-12-25 2015-07-29 江苏师范大学 一种合成手性Tr*ger′s base衍生物的方法
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US10570150B2 (en) * 2014-01-17 2020-02-25 The Board Of Trustees Of The Leland Stanford Junior University 6,7-trans cephalosporin-based probes for detecting bacteria expressing a metallo-beta-lactamase
US10618927B1 (en) 2019-03-22 2020-04-14 Metro International Biotech, Llc Compositions and methods for modulation of nicotinamide adenine dinucleotide
US11180521B2 (en) 2018-01-30 2021-11-23 Metro International Biotech, Llc Nicotinamide riboside analogs, pharmaceutical compositions, and uses thereof
US11414407B2 (en) 2017-12-22 2022-08-16 Elysium Health, Inc. Crystalline forms of nicotinamide riboside chloride
WO2023147161A3 (fr) * 2022-01-31 2023-10-05 New Frontier Bio, Inc. Composés à base de nicotinate riboside et de nicotinamide riboside et leurs dérivés
US11787830B2 (en) 2021-05-27 2023-10-17 Metro International Biotech, Llc Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use
US11939348B2 (en) 2019-03-22 2024-03-26 Metro International Biotech, Llc Compositions comprising a phosphorus derivative of nicotinamide riboside and methods for modulation of nicotinamide adenine dinucleotide
CN118026953A (zh) * 2024-04-12 2024-05-14 四川大学华西医院 生物发光探针及其制备方法和用途、用于检测羧酸酯酶2的生物发光检测试剂盒和检测方法
CN119390665A (zh) * 2024-11-06 2025-02-07 四川大学华西医院 一种活体检测羧酸酯酶2的化合物、或其盐、或其立体异构体，及其制备方法与应用

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