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WO2000001663A1 - Nouveaux chelates fluorescents aux lanthanides - Google Patents

Nouveaux chelates fluorescents aux lanthanides Download PDF

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Publication number
WO2000001663A1
WO2000001663A1 PCT/US1999/015366 US9915366W WO0001663A1 WO 2000001663 A1 WO2000001663 A1 WO 2000001663A1 US 9915366 W US9915366 W US 9915366W WO 0001663 A1 WO0001663 A1 WO 0001663A1
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WO
WIPO (PCT)
Prior art keywords
group
dtpa
iii
compound
formula
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Ceased
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PCT/US1999/015366
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English (en)
Inventor
George Wai-Kin Chan
Robert P. Hertzberg
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication date
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Priority to JP2000558068A priority Critical patent/JP2002519404A/ja
Priority to US09/720,965 priority patent/US6740756B1/en
Priority to CA002336904A priority patent/CA2336904A1/fr
Priority to EP99932334A priority patent/EP1095011A4/fr
Publication of WO2000001663A1 publication Critical patent/WO2000001663A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K49/0026—Acridine dyes
    • 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
    • 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
    • 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
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • 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
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/16—Isothiocyanates
    • C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention relates to the identification and preparation of organic agents that can complex lanthanide cations.
  • this invention relates to complexing agents which contain novel photosensitizers and can produce long-lived fluorescence for use in bioaffinity assays, especially HTRF (homogeneous time-resolved fluorescence) assays.
  • HTRF homogeneous time-resolved fluorescence
  • a wide variety of bioassays are used in the pharmaceutical industry to identify drug development candidate compounds. Recent advances in the identification of pharmaceutical targets, together with the vastly increased output of new compounds using techniques such as combinatorial chemistry have created a need to increase bioassay throughput (number of samples measured per unit time) drastically to meet discovery objectives.
  • Robotics, miniaturization and homogeneous assay formats have all been incorporated into high throughput screening (HTS) assays to increase throughput.
  • HTS high throughput screening
  • an analytical technique suitable for both miniaturization and homogeneous assay formats must provide maximal detection sensitivity and interaction in situ, while requiring only minimal assay time and liquid handling (e.g., separation and filtration).
  • Present analytical techniques, such as those which use radiolabels are unsatisfactory for HTS use because they lack sensitivity, require large sample size and manual liquid handling.
  • fluorescent labels Compared to traditional radiolabels, fluorescent labels have more desirable lifetime, solubility and sensitivity properties for use in HTS assays.
  • the unique lifetime properties of fluorescent labels also meet the needs of fluorescence polarization (FP) and fluorescence correlation spectroscopy (FCS) in the investigation of slow rotational and translational changes in macromolecules.
  • FP fluorescence polarization
  • FCS fluorescence correlation spectroscopy
  • lanthanide chelates have been developed as fluorescence agents for use in the bioassay field. These lanthanide chelates have been reviewed. See Dickson, J. Photochemistry and Photobiology, 27 (1995) 3-19; and Mathis, J. Clinical Ligand Assay 20 (1997) 141-145.
  • the lanthanide chelates are capable of producing long-lived and long wavelength fluorescent emissions upon excitation. In time-delay measurements, they have demonstrated clear advantages over conventional fluorescent labels, in particular less quenching and background interference, while exhibiting increased detection sensitivity.
  • lanthanide chelates have demonstrated superior solubility properties and are able to efficiently transfer energy from their excited states to neighboring acceptor molecules. These advantages render lanthanide chelates ideal agents for HTRF use, especially for developing high-throughput automated and miniaturized binding assays, inncluding immunoassays, DNA hybridization assays, receptor binding assays, enzyme assays, cell-based assays, immunocytochemcial or immunohistochemical assays.
  • lanthanide e.g. terbium, europium
  • Table I three classes of lanthanide chelates, exemplified by the compounds shown in Table I below, are considered to be useful in HTRF:
  • DTPA Chelates (Berkeley) diethylenetriamine-pentaacetic acid type; i.e.
  • PMDA Chelates (Wallac) pyridylmethylamine-diacetic acid type; i.e. These chelates have been described as having chemical stability, long-lived fluorescence (greater than 0.1 ms lifetime) after bioconjugation and significant energy- transfer in specific bioaffinity assays.
  • US5162508, issued to Lehn, et al. on November 10, 1992 discloses bipyridine cryptates.
  • Polycarboxylate chelators with TEKES type photosensitizers (EP 0203047 Al) and te ⁇ yridine type photosensitizers (EP 0649020 Al) are known.
  • WO 96/00901 of Selvin et al. having an International Publication Date of January 11, 1996, discloses diethylenetriaminepentaacetic acid (DTPA) chelates which used carbostyril as sensitizer.
  • DTPA diethylenetriaminepentaacetic acid
  • Bailey, et al., Analyst, 109, (1984) 1449; Ando, et al. Biochim. Biophys. Acta. 1102, (1992) 186; and Heyduk et al., Anal. Biochemistry, 248, (1997) 216 also describe DTPA lanthanide chelates which contain different sensitizers. Additional DTPA chelates with other sensitizers and other tracer metals are known for diagnostic or imaging use (e.g., EP 0450742 Al).
  • the lanthanide chelates provided by the present invention include novel sensitizers which differ from carbostyril and other known chelates. More specifically, these novel sensitizers impart onto the present chelates advantageous physicochemical properties pertaining to excitation wavelength, lifetime, quantum yield, quenching effect, complex stability, photostability, solubility, charge, nonspecific protein interaction, biocoupling efficiency and ease of preparation. Such advantages are desirable to provide a diversity of novel fluorescent probes for use in, and development of, HTRF assays.
  • An object of the present invention is to provide novel lanthanide chelate compounds, and a method for using such compounds in fluorescence detection-based techniques or bioassays. Accordingly, in the first aspect, this invention provides a compound according to
  • this invention provides a method for using the compounds of Formula I in fluorescence detection-based techniques or bioassays.
  • this invention provides a kit for fluorescence detection-based techniques or bioassays which use the compounds of Formula I as the basis for signal detection and measurement.
  • Each compound of the present invention comprises four functional parts: a lanthanide metal cation (e.g. Tb III, Eu III, Sm III, Dy III), a chelator for the lanthanide metal, a photosensitizer for photoexcitation and energy transfer, and a linker for bioconjugation to the target biomolecule, that is, the biomolecule being measured using a fluorescence detection -based spectroscopic technique or bioassay.
  • a lanthanide metal cation e.g. Tb III, Eu III, Sm III, Dy III
  • a chelator for the lanthanide metal e.g. Tb III, Eu III, Sm III, Dy III
  • a photosensitizer for photoexcitation and energy transfer e.g., a photosensitizer for photoexcitation and energy transfer
  • a linker for bioconjugation to the target biomolecule that is, the biomolecule being measured using a fluorescence detection -based spectroscopic technique or bio
  • the present invention provides compounds of Formula I:
  • DTPA diethylenetriaminepentaacetic acid
  • TTHA triethylenetetraaminehexaacetic acid
  • DTPA a polyaminocarboxylate derivative of DTPA or TTHA, preferably DTPA, which chelates a lanthanide metal cation, preferably selected from the group consisting of: Tb III, Eu III, Sm III, and Dy III.
  • the sensitizer Rl is usually related to an aromatic or heteroaromatic amine whose chromophore plays a vital role in excitation and energy transfer. Superior sensitizers usually have highly conjugated systems and an added capacity for lanthanide complexation. We have found several sensitizers, belonging to two structural classes- phenones and quinolines - that provide highly fluorescent compounds of Formula I. Rl is more preferably selected from the following group: aminoacetophenones (AAP), aminobenzophenones (ABP), aminofluorenones (AF), aminoxantones (AX), amino- azaxanthones (AAX), aminoanthraquinones (AAQ), and aminoacridones (AAC):
  • AAP aminoacetophenones
  • ABSP aminobenzophenones
  • AF aminofluorenones
  • AX aminoxantones
  • AAX amino- azaxanthones
  • AAQ aminoanthraquinones
  • AAC aminoacridon
  • R3 and R4 are independently selected from the group consisting of: H, OH, NH2, COCH3, COPh, OPh, NHPh, CN, N0 2 , C0 2 H, C0 CH 3 , 1, Br and Cl.
  • Sensitizers of the present invention belonging to the quinoline class can be further categorized into 3- aminoquinolines (3AQ), and 6-aminoquinolines (6AQ).
  • Rl is selected from the group consisting of:
  • R3 and R4 are as defined herein above.
  • the linker R2 is an amine or other moiety having a functional group that can bioconjugate or can be derivatized to couple with biomolecules.
  • R2 is selected from the group consisting of: OH, NH(CH 2 ) n OH, NH(CH2) n NH 2 , NH(CH 2 ) n PhNH 2 , NH(CH 2 ) n PhOH, NHCH(C02H)CH 2 PhNH 2) , NH(CH2) n PhNCS; wherein n is 1-12.
  • the present invention also contemplates the use of other linkers known in the art for coupling.
  • Particularly preferred compounds of the present invention include the DTPA chelates listed in Table II below:
  • TTHA Triethylene-tetramine-hexaacetic acid
  • More particularly preferred compounds of the present invention include the DTPA chelates below:
  • Sensitizer and chelator moiety abbreviations are as defined in Table II above.
  • bioconjugate and “bioconjugatable” mean the ability of a functional group or groups on a chemical moiety to form covalent linkage to biomolecules.
  • polycarboxylate derivative of DTPA or TTHA means a compound which differs from DTPA and TTHA by changing the length of N-acetic acid units, or by rearranging the units from a linear to a cyclic form.
  • bioassay means immunoassays, DNA hybridization assays, receptor binding assays, enzyme assays, cell-based assays, immunocytochemcial or immunohistochemical assays and the like.
  • the sensitizers and space linkers with structures described herein above are employed in a manner shown in Scheme I and in the Examples.
  • the first step in the synthetic route involves reacting the sensitizer amine, hereby exemplified by 3- aminoacetophenone, with equal or higher molar ratio of DTPAA (diethylene-triamine- pentaacetic anhydride) in the presence of triethylamine.
  • DTPAA diethylene-triamine- pentaacetic anhydride
  • the product formed is not isolated but allowed to react with an equal or a slight molar excess of the linker amine, hereby exemplified by 4-aminophenethylamine.
  • the disubstituted derivative is then isolated and purified by HPLC before converting the linker amino group into a bioconjugatable function.
  • the final step is to react the product (Compound 5) with thiophosgene in a slightly acidic condition to form the isothiocyanate (Compound 6).
  • a chlorotirazine derivative instead of an isothiocyanate can also be prepared from Compound 5 for facile labelling of target molecules with a reactive amino function.
  • the compounds of this invention can be used for labelling donor peptides, proteins,
  • bioassays can be also formated for ultrasensitive high-throughput screening assays.
  • the lanthanide chelate is excited in a fluorescence instrument and provide energy transfer to an acceptor molecule such as an organic dye (e.g. allophycocyanin (APC), or indodicarbocyanin or CY-5) capable of providing the desired long-lived fluorescense emission for quantitation.
  • an organic dye e.g. allophycocyanin (APC), or indodicarbocyanin or CY-5
  • the present invention also provides a method for using the compounds of Formula I in fluorescence detection-based techniques or bioassays.
  • the present method comprises the steps of:
  • a suitable organic dye preferably selected from the group consisting of: allophycocyanin (APC) and indodicarbocyanin (CY-5), to the labelled biomolecule assay sample;
  • Fluorescence instruments suitable for use in the inventive method include the Photon Technology International, Model LS-100, Luminescence System.
  • the present invention further provides a kit for fluorescence detection-based techniques or bioassays which use the compounds of Formula I as the basis for signal detection and measurement, such kit comprising:
  • organic dye preferably selected from the group consisting of: allophycocyanin (APC), indodicarbocyanin (CY-5) and rhodamine.
  • kit provides instructions for proper use thereof, including the appropriate amounts of the compound of Formula I and the organic dye to use for a particular bioassay sample molecular type and size.
  • FTIR Fourier transform infrared
  • Example 2 Preparation of 4AAP-DTPA-APEA-ITC (6).
  • 4AAP-DTPA-APEA 3, 12 mg, 0.019 mmol
  • thiophosgene 85% in CCI4
  • the two phase reaction was allowed to stirred vigorously for 1 h .
  • the mixture was worked up by separating the layers in a separatory funnel and the aqueos solution was washed by additional methylene chloride and then chromatographed on a small reversed-phase C18 column to give the thioisocyanate product (6), an off-white solid in 10 mg yield after lyophilization.

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  • Life Sciences & Earth Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrane Compounds (AREA)

Abstract

L'invention concerne des agents complexants de formule (I), qui contiennent des nouveaux photosensibilisants et produisent une fluorescence de longue durée, à utiliser dans les essais de bioaffinité, notamment les essais à fluorescence en temps différé homogène (HTRF).
PCT/US1999/015366 1998-07-07 1999-07-07 Nouveaux chelates fluorescents aux lanthanides Ceased WO2000001663A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000558068A JP2002519404A (ja) 1998-07-07 1999-07-07 新規蛍光ランタニドキレート
US09/720,965 US6740756B1 (en) 1998-07-07 1999-07-07 Fluorescent lanthanide chelates
CA002336904A CA2336904A1 (fr) 1998-07-07 1999-07-07 Nouveaux chelates fluorescents aux lanthanides
EP99932334A EP1095011A4 (fr) 1998-07-07 1999-07-07 Nouveaux chelates fluorescents aux lanthanides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9194498P 1998-07-07 1998-07-07
US60/091,944 1998-07-07

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WO2000001663A1 true WO2000001663A1 (fr) 2000-01-13

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JP (1) JP2002519404A (fr)
CA (1) CA2336904A1 (fr)
WO (1) WO2000001663A1 (fr)

Cited By (18)

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WO2003053980A1 (fr) * 2001-12-21 2003-07-03 Honeywell Speciality Chemicals Seelze Gmbh Composes de metaux de terres rares et melanges de ces composes
WO2002005858A3 (fr) * 2000-07-19 2003-07-24 Gen Hospital Corp Agents fluorescents utilises pour mesurer en temps reel le fonctionnement d'un organe
DE102004022628A1 (de) * 2004-05-07 2005-12-15 Sensient Imaging Technologies Gmbh FRET-Bioassay
WO2006120444A1 (fr) * 2005-05-11 2006-11-16 University Of Durham Complexes de lanthanide a reponse luminescente
US7390861B2 (en) 2000-10-19 2008-06-24 Exxonmobil Chemical Patents Inc. Cationic group-3 catalyst system
GB2451106A (en) * 2007-07-18 2009-01-21 Cis Bio Int Lanthanide (III) ion complexing pyrazoyl-aza(thio)xanthone comprising compounds, their complexes and their use as fluorescent labels
EP1771440A4 (fr) * 2004-07-23 2009-09-02 Amgen Inc Sondes generiques pour la detection de sequences phosphorylees
WO2011045166A1 (fr) 2009-09-24 2011-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Interaction fkbp52-tau comme nouvelle cible thérapeutique pour traiter les troubles neurologiques mettant en jeu un dysfonctionnement de tau
WO2011083124A1 (fr) 2010-01-05 2011-07-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes du récepteur flt3 destinés au traitement ou à la prévention de troubles douloureux
EP2399575A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés, utilisations et compositions pour le traitement d'une infection par un virus de la famille de Flaviviridae par l'inhibition de récepteur farnésoïde X (FXR)
DE102011101207B3 (de) * 2011-05-11 2012-05-10 Sartorius Stedim Biotech Gmbh Fluoreszenzfarbstoff für pH-Sensor
US8193174B2 (en) 2005-05-11 2012-06-05 University Of Durham Responsive luminescent lanthanide complexes
DE102011001368A1 (de) 2011-03-17 2012-09-20 Bundesanstalt für Materialforschung und -Prüfung (BAM) Lanthanoid-Chelate enthaltende Partikel, deren Herstellung sowie deren Verwendung in der Bioanalytik
WO2012156476A2 (fr) 2011-05-16 2012-11-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour identifier par criblage des substances capables de moduler la réplication d'un virus de la grippe
WO2014053871A1 (fr) 2012-10-04 2014-04-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédé de criblage d'un composé apte à inhiber l'activité transcriptionnelle de notch1
WO2015124588A1 (fr) 2014-02-18 2015-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et compositions pharmaceutiques pour le traitement de maladies induites par la voie de signalisation du complexe nrp-1/obr
WO2015158810A1 (fr) 2014-04-17 2015-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Polypeptides et leurs utilisations pour réduire la motilité cellulaire médiée par cd95
WO2020144324A1 (fr) 2019-01-11 2020-07-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour cribler des inhibiteurs contre le virus chikungunya et pour déterminer si des sujets sont prédisposés à une infection par ledit virus

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Publication number Priority date Publication date Assignee Title
WO2002005858A3 (fr) * 2000-07-19 2003-07-24 Gen Hospital Corp Agents fluorescents utilises pour mesurer en temps reel le fonctionnement d'un organe
US7390861B2 (en) 2000-10-19 2008-06-24 Exxonmobil Chemical Patents Inc. Cationic group-3 catalyst system
EP1337536A4 (fr) * 2000-10-19 2010-09-01 Exxonmobil Chem Patents Inc Systeme catalyseur du groupe 3 cationique
JP2005513134A (ja) * 2001-12-21 2005-05-12 ハネウェル・スペシャルティ・ケミカルズ・ゼールツェ・ゲーエムベーハー 希土類金属化合物及びこれらの混合物
WO2003053980A1 (fr) * 2001-12-21 2003-07-03 Honeywell Speciality Chemicals Seelze Gmbh Composes de metaux de terres rares et melanges de ces composes
US7399434B2 (en) 2001-12-21 2008-07-15 Honeywell International Inc Rare metal compounds and mixtures of these
US7198732B2 (en) 2001-12-21 2007-04-03 Honeywell International Inc. Rare earth metal compounds and mixtures of these
CN1329399C (zh) * 2001-12-21 2007-08-01 霍尼韦尔特殊化学品西尔兹有限责任公司 稀土金属化合物及其混合物
US8257981B2 (en) 2004-05-07 2012-09-04 Sensient Imaging Technologies Gmbh Lanthanide chelates and use thereof in bioanalysis
WO2005108405A3 (fr) * 2004-05-07 2006-02-09 Sensient Imaging Technologies Chelates de lanthanide et leur application en bioanalytique
JP2007536286A (ja) * 2004-05-07 2007-12-13 センサイエント・イメージング・テクノロジーズ・ゲーエムベーハー ランタニド・キレートと、バイオアッセイにおけるその使用
DE102004022628A1 (de) * 2004-05-07 2005-12-15 Sensient Imaging Technologies Gmbh FRET-Bioassay
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