EP2044035A1 - Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons - Google Patents

Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons

Info

Publication number
EP2044035A1
EP2044035A1 EP07726066A EP07726066A EP2044035A1 EP 2044035 A1 EP2044035 A1 EP 2044035A1 EP 07726066 A EP07726066 A EP 07726066A EP 07726066 A EP07726066 A EP 07726066A EP 2044035 A1 EP2044035 A1 EP 2044035A1
Authority
EP
European Patent Office
Prior art keywords
tetrazine
diene
darinv
dienophile
sub
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07726066A
Other languages
German (de)
English (en)
Inventor
Manfred Wiessler
Eduard Müller
Peter Lorenz
Christian Kliem
Heinz Fleischhacker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Deutsches Krebsforschungszentrum DKFZ
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Deutsches Krebsforschungszentrum DKFZ filed Critical Deutsches Krebsforschungszentrum DKFZ
Priority to EP07726066A priority Critical patent/EP2044035A1/fr
Publication of EP2044035A1 publication Critical patent/EP2044035A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the object of the present invention is therefore to provide a method with which complex compounds can be covalently and irreversibly linked to each other and which can also be used for the construction of substance libraries.
  • R H, alkyl, aryl, heterocycle, which in turn may be optionally substituted with alkyl, OH, SH, halogen, aryl, heterocycle, nitro, carboxyamido, or amine Group.
  • the diene component may, however, also carry amino acid, peptide, saccharide, lipid or oligonucleotide or nucleic acid substituents at one or more positions.
  • the diene component can also be coupled to all types of pharmaceutical actives, labels, dyes, complexes (e.g., carborane, ferrocene), quantum dots, chelating agents, diagnostics or therapeutics, and combinations thereof
  • Tetrazines have a high reactivity as dienes in the inverse DAR.
  • the model compound for many studies is the readily available tetrazinodicarboxylic acid dimethyl ester.
  • changes to this compound such as nucleophilic substitutions, but lead to decomposition.
  • many reactions of the ester function with nucleophiles can be easily and quickly performed on the dihydro precursor. Since the rate of the first nucleophilic substitution with amines is usually greater than the rate of the second nucleophilic substitution, monosubstituted amides are easily prepared, thus opening the way to the preparation of unsymmetrical diamides.
  • the peptides can also be labeled either on the solid phase or after cleavage by the DARinv with dyes or biotin.
  • the aim is to produce platinum complexes in which either the diamine ligand or the dicarboxylic acids used as the leaving group are formed as dienophile or as diene.
  • the structures listed below are intended to illustrate this concept. This makes it possible to selectively the respective part of the Complex by the DARinv targeted change. This makes possible the construction of libraries of the original complex.
  • the change in the leaving group, in this case the dicarboxylic acid, by the DARinv appears to be particularly interesting since this leaving group is split off during the intracellular activation of the Pt complexes and thus also the respective part attached by the DARinv.
  • platinum complex of 1,2,3-triaminopropane shown is known, it can be bound to the tetrazine via its free amino group, thus providing another building block for the incorporation of Pt complexes into proteins, saccharides and other biomolecules and therapeutics.
  • Positron emission tomography is a radioactive, non-invasive, but very sensitive diagnostic method.
  • the most commonly used positron emitter is F18, which decays into the element oxygen with a half-life of 18 min, releasing a positron. Because of the low Half life requires the preparation of appropriate F18-labeled compound in particular synthetic methods. They have to run fast and necessary cleaning procedures have to be easy.
  • the most commonly used compound today is 2-fluoro18-2-deoxy-glucose.
  • the ligation reaction based on the DARinv can be used very well for labeling peptides, oligonucleotides and saccharides with F18.
  • Nucleophilic substitution reactions on aromatics are facilitated as the number of nitrogen atoms in the ring increases, such as in the series benzene, pyridine, pyrimidine and triazine.
  • a thiomethyl radical can easily be replaced by a number of nucleophiles, including halogens.
  • triazines react as dienes in the DARinv
  • the prior introduction of F18 into such a triazine offers the elegant possibility to label the abovementioned biopolymers with F18 with the aid of the DARinv and thus make them accessible for detection by PET.
  • the classical way of nucleophilic substitution on tosylates with fluoride can be labeled (see below).
  • the introduction of trifluoroacetyl groups labeled F18 via the amine function of the described tetrazines and triazines can be used here.
  • the tetrazine can be trifluoacetylated in pyridine and directly in the Solution that DARinv perform.
  • the DARinv allows very short reaction times and usually proceeds without the formation of by-products.
  • the dihydro-tetrazine dicarboxylic acid ester can be reacted with amines at RT with primary amines.
  • This high reactivity can be used to build up reactive solid phases.
  • the reaction sequences shown here can be carried out in yields between 70 and 90%.
  • solid phases are available which carry either a diene or a dienophile for the DARinv.
  • the reactivity in the DARinv is so high that the dienophile-bearing solid phase can be literally titrated with a tetrazine.
  • the resulting applications range from the chip technology for oligonucleotides, proteins or saccharides to catalytic surfaces and solid phase reagents.
  • any substituents can be introduced into oligonucleotides obtained by synthesis.
  • the required amidites have been prepared by and. In this way, a multiple mark is possible.
  • Quantum dots are nanoparticles made up of compounds such as CdS or CdSe and have special optical properties. Upon excitation with lasers they fluoresce very strongly depending on their size and therefore find more and more use in the diagnostic field, especially as they make the detection of single molecules possible. The prerequisite for this, however, is their doping with functional groups which proceeds via SH groups and permits a subsequent interaction with the molecules to be detected. Due to their special properties, gold nanoparticles are used for electron microscopic investigations of biomolecules. Again, the anchoring of molecules on the surface via SH groups accomplished. Again, the new ligation technique can be used by DARinv.
  • SH-group-containing triazines and tetrazines were prepared, wherein first the disulfides were prepared and from this by reduction with dithiothreitol the mercapto compound.
  • SH-containing dienophiles of the norbornene type can also be prepared. The disulfides themselves were also anchored to gold surfaces.
  • both the dienes tetrazines, triazines and diazines
  • dienophiles can be deposited via the disulfide group as to the surface of the quantum dots or other metals and are therefore accessible to the DARinv.
  • antibodies, peptides, saccharides or therapeutics can be anchored to the surface of the quantum dots for diagnostic or therapeutic purposes.
  • the synthesis of complex saccharide structures requires a sophisticated protecting group strategy.
  • the reducing end is often protected by an allyl group or a pentenoyl group.
  • isolated oligosaccharides can be easily provided with an allyl group or pentenoyl group at the reducing end.
  • the conditions for anchoring these oligosaccharides to a solid phase or surface are given by the DARinv.
  • the furan saccharide mimetics described in DE-A-100 41 221.1 can likewise be anchored either to biomolecules or surfaces with the aid of this DARinv technology.
  • Prerequisite is the introduction of an allyl ether group or the use of linker molecules as described above.
  • saccharide mimetics are also suitable as inverse dienophiles in the DARinv and can thus be introduced into any biomolecules.
  • vitamin A, vitamin C, curcumin or other therapeutic agents can be coupled to proteins or surfaces and released there by hydrolysis or enzymatic cleavage.
  • Another example of this application is the temozolomide used to treat brain tumors, which can be coupled via its acid function either to a tetrazine or to a dienohile.
  • the DARinv then the coupling to peptides is possible.
  • liposomes containing double bonds that are active in the DARinv can be easily modified with this technology, thereby improving targeting or modification
  • Both systems are suitable for the sequential coupling of molecules which carry either the same dienophile as L 1820 or different dienophiles such as L 1825.
  • This type of compound is also suitable for anchoring to a solid phase by reaction with the carbonyl or the carbonyl group
  • the ketone dicyclopentadienone is an orthogonal dienophile that is accessible to both normal DAR and DARinv. By reaction with butadiene, it can also be converted into a double inverse dienophile (s. In addition to these linkers from dienophiles, linkers from dienes that allow DAR and DARinv at the same time are also available.
  • linkers from dienophiles linkers from dienes that allow DAR and DARinv at the same time are also available.
  • the combination of tetrazine or triazine with a dienophile, such as a maleimide, for the classical DAR is possible. The structures are listed below.
  • novel tetrazines, triazines and diazines as dienes in the DARinv can be with dienophiles, such as enamines, enol ethers, etc., build novel libraries of substances to search for new drugs.
  • the diamides themselves are, as described, accessible in large numbers by successive reactions with various amines and subsequent oxidation. This reaction sequence can be automated.
  • sufficient water solubility is an important prerequisite.
  • One possible approach to improving water solubility and thus oral availability is the covalent attachment of drugs to saccharides to form conjugates.
  • Fig. 2 Diels-Alder reaction with inverse electron demand
  • the peptide was synthesized on the synthesizer, with the previously described lysine derivative added with the tricyclic dienophile. This peptide was purified by HPLC and the structure confirmed by the mass spectrum. Molecular peak at m / e 899.
  • Dihydro-tetrazine-3,6-dicarboxylic acid dimethyl ester 200 mg (1 mmol) are suspended in 5 ml of methanol and (2.5 mmol) glycine methyl ester in 5 ml of methanol - from 2.5 mmol glycine methyl ester hydrochloride and 2.5 mmol triethylamine prepared - added dropwise and stirred overnight at room temperature.
  • the reddish solution has turned pale yellow and a yellow precipitate has formed. After cooling to -18 ° C, this precipitate is filtered off and recrystallized from methanol. Yield 55%.
  • Mass spectrum and NMR confirm the structure.
  • the resulting silica gel was suspended in ethyl acetate and shaken with a 5-fold excess of isoamyl nitrite for 5 hrs at room temperature. It was filtered, washed several times with ethyl acetate and ether and dried. The silica had now assumed a light pink color.
  • the elemental analysis revealed only minor changes in the C / N ratio.
  • the Diels Alder reaction was carried out with the already used tricyclic anhydride. 100 mg of the tetrazine-loaded silica gel were suspended in ethyl acetate and shaken with 0.3 mmol of the anhydride for 2 hours at room temperature. It was filtered again, washed 5 times with ethyl acetate and dried.
  • the C / N ratio of the elemental analysis confirmed the original specific silica occupancy with dihydrotetrazine at about 70%.
  • Amino-functionalized silica gel (1g.) was suspended in 10 ml of ethanol, 2 mmol (400mg) of the tricyclic anhydride was added and shaken for 3 hrs. At 80 0 C. It was filtered off with suction through a frit, washed several times with ethanol and finally with ether and dried. The determination of the C / N ratio by elemental analysis revealed a coverage of 70% of the available amino groups.
  • the triazine tri-carboxylic acid methyl ester 1 mmol (255 mg) was dissolved in 2 ml THF and treated dropwise with a solution of 1 mmol (248 mg) of the tricyclic dicarboxylic acid dimethyl ester in 1 ml of THF. It is observed nitrogen evolution and a color lightening. After 2 hours at room temperature, the mixture is concentrated and the residue is chromatographed on silica gel with hexane / ethyl acetate 1: 1. 250 mg of the adduct are isolated corresponding to 50% yield. The mass spectrum confirms the structure, molecular peak at m / e 475.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne un procédé de liaison de deux molécules par réaction de Diels-Alder avec demande inverse d'électrons, ledit procédé comprenant les étapes consistant à : faire réagir une (a) triazine ou tétrazine avec un ou plusieurs substituants accepteurs d'électrons sur le cycle, en tant que composant diène, les substituants accepteurs d'électrons étant choisis parmi : - COOR - C(O)NR<SUB>2</SUB> - CX<SUB>3 </SUB>(X = halogène) - halogène -CN -SO<SUB>2</SUB>-R ou SO<SUB>3</SUB>-R - PR<SUB>2</SUB> avec R = H, alkyle, aryle, hétérocycle qui peuvent éventuellement à nouveau être substitués par les groupements alkyle, OH, SH, halogène, aryle, hétérocycle, nitro, carboxyamido ou amine, des cycles hétérocycliques avec 1, 2 ou 3 atomes N, O ou S, avec une taille de cycle de 5 ou 6 atomes, substitués par au moins un groupement carboxyle, acide sulfonique ou phosphonique, avec (b) une double ou triple liaison isolée définiques dans un cycle (hétéro)carbocyclique ou une double ou triple liaison isolée dans une chaîne hydrocarbonée linéaire ou ramifiée, pouvant éventuellement contenir des hétéroatomes, en tant que composants diénophiles.
EP07726066A 2006-06-16 2007-06-18 Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons Withdrawn EP2044035A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07726066A EP2044035A1 (fr) 2006-06-16 2007-06-18 Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06012414A EP1867638A1 (fr) 2006-06-16 2006-06-16 Procédé pour le lien de deux molécules par une réaction Diels-Alder avec une demande d'électron inverse
EP07726066A EP2044035A1 (fr) 2006-06-16 2007-06-18 Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons
PCT/EP2007/005361 WO2007144200A1 (fr) 2006-06-16 2007-06-18 Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons

Publications (1)

Publication Number Publication Date
EP2044035A1 true EP2044035A1 (fr) 2009-04-08

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EP06012414A Withdrawn EP1867638A1 (fr) 2006-06-16 2006-06-16 Procédé pour le lien de deux molécules par une réaction Diels-Alder avec une demande d'électron inverse
EP07726066A Withdrawn EP2044035A1 (fr) 2006-06-16 2007-06-18 Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons

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US (1) US8552183B2 (fr)
EP (2) EP1867638A1 (fr)
JP (1) JP5641735B2 (fr)
WO (1) WO2007144200A1 (fr)

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US8236949B2 (en) 2007-07-17 2012-08-07 University Of Delaware Tetrazine-based bio-orthogonal coupling reagents and methods
US8900549B2 (en) 2008-10-31 2014-12-02 The General Hospital Corporation Compositions and methods for delivering a substance to a biological target
EP2360167A1 (fr) 2010-02-03 2011-08-24 Deutsches Krebsforschungszentrum Modification post-synthétique d'acides nucléiques par réaction Diels-Alder inverse
EP2423191A1 (fr) * 2010-08-13 2012-02-29 Deutsches Krebsforschungszentrum Procédé d'application d'un premier métal sur un second, isolateur ou substrat à semi-conducteur et unités de liaison respectives
EP2441754A1 (fr) * 2010-10-13 2012-04-18 Deutsches Krebsforschungszentrum Nouveau dérivé de la dimédone et procédé de purification de PNA et oligomères de peptide
WO2012121746A2 (fr) 2011-03-09 2012-09-13 The General Hospital Corporation Imagerie de la masse des cellules bêta
JP2015518722A (ja) * 2012-05-21 2015-07-06 アジレント・テクノロジーズ・インクＡｇｉｌｅｎｔ Ｔｅｃｈｎｏｌｏｇｉｅｓ， Ｉｎｃ． Ｄｎａ／ｒｎａ用途における切断可能なリンカーとしてのレトロディールスアルダー反応
US9902705B2 (en) 2012-10-24 2018-02-27 The General Hospital Corporation Functionalized 1,2,4,5-tetrazine compounds for use in bioorthogonal coupling reactions
WO2014182704A2 (fr) 2013-05-06 2014-11-13 The General Hospital Corporation Sondes d'activation bio-orthogonales
CN105611914B (zh) 2013-06-19 2020-09-08 加利福尼亚大学董事会 局部递送治疗剂的化学构造物
ES2880468T3 (es) 2014-03-14 2021-11-24 Univ California Conjugados de TCO y métodos para el suministro de agentes terapéuticos
AU2015236392A1 (en) 2014-03-24 2016-10-20 Genia Technologies, Inc. Chemical methods for producing tagged nucleotides
US10731018B2 (en) 2015-08-11 2020-08-04 Arizona Board Of Regents On Behalf Of The University Of Arizona Antioxidant polydihydropyridazine and polypyridazine foams from 1,2,4,5-tetrazine
US10619023B2 (en) * 2015-08-11 2020-04-14 Arizona Board Of Regents On Behalf Of The University Of Arizona Green chemistry method of synthesizing polymer structures that can function as a built-in antioxidant
US10851192B2 (en) 2015-08-11 2020-12-01 Arizona Board Of Regents On Behalf Of The University Of Arizona Dihydropyridazine-based antioxidants and uses thereof
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WO2017106427A1 (fr) * 2015-12-15 2017-06-22 Joseph Fox Procédés pour induire une réactivité bio-orthogonale
WO2018005864A1 (fr) * 2016-06-29 2018-01-04 The Arizona Board Of Regents On Behalf Of The University Of Arizona Procédé de formation d'un réseau robuste de mousse à travers la réaction de diels-alder
JP6873744B2 (ja) * 2017-02-28 2021-05-19 大塚化学株式会社 ゴム組成物、及びこれを用いたタイヤ
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US11325925B2 (en) 2017-09-01 2022-05-10 Arizona Board Of Regents On Behalf Of The University Of Arizona Dihydropyridazine antioxidant sunscreens
WO2019084323A1 (fr) 2017-10-25 2019-05-02 Georgia State University Research Foundation, Inc. Système de libération de produits chimiques déclenchée par enrichissement
CN107827834B (zh) * 2017-11-29 2021-04-06 天津大学 5-芳基-6-三氟甲基-1,2,4-三氮嗪-3-甲酸酯化合物及制备方法
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US8552183B2 (en) 2013-10-08
JP2009539911A (ja) 2009-11-19
US20100016545A1 (en) 2010-01-21
EP1867638A1 (fr) 2007-12-19
JP5641735B2 (ja) 2014-12-17
WO2007144200A1 (fr) 2007-12-21

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