EP0934327A1 - Saccharide library - Google Patents

Saccharide library

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Publication number
EP0934327A1
EP0934327A1 EP97912056A EP97912056A EP0934327A1 EP 0934327 A1 EP0934327 A1 EP 0934327A1 EP 97912056 A EP97912056 A EP 97912056A EP 97912056 A EP97912056 A EP 97912056A EP 0934327 A1 EP0934327 A1 EP 0934327A1
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EP
European Patent Office
Prior art keywords
saccharide
library according
saccharides
saccharide library
groups
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.)
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Application number
EP97912056A
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German (de)
French (fr)
Inventor
Manfred Wiessler
Christian Kliem
Walter Mier
Stefan Menzler
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
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Application filed by Deutsches Krebsforschungszentrum DKFZ filed Critical Deutsches Krebsforschungszentrum DKFZ
Publication of EP0934327A1 publication Critical patent/EP0934327A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • the invention relates to a saccharide library, processes for producing such and their use.
  • active ingredients e.g. B. Therapeutics on a saccharide basis. This is especially true if the active ingredients
  • Agonists or antagonists of Zeil receptors are said to be. So far, however, it has been extremely difficult to provide saccharide-based drugs, i.e. to find those that exactly match target proteins, e.g. Receptors, react.
  • the present invention is therefore based on the object of providing an agent with which active substances based on saccharide can be found.
  • the invention thus relates to a saccharide library with different saccharide-containing molecules, the saccharide-containing molecules each comprising a core molecule with at least two functional groups and at least two saccharides.
  • saccharide library means a variety, e.g. at least 6, preferably at least 20, particularly preferably at least 50 and most preferably at least 100 of different saccharide-containing molecules. These molecules can be unbound or attached to a carrier. All matrices suitable for use in the
  • Solid phase chemistry can be used, such as solid phases based on poly styrene, polyethylene glycol, diatomaceous earth, CPC (controlled pore ceramics), cellulose and glass.
  • core molecule with at least two functional groups encompasses aliphatic compounds which have at least two, in particular
  • core molecules are cyclic aliphates. Representatives of these are C 6 cycloalkanes, such as trihydroxycycloalkanes, for example 1, 3, 5-trihydroxycycloalkanes, in particular 1, 3,5-trihydroxycyclohexane, inositols, in particular myo-inositol, and C 5 cycloalkanes, such as tri- and tetrahydroxycykiopentanes and derivatives thereof.
  • Core molecules are also heterocyclic hydroxy compounds.
  • core molecules are aliphatic amines, such as triamines, in particular methylene triamines, and pentaerythritol. Particularly preferred core molecules are shown in Fig.
  • Steroids, methyl cholates and saccharides are not core molecules in the sense of the invention.
  • saccharide includes saccharides of all kinds in all stereoisomeric and enantiomeric forms, especially monosaccharides, e.g.
  • Pentoses and hexoses such as a- and ⁇ -D-glucose and a- and? -D-mannose, as well
  • Saccharides here also include inositols, very particularly optically active derivatives of myo-inositol and quebrachitol, e.g. out
  • Galactinols both from plant sources, such as sugar beet, and from milk products, or by enzymatic separation of enantiomers
  • Saccharides are also glycoconjugates. These can be conjugates of
  • glycoconjugates Z1 -Z1 0, a mixture of 1 0 glycoconjugates.
  • the compounds Z1-Z10 are naturally occurring glycopeptides, glycoproteins and lipopolysaccharides. All of these compounds are of great biological interest because of their role in various immunological processes. An example of one is
  • R amino acids e.g. Aspartic acid, lysine, glycine, alanine, etc. or fatty acids means.
  • Derivatives of the above saccharides such as those with protective groups, e.g. Benzyl, protected saccharides and / or saccharides modified with functional groups such as amino groups, phosphate groups or haiogenide groups.
  • the above saccharides can occur naturally or can be made synthetically.
  • a saccharide-containing molecule preferably has 3, 4, 5 or 6 saccharides.
  • the saccharides can be the same or different from one another. Also, several of the saccharides in the saccharide-containing molecule may be the same and one or more of the remaining saccharides may differ from one another.
  • a saccharide can be a di, tri, or oligosaccharide and the rest are e.g. B. a monosaccharide. This is referred to as the saccharide background library (see FIG. 3).
  • the saccharides can be bound to the core molecule at their functional groups. This is preferably done with the formation of an O-glycosidic bond.
  • a spacer is present between the core molecule and one or at most all of the saccharides.
  • examples of such are aliphatic compounds such as alkanes.
  • the spacer can also be an unsaturated aliphatic compound.
  • the spacer preferably has 3 to 10 carbon atoms.
  • the spacer can be bound to the functional groups of the core molecule and / or the saccharides. If there are several spacers, these can be the same or different from one another.
  • a saccharide-containing molecule present in the library according to the invention preferably has an organic compound.
  • This can be the core molecule and / or be bound to one or more of the saccharides.
  • organic compounds are alkanes with a functional group, e.g. B. a halogen, such as bromine, a hydroxy, azido and / or amino group, or alkenes, in particular with a terminal double bond.
  • the alkenes can also have the above functional groups.
  • the above organic compound preferably has 3 to 10 carbon atoms.
  • one or more of the organic compound can be present. If there are several, these can be the same or different from one another. With the organic compounds it is possible, for example, to bind the saccharide-containing molecule to a support and / or dyes, magnetic particles and / or other components to the
  • Bind saccharide-containing molecule Bind saccharide-containing molecule.
  • the components of the saccharide-containing molecules are shown as starting materials. In the saccharide-containing molecules, however, they are in a derivatized form.
  • a method for producing the above saccharide libraries is also provided.
  • the individual components i.e. Core molecules, saccharides, possibly linkers, possibly organic compounds and possibly carriers are covalently linked to one another.
  • a core molecule bound to a support is provided in which the functional groups have protective groups.
  • the protecting groups can be orthogonal protecting groups. These protecting groups are characterized by the fact that they are isolated (selective), i.e. one by one, from one molecule
  • the presence of other protective groups can be split off without these other protective groups being influenced by the split-off conditions.
  • protecting groups are acyl groups such as benzoyl, acetyl and chloroacetyl, benzyl groups and silyl groups.
  • acyl groups such as benzoyl, acetyl and chloroacetyl, benzyl groups and silyl groups.
  • the person skilled in the art knows how they can be split off selectively.
  • One of these protective groups is split off. Then it is reacted with a saccharide or a mixture of saccharides so that the saccharides attach to the functional group be bound. Then the next protecting group is selectively split off and the reaction is repeated.
  • a new saccharide, a new mixture of saccharides or the saccharide or mixture of saccharides used in the above step can be used.
  • A, B, C 3 different carbohydrates that can be coupled to the solid phase
  • monosaccharides for example, can be bound to the core molecule. These can be the same or different from each other. One of these monosaccharides has a group capable of binding to another saccharide, for example an acetyl group. A saccharide different from the already bound saccharides is then bound at this point. Finally, the saccharide-containing molecules obtained can be split off from the support and, if desired, the protective groups which may be present on the saccharides. In this way, a saccharide background library can be obtained.
  • a core molecule as described in FIGS. 2-4, can be glycosidated chemically and enzymatically.
  • the latter takes advantage of the fact that glycosidases can transfer monosaccharides from activated donor saccharides (nitrophenylglycosides, glycals, glycosylfluorides, disaccharides etc.) to suitable acceptors (transglycosidation).
  • the glycosides obtained are anomerically pure.
  • a circular process in which the core molecule is continuously treated with a solution of glycosidase and donor sugar can achieve almost quantitative conversion.
  • Glycosidases with broad donor specificity can be used in the form of combinatorial batch synthesis.
  • a core molecule is e.g. reacted with a glycosidase and a mixture of different donor sugars.
  • a saccharide library is obtained, the composition of which, inter alia, is determined by the specificity of the enzyme and the reactivity of the donor sugar. The methods suitable for the enzymatic binding of saccharides to core molecules and the materials required for this are
  • Saccharide libraries according to the invention are distinguished in that they provide a large number of different saccharide-containing molecules. Furthermore, saccharide libraries according to the invention, in particular their
  • saccharide libraries according to the invention are ideally suited for a screening method with which specific active substances can be fished out of the saccharide library.
  • the procedure can be as follows: When developing a saccharide-based active ingredient that, for example, specifically reacts with a known receptor, one will use affinity chromatography, for example. For this purpose, the known receptor is immobilized, e.g. B. on a solid phase. By applying the saccharide library to this solid phase, only those saccharide-containing molecules that bind to the receptor are retained. All other saccharide-containing molecules are separated. Then all binding saccharide-containing molecules are eluted, for example by increasing the salt concentration of the solvent, and then analyzed.
  • Branch libraries can e.g. B. can be obtained in the following way: According to the method described above, after the selective cleavage of a protective group (R.,), coupling with components A, B and C is carried out separately. This results in three pots, each of which is the first
  • Figure 2 shows the preparation of a saccharide library with a triamine as a core molecule
  • Fig. 3 shows the preparation of a saccharide background library
  • Fig. 4 shows the preparation of a saccharide library with an inositol as

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Saccharide Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

The invention relates to a saccharide library with different saccharide-containing molecules, in which each of the molecules comprises a nuclear molecule with at least two functional groups and at least two saccharides. The invention also relates to the production of such a library and its use.

Description

Beschreibung description
"Saccharid-Bibliothek""Saccharide Library"
Die Erfindung betrifft eine Saccharid-Bibliothek, Verfahren zur Herstellung einer solchen sowie ihre Verwendung.The invention relates to a saccharide library, processes for producing such and their use.
Seit einiger Zeit wird daran gedacht, Wirkstoffe, z. B. Therapeutika, auf Sac- charid-Basis bereitzustellen. Dies trifft insbesondere zu, wenn die WirkstoffeFor some time it has been considered to use active ingredients, e.g. B. Therapeutics on a saccharide basis. This is especially true if the active ingredients
Agonisten bzw. Antagonisten von Zeil-Rezeptoren sein sollen. Bisher ist es allerdings äußerst schwierig, Wirkstoffe auf Saccharid-Basis bereitzustellen, d.h. solche zu finden, die exakt mit Zielproteinen, z.B. Rezeptoren, reagieren.Agonists or antagonists of Zeil receptors are said to be. So far, however, it has been extremely difficult to provide saccharide-based drugs, i.e. to find those that exactly match target proteins, e.g. Receptors, react.
Der vorliegenden Erfindung liegt somit die Aufgabe zugrunde, ein Mittel bereitzustellen, mit dem Wirkstoffe auf Saccharid-Basis gefunden werden können.The present invention is therefore based on the object of providing an agent with which active substances based on saccharide can be found.
Erfindungsgemäß wird dies durch die Gegenstände in den Patentansprüchen erreicht.According to the invention, this is achieved by the subject matter in the claims.
Gegenstand der Erfindung ist somit eine Saccharid-Bibliothek mit verschiedenen Saccharid-enthaltenden Molekülen, wobei die Saccharid-enthaltenden Moleküle jeweils ein Kernmolekül mit mindestens zwei funktionellen Gruppen und mindestens zwei Sacchariden umfassen.The invention thus relates to a saccharide library with different saccharide-containing molecules, the saccharide-containing molecules each comprising a core molecule with at least two functional groups and at least two saccharides.
Der vorstehende Ausdruck "Saccharid-Bibliothek" bedeutet eine Vielzahl, z.B. mindestens 6, vorzugsweise mindestens 20, besonders bevorzugt mindestens 50 und am meisten bevorzugt mindestens 1 00, von verschiedenen Saccharid- enthaltenden Molekülen. Diese Moleküle können ungebunden oder an einen Träger gebunden vorliegen. Als Träger sind alle Matrices geeignet, die in derThe above term "saccharide library" means a variety, e.g. at least 6, preferably at least 20, particularly preferably at least 50 and most preferably at least 100 of different saccharide-containing molecules. These molecules can be unbound or attached to a carrier. All matrices suitable for use in the
Festphasenchemie verwendet werden, wie Festphasen auf der Basis von Poly- styrol, Polyethyienglykol, Kieselgur, CPC (controlled pore ceramics), Cellulose und Glas.Solid phase chemistry can be used, such as solid phases based on poly styrene, polyethylene glycol, diatomaceous earth, CPC (controlled pore ceramics), cellulose and glass.
Der vorstehende Ausdruck " Kernmolekül mit mindestens zwei funktionellen Gruppen" umfaßt aliphatische Verbindungen, die mindestens zwei, insbesondereThe above term "core molecule with at least two functional groups" encompasses aliphatic compounds which have at least two, in particular
3, 4, 5 oder 6, funktionelle Gruppen z.B. Hydroxygruppen, Aminogruppen, Carbonsäuregruppen, Metall-organische Gruppen und/oder Halogenidgruppen, aufweisen. Die funktionellen Gruppen können gleich oder verschieden voneinander sein. Beispiele von Kernmolekülen sind cyclische Aliphate. Vertreter dieser sind C6-Cykloalkane, wie Trihydroxycykloalkane, z.B. 1 ,3, 5-Trihydroxycykloalka- ne, insbesondere 1 ,3,5-Trihydroxycyclohexan, Inosite, insbesondere myo-lnosit, und C5-Cykloalkane, wie Tri- und Tetrahydroxycykiopentane, sowie Derivate davon. Ferner sind Kernmoleküle heterocyclische Hydroxyverbindungen. Desweiteren sind Kernmoleküle aliphatische Amine, wie Triamine, insbesondere Methy- lentriamine, und Pentaerythrite. Besonders bevorzugte Kernmoleküle sind in Fig.3, 4, 5 or 6, functional groups, for example hydroxyl groups, amino groups, carboxylic acid groups, organometallic groups and / or halide groups. The functional groups can be the same or different from one another. Examples of core molecules are cyclic aliphates. Representatives of these are C 6 cycloalkanes, such as trihydroxycycloalkanes, for example 1, 3, 5-trihydroxycycloalkanes, in particular 1, 3,5-trihydroxycyclohexane, inositols, in particular myo-inositol, and C 5 cycloalkanes, such as tri- and tetrahydroxycykiopentanes and derivatives thereof. Core molecules are also heterocyclic hydroxy compounds. Furthermore, core molecules are aliphatic amines, such as triamines, in particular methylene triamines, and pentaerythritol. Particularly preferred core molecules are shown in Fig.
1 dargestellt. Keine Kernmoleküle im Sinn der Erfindung sind Steroide, Cholsäu- remethylester und Saccharide.1 shown. Steroids, methyl cholates and saccharides are not core molecules in the sense of the invention.
Der vorstehende Ausdruck "Saccharid" umfaßt Saccharide jeglicher Art in allen stereoisomeren und enantiomeren Formen, insbesondere Monosaccharide, z.B.The above term "saccharide" includes saccharides of all kinds in all stereoisomeric and enantiomeric forms, especially monosaccharides, e.g.
Pentosen und Hexosen, wie a- und ^-D-Glukose und a- und ?-D-Mannose, sowiePentoses and hexoses such as a- and ^ -D-glucose and a- and? -D-mannose, as well
Di-, Tri- und Oligosaccharide. Als Saccharide gelten hier auch Inosite, ganz besonders optisch aktive Derivate von myo-lnosit und Quebrachitol, z.B. ausDi-, tri- and oligosaccharides. Saccharides here also include inositols, very particularly optically active derivatives of myo-inositol and quebrachitol, e.g. out
Galactinolen, sowohl aus pflanzlichen Quellen, wie Zuckerrüben, als auch aus Milchprodukten, oder durch enzymatische Enantiomerentrennung gewonneneGalactinols, both from plant sources, such as sugar beet, and from milk products, or by enzymatic separation of enantiomers
Derivate. Ferner sind Saccharide Glykokonjugate. Diese können Konjugate vonDerivatives. Saccharides are also glycoconjugates. These can be conjugates of
Sacchariden mit Peptiden, Heterocyklen und anderen Kohlehydraten sein. EinSaccharides with peptides, heterocycles and other carbohydrates. On
Beispiel von Glykokonjugaten ist Z1 -Z1 0, ein Gemisch von 1 0 Glykokonjugaten.An example of glycoconjugates is Z1 -Z1 0, a mixture of 1 0 glycoconjugates.
Bei den Verbindungen Z1 -Z10 handelt es sich um in der Natur vorkommende Glycopeptide, Glycoproteine und Lipopolysaccharide. Alle diese Verbindungen sind wegen ihrer Rolle in verschiedenen immunologischen Prozessen von großem biologischen Interesse. Ein Beispiel einer solchen ist The compounds Z1-Z10 are naturally occurring glycopeptides, glycoproteins and lipopolysaccharides. All of these compounds are of great biological interest because of their role in various immunological processes. An example of one is
wobei R Aminosäuren, z.B. Asparaginsäure, Lysin, Glycin, Alanin, etc. oder Fettsäuren bedeutet. Als Saccharide werden auch Derivate vorstehender Saccharide, wie mit Schutzgruppen, z.B. Benzyl, geschützte Saccharide und/oder mit funktionellen Gruppen, wie Aminogruppen, Phosphatgruppen oder Haioge- nidgruppen, modifizierte Saccharide, verstanden . Vorstehende Saccharide können natürlich vorkommen oder synthetisch hergestellt werden. Vorzugsweise weist ein Saccharid-enthaltendes Molekül 3, 4, 5 oder 6 Saccharide auf. Die Saccharide können gleich oder verschieden voneinander sein. Auch können im Saccharid-enthaltenden Molekül mehrere der Saccharide gleich sein und eines oder mehrere der restlichen Saccharide sich davon underscheiden. Beispielsweise kann ein Saccharid ein Di-, Tri-, oder Oligosaccharid sein und die restlichen sind z. B. ein Monosaccharid. Dies wird als Saccharid-Hintergrundbibliothek bezeichnet (vgl Fig. 3) . Die Bindung der Saccharide an das Kernmolekül kann an dessen funktioneile Gruppen erfolgen. Vorzugsweise geschieht dies unter Ausbildung einer O-glykosidischen Bindung.where R amino acids, e.g. Aspartic acid, lysine, glycine, alanine, etc. or fatty acids means. Derivatives of the above saccharides, such as those with protective groups, e.g. Benzyl, protected saccharides and / or saccharides modified with functional groups such as amino groups, phosphate groups or haiogenide groups. The above saccharides can occur naturally or can be made synthetically. A saccharide-containing molecule preferably has 3, 4, 5 or 6 saccharides. The saccharides can be the same or different from one another. Also, several of the saccharides in the saccharide-containing molecule may be the same and one or more of the remaining saccharides may differ from one another. For example, a saccharide can be a di, tri, or oligosaccharide and the rest are e.g. B. a monosaccharide. This is referred to as the saccharide background library (see FIG. 3). The saccharides can be bound to the core molecule at their functional groups. This is preferably done with the formation of an O-glycosidic bond.
In einer bevorzugten Ausführungsform liegt zwischen dem Kernmolekül und einem bis maximal allen der Saccharide ein Spacer vor. Beispiele eines solchen sind aliphatische Verbindungen, wie Alkane. Auch kann der Spacer eine ungesättigte aliphatische Verbindung sein. Der Spacer weist vorzugsweise 3 bis 10 C- Atome auf. Ferner kann der Spacer an die funktionellen Gruppen des Kernmoleküls und/oder der Saccharide gebunden sein. Liegen mehrere Spacer vor, dann können diese gleich oder verschieden voneinander sein.In a preferred embodiment, a spacer is present between the core molecule and one or at most all of the saccharides. Examples of such are aliphatic compounds such as alkanes. The spacer can also be an unsaturated aliphatic compound. The spacer preferably has 3 to 10 carbon atoms. Furthermore, the spacer can be bound to the functional groups of the core molecule and / or the saccharides. If there are several spacers, these can be the same or different from one another.
Vorzugsweise weist ein in der erfindungsgemäßen Bibliothek vorliegendes Saccharid-enthaltendes Molekül eine organische Verbindung auf. Diese kann an das Kernmolekül und/oder an eines oder mehrere der Saccharide gebunden sein. Beispiele von organischen Verbindungen sind Alkane mit einer funktionellen Gruppe, z. B. einem Halogen, wie Brom, einer Hydroxy-, Azido- und/oder Amino- Gruppe, oder Alkene, insbesondere mit endständiger Doppelbindung. Die Alkene können auch vorstehende funktionelle Gruppen aufweisen. Vorzugsweise hat vorstehende organische Verbindung 3 bis 1 0 C-Atome. Ferner können von der organischen Verbindung eine oder mehrere vorliegen. Bei mehreren können diese gleich oder verschieden voneinander sein. Mit den organischen Verbindungen ist es z.B. möglich, das Saccharid-enthaltende Molekül an einen Träger zu binden und/oder Farbstoffe, magnetische Partikel und/oder andere Komponenten an dasA saccharide-containing molecule present in the library according to the invention preferably has an organic compound. This can be the core molecule and / or be bound to one or more of the saccharides. Examples of organic compounds are alkanes with a functional group, e.g. B. a halogen, such as bromine, a hydroxy, azido and / or amino group, or alkenes, in particular with a terminal double bond. The alkenes can also have the above functional groups. The above organic compound preferably has 3 to 10 carbon atoms. Furthermore, one or more of the organic compound can be present. If there are several, these can be the same or different from one another. With the organic compounds it is possible, for example, to bind the saccharide-containing molecule to a support and / or dyes, magnetic particles and / or other components to the
Saccharid-enthaltende Molekül zu binden.Bind saccharide-containing molecule.
Die Komponenten der Saccharid-enthaltenden Moleküle sind als Edukte dargestellt. In den Saccharid-enthaltenden Molekülen liegen sie jedoch in derivati- sierter Form vor.The components of the saccharide-containing molecules are shown as starting materials. In the saccharide-containing molecules, however, they are in a derivatized form.
Erfindungsgemäß wird auch ein Verfahren zur Herstellung vorstehender Sac- charid-Bibliotheken bereitgestellt. In diesem Verfahren werden die einzelnen Komponenten, d.h. Kernmoleküle, Saccharide, ggf. Linker, ggf. organische Verbindung und ggf. Träger kovalent miteinander verbunden.According to the invention, a method for producing the above saccharide libraries is also provided. In this process, the individual components, i.e. Core molecules, saccharides, possibly linkers, possibly organic compounds and possibly carriers are covalently linked to one another.
Beispielsweise wird ein an einen Träger gebundenes Kernmolekül bereitgestellt, bei dem die funktionellen Gruppen Schutzgruppen aufweisen. Die Schutzgruppen können orthogonale Schutzgruppen sein. Diese Schutzgruppen zeichnen sich dadurch aus, daß sie einzeln (selektiv), d.h. nacheinander, von einem Molekül beiFor example, a core molecule bound to a support is provided in which the functional groups have protective groups. The protecting groups can be orthogonal protecting groups. These protecting groups are characterized by the fact that they are isolated (selective), i.e. one by one, from one molecule
Anwesenheit anderer Schutzgruppen abgespalten werden können, ohne daß diese anderen Schutzgruppen durch die Abspaltungsbedingungen beeinflußt werden. Beispiele solcher Schutzgruppen sind Acyl-Gruppen, wie Benzoyl, Acetyl und Chloracetyl, Benzyl-Gruppen und Silyl-Gruppen. Der Fachmann weiß, wie sie selektiv abgespalten werden können. Von diesen Schutzgruppen wird eine abgespalten. Anschließend wird mit einem Saccharid oder einem Gemisch von Sacchariden umgesetzt, so daß die Saccharide an die funktionelle Gruppe gebunden werden. Dann wird die nächste Schutzgruppe selektiv abgespalten, und die Umsetzung wird wiederholt. Dabei kann ein neues Saccharid, ein neues Gemisch von Sacchariden oder das in vorstehendem Schritt verwendete Saccharid oder Gemisch von Sacchariden verwendet werden. Diese Reaktionen können wiederholt werden, bis alle gewünschten funktionellen Gruppen des Kernmoleküls ein Saccharid aufweisen. Schließlich können die erhaltenen Saccharid-enthaltenden Moleküle vom Träger und, wenn es gewünscht wird, die ggf. an den Sacchariden vorliegenden Schutzgruppen abgespalten werden. Auf diese Weise werden erfindungsgemäße Saccharid-Bibliotheken erhalten. Werden als Saccharide in den einzelnen Schritten nur eine Art von Sacchariden eingesetzt, dann wird auch nur eine Art von Saccharid-enthaltenden Molekülen erhalten. Diese können mit davon verschiedenen Saccharid-enthaltenden Molekülen zu einer Saccharid-Bibliothek gemischt werden. Werden in vorstehender Reaktion Gemische von Sacchariden eingesetzt, so erhält man eine Kombination von verschiedenen Saccharid-enthaltenden Molekülen ( = Sacharid-Bibliothek). Dies kann am Beispiel eines festphasengekoppelten Inositols wie folgt dargestellt werden:The presence of other protective groups can be split off without these other protective groups being influenced by the split-off conditions. Examples of such protecting groups are acyl groups such as benzoyl, acetyl and chloroacetyl, benzyl groups and silyl groups. The person skilled in the art knows how they can be split off selectively. One of these protective groups is split off. Then it is reacted with a saccharide or a mixture of saccharides so that the saccharides attach to the functional group be bound. Then the next protecting group is selectively split off and the reaction is repeated. A new saccharide, a new mixture of saccharides or the saccharide or mixture of saccharides used in the above step can be used. These reactions can be repeated until all desired functional groups of the core molecule have a saccharide. Finally, the saccharide-containing molecules obtained can be split off from the carrier and, if desired, the protective groups which may be present on the saccharides. In this way, saccharide libraries according to the invention are obtained. If only one type of saccharide is used as saccharide in the individual steps, then only one type of saccharide-containing molecule is obtained. These can be mixed with different saccharide-containing molecules to form a saccharide library. If mixtures of saccharides are used in the above reaction, a combination of different saccharide-containing molecules (= saccharide library) is obtained. This can be illustrated using the example of a solid-phase-coupled inositol as follows:
Festphase, an welches Inositol gebunden ist; Ri - R5 : orthogonale SchutzgruppenSolid phase to which inositol is bound; Ri - R 5 : orthogonal protecting groups
A, B, C 3 verschiedene Kohlenhydrate, die an die Festphase gekoppelt werden könnenA, B, C 3 different carbohydrates that can be coupled to the solid phase
1. Selektive Abspaltung von Ri1. Selective spin-off from Ri
I. KopplungI. Coupling
2. Kopplung mit einer Mischung von A, B und C2. Coupling with a mixture of A, B and C
BERICHTIGTES BLATT (REGEL 91) ISA / EP CORRECTED SHEET (RULE 91) ISA / EP
II. Kopplung 1. Selektive Abspaltung von R2II. Coupling 1. Selective Cleavage of R2
2. Kopplung mit einer Mischung von A, B und C2. Coupling with a mixture of A, B and C
III. KopplungIII. coupling
IV. KopplungIV. Coupling
V. KopplungV. coupling
Die Zahl der unterschiedlichen Bibliotheksbausteine nach 5 Kopplungen (wie oben dargestellt) ergibt sich dann nach der allgemein gültigen Formel:The number of different library blocks after 5 couplings (as shown above) is then calculated using the general formula:
Z = MF Z = Zahl der unterschiedlichen Bibliotheksbausteine; M = Zahl der unterschiedlichen Kohlenhydratspezies, die als Gemisch zur Kopplung an den Zentralbaustein eingesetzt werden (hier: 3 unterschiedliche Monosaccharide); F = Zahl der Funktionalitäten des Zentralbausteins (OH-, NH2- Gruppen...., hier: 5 OH-Gruppen).Z = M F Z = number of different library blocks; M = number of different carbohydrate species that are used as a mixture for coupling to the central building block (here: 3 different monosaccharides); F = number of functionalities of the central building block (OH, NH 2 groups ..., here: 5 OH groups).
Z = 35 = 243Z = 3 5 = 243
BERICHTIGTES BLATT (REGEL 91) ISA / EP Wie vorstehend beschrieben können an das Kernmolekül z.B. Monosaccharide gebunden werden. Diese können gleich oder verschieden voneinander sein. Eines dieser Monosaccharide weist eine zur Bindung mit einem anderen Saccharid fähige Gruppe auf, z.B. eine Acetyl-Gruppe. An diese Stelle wird dann ein von den bereits gebundenen Sacchariden verschiedenes Saccharid gebunden. Schließlich können die erhaltenen Saccharid-enthaltenden Moleküle vom Träger und, wenn es gewünscht wird, die ggf. an den Sacchariden vorliegenden Schutzgruppen abgespalten werden. Auf diese Weise kann eine Saccharid-Hintergrund- bibliothek erhalten werden.CORRECTED SHEET (RULE 91) ISA / EP As described above, monosaccharides, for example, can be bound to the core molecule. These can be the same or different from each other. One of these monosaccharides has a group capable of binding to another saccharide, for example an acetyl group. A saccharide different from the already bound saccharides is then bound at this point. Finally, the saccharide-containing molecules obtained can be split off from the support and, if desired, the protective groups which may be present on the saccharides. In this way, a saccharide background library can be obtained.
Die Glycosidierung eines Kernmoleküls, wie es in den Figuren 2 - 4 beschrieben ist, kann chemisch und enzymatisch erfolgen. Bei der letzteren wird ausgenutzt, daß Glycosidasen Monosaccharide von aktivierten Donorsacchariden (Nitrophe- nylglycoside, Glycale, Glycosylfluoride, Disaccharide etc.) auf geeignete Akzeptoren übertragen könen (Transglycosidierung) . Die dabei erhaltenen Glycoside sind anomerenrein. Durch ein Kreislaufverfahren, in dem das Kernmolekül kontinuierlich mit einer Lösung von Glycosidase und Donorzucker behandelt wird, kann annähernd quantitativer Umsatz erreicht werden. Glycosidasen mit breiter Donorspezifität sind in Form der kombinatorischen Batch-Synthese einsetzbar.A core molecule, as described in FIGS. 2-4, can be glycosidated chemically and enzymatically. The latter takes advantage of the fact that glycosidases can transfer monosaccharides from activated donor saccharides (nitrophenylglycosides, glycals, glycosylfluorides, disaccharides etc.) to suitable acceptors (transglycosidation). The glycosides obtained are anomerically pure. A circular process in which the core molecule is continuously treated with a solution of glycosidase and donor sugar can achieve almost quantitative conversion. Glycosidases with broad donor specificity can be used in the form of combinatorial batch synthesis.
Ein Kernmolekül wird z.B. mit einer Glycosidase und einem Gemisch verschiedener Donorzucker umgesetzt. Man erhält dabei eine Saccharid-Bibliothek, deren Zusammensetzung u.a. von der Spezifität des Enzyms und der Reaktivität der Donorzucker bestimmt wird. Die zur enzymatischen Bindung von Sacchariden an Kernmoleküle geeignete Verfahren und hierzu notwendige Materialien sind demA core molecule is e.g. reacted with a glycosidase and a mixture of different donor sugars. A saccharide library is obtained, the composition of which, inter alia, is determined by the specificity of the enzyme and the reactivity of the donor sugar. The methods suitable for the enzymatic binding of saccharides to core molecules and the materials required for this are
Fachmann bekannt.Known specialist.
Erfindungsgemäße Saccharid-Bibliotheken zeichnen sich dadurch aus, daß sie eine Vielzahl unterschiedlicher Saccharid-enthaltender Moleküle bereitstellen. Ferner sind erfindungsgemäße Saccharid-Bibliotheken, insbesondere derenSaccharide libraries according to the invention are distinguished in that they provide a large number of different saccharide-containing molecules. Furthermore, saccharide libraries according to the invention, in particular their
Kernmoleküle, gegen Abbau durch Glukosidase stabil. Daher eignen sich erfindungsgemäße Saccharid-Bibliotheken bestens für ein Screening-Verfahren, mit dem aus der Saccharid-Bibliothek spezifische Wirkstoffe herausgefischt werden können. Dabei kann wie folgt vorgegangen werden: Bei der Entwicklung eines Wirkstoffs auf Saccharid-Basis, welcher z.B. spezifisch mit einem bekannten Rezeptor reagiert, wird man z.B. die Affinitätschromatographie anwenden. Dazu wird der bekannte Rezeptor immobilisiert, z. B. an einer Festphase. Durch Auftragen der Sacharid-Bibliothek auf diese Festphase werden nur jene Saccharid-enthaltenden Moleküle zurückgehalten, die an den Rezeptor binden. Alle anderen Saccharid-enthaltenden Moleküle werden abgetrennt. Anschließend werden alle bindenden Saccharid-enthaltenden Moleküle eluiert, z.B. durch Erhöhung der Salzkonzentration des Lösungsmittels, und dann analysiert. Günstig kann es sein, die Analyse schon bei der Bibliothekssynthese zu berücksichtigen. Dies kann z.B. dadurch erfolgen, daß nicht, wie vorstehend beschrieben, eine vollständige Bibliothek eingesetzt wird, sondern durch geschickte Aufteilung des Syntheseschemas eine Gruppierung unterschiedlicher Teilbibliotheken erhalten wird, die dann eingesetzt wird. Teilbibliotheken können z. B. auf folgende Weise erhalten werden: Nach dem vorstehend beschriebenen Verfahren wird nach der selektiven Abspaltung einer Schutzgruppe (R., ) die Kopplung mit den Komponenten A,B und C getrennt durch- geführt. Es ergeben sich somit drei Töpfe, die sich jeweils durch das ersteCore molecules, stable against degradation by glucosidase. Therefore, saccharide libraries according to the invention are ideally suited for a screening method with which specific active substances can be fished out of the saccharide library. The procedure can be as follows: When developing a saccharide-based active ingredient that, for example, specifically reacts with a known receptor, one will use affinity chromatography, for example. For this purpose, the known receptor is immobilized, e.g. B. on a solid phase. By applying the saccharide library to this solid phase, only those saccharide-containing molecules that bind to the receptor are retained. All other saccharide-containing molecules are separated. Then all binding saccharide-containing molecules are eluted, for example by increasing the salt concentration of the solvent, and then analyzed. It can be beneficial to take the analysis into account during library synthesis. This can be done, for example, by not using a complete library, as described above, but by skillfully dividing the synthesis scheme into a grouping of different sub-libraries, which is then used. Branch libraries can e.g. B. can be obtained in the following way: According to the method described above, after the selective cleavage of a protective group (R.,), coupling with components A, B and C is carried out separately. This results in three pots, each of which is the first
Sacharid unterscheiden. Jeder dieser drei Töpfe wird nun weiter, jedoch getrennt bearbeitet. Am Ende liegen dann drei verschiedene Teilbibliotheken vor, die getrennt für das Screening eingesetzt werden können. Je nachdem, in welchem Topf der aktivste Wirkstoff ist, kann die entsprechende Teiibibliothek erneut aber weiter differenziert dargestellt werden. Auf diese Weise kann der Strukturbeweis für den aktivsten Wirkstoff geführt werden.Differentiate saccharide. Each of these three pots is now processed further, but separately. In the end, there are three different sub-libraries that can be used separately for the screening. Depending on the pot in which the most active ingredient is, the corresponding part library can again be presented in a more differentiated manner. In this way, the structural evidence for the most active ingredient can be provided.
Kurze Beschreibung der Zeichnung:Brief description of the drawing:
Fig. 1 zeigt bevorzugte Kernmoleküle,1 shows preferred core molecules,
Fig. 2 zeigt die Herstellung einer Saccharid-Bibliothek mit einem Triamin als Kernmolekül,Figure 2 shows the preparation of a saccharide library with a triamine as a core molecule,
Fig. 3 zeigt die Herstellung einer Saccharid-Hintergrundbibliothek undFig. 3 shows the preparation of a saccharide background library and
Fig. 4 zeigt die Herstellung einer Saccharid-Bibliothek mit einem Inosit alsFig. 4 shows the preparation of a saccharide library with an inositol as
Kernmolekül. Core molecule.

Claims

Patentansprüche claims
1 . Saccharid-Bibliothek mit verschiedenen Saccharid-enthaltenden Molekülen, wobei die Moleküle jeweils ein Kernmolekül mit mindestens zwei funktionellen Gruppen und mindestens zwei Sacchariden umfassen.1 . Saccharide library with different saccharide-containing molecules, the molecules each comprising a core molecule with at least two functional groups and at least two saccharides.
2. Saccharid-Bibliothek nach Anspruch 1 , dadurch gekennzeichnet, daß das Kernmolekül ein cyclischer Aliphat ist.2. Saccharide library according to claim 1, characterized in that the core molecule is a cyclic aliphatic.
3. Saccharid-Bibliothek nach Anspruch 2, dadurch gekennzeichnet, daß der cyclische Aliphat ein C6- oder C5-Cykloalkan ist.3. Saccharide library according to claim 2, characterized in that the cyclic aliphatic is a C 6 - or C 5 cycloalkane.
4. Saccharid-Bibliothek nach Anspruch 3, dadurch gekennzeichnet, daß das C6-Cykloalkan ein Trihydroxycyklohexan, ein Inosit oder ein Derivat von diesen ist.4. Saccharide library according to claim 3, characterized in that the C 6 cycloalkane is a trihydroxycyklohexane, an inositol or a derivative of these.
5. Saccharid-Bibliothek nach einem der Ansprüche 1 -4, dadurch gekennzeichnet, daß die funktionellen Gruppen Hydroxygruppen, Aminogruppen, Carbonsäuregruppen, Metall-organische Gruppen und/oder Halogenid- gruppen sind.5. saccharide library according to any one of claims 1 -4, characterized in that the functional groups are hydroxyl groups, amino groups, carboxylic acid groups, metal-organic groups and / or halide groups.
6. Saccharid-Bibliothek nach einem der Ansprüche 1 -5, dadurch gekennzeichnet, daß die Saccharide ein Mono-, Di-, Tri- und/oder Oligosaccharid, ein Inosit und/oder ein Derivat von diesen sind.6. Saccharide library according to one of claims 1 -5, characterized in that the saccharides are a mono-, di-, tri- and / or oligosaccharide, an inositol and / or a derivative of these.
7. Saccharid-Bibliothek nach Anspruch 6, dadurch gekennzeichnet, daß das Monosaccharid Glukose oder Mannose ist. 7. saccharide library according to claim 6, characterized in that the monosaccharide is glucose or mannose.
8. Saccharid-Bibliothek nach einem der Ansprüche 1 -7, dadurch gekennzeichnet, daß das Saccharid-aufweisende Molekül 3, 4, 5 oder 6 Saccharide aufweist.8. Saccharide library according to any one of claims 1-7, characterized in that the saccharide-containing molecule has 3, 4, 5 or 6 saccharides.
9. Saccharid-Bibliothek nach einem der Ansprüche 1 -8, dadurch gekennzeichnet, daß die Saccharide gleich oder verschieden voneinander sind.9. Saccharide library according to any one of claims 1-8, characterized in that the saccharides are the same or different from one another.
1 0. Saccharid-Bibliothek nach einem der Ansprüche 1 -9, dadurch gekennzeichnet, daß zwischen dem Kernmolekül und einem bis maximal allen Sacchariden ein Spacer vorliegt.1 0. saccharide library according to any one of claims 1-9, characterized in that a spacer is present between the core molecule and one to at most all saccharides.
1 1 . Saccharid-Bibliothek nach Anspruch 1 0, dadurch gekennzeichnet, daß der Spacer eine aliphatische. Verbindung ist.1 1. Saccharide library according to claim 1 0, characterized in that the spacer is an aliphatic. Connection is.
1 2. Saccharid-Bibliothek nach Anspruch 1 0 oder 1 1 , dadurch gekennzeichnet, daß der Spacer 3 bis 1 0 C-Atome aufweist,1 2. saccharide library according to claim 1 0 or 1 1, characterized in that the spacer has 3 to 1 0 carbon atoms,
1 3. Saccharid-Bibliothek nach einem der Ansprüche 1 - 1 2, dadurch gekennzeichnet, daß das Saccharid-enthaltende Molekül eine organische Ver- bindung aufweist.1 3. Saccharide library according to one of claims 1 - 1 2, characterized in that the saccharide-containing molecule has an organic compound.
1 4. Saccharid-Bibliothek nach Anspruch 1 3, dadurch gekennzeichnet, daß die organische Verbindung ein Alkan mit einer funktionellen Gruppe und/oder ein Alken ist.1 4. Saccharide library according to claim 1 3, characterized in that the organic compound is an alkane with a functional group and / or an alkene.
1 5. Saccharid-Bibliothek nach Anspruch 1 4, dadurch gekennzeichnet, daß die funktionelle Gruppe ein Halogen, eine Hydroxy-, eine Azido- und/oder eine Amino-Gruppe ist.1 5. Saccharide library according to claim 1 4, characterized in that the functional group is a halogen, a hydroxy, an azido and / or an amino group.
1 6. Saccharid-Bibliothek nach einem der Ansprüche 1 3-1 5, dadurch gekennzeichnet, daß die organische Verbindung 3 bis 1 0 C-Atome aufweist. 1 6. Saccharide library according to any one of claims 1 3-1 5, characterized in that the organic compound has 3 to 1 0 carbon atoms.
1 7. Saccharid-Bibliothek nach einem der Ansprüche 1 3-1 6, dadurch gekennzeichnet, daß mehrere organische Verbindungen vorliegen.1 7. Saccharide library according to one of claims 1 3-1 6, characterized in that several organic compounds are present.
1 8. Verfahren zur Herstellung einer Saccharid-Bibliothek nach einem der Ansprüche 1 -1 7, dadurch gekennzeichnet, daß das Kernmolekül, die Saccharide, ggf. der Linker und ggf. die organische Verbindung kovalent miteinander verbunden werden.1 8. A method for producing a saccharide library according to any one of claims 1 -1 7, characterized in that the core molecule, the saccharides, optionally the linker and optionally the organic compound are covalently linked together.
1 9. Verwendung einer Saccharid-Bibliotheks nach einem der Ansprüche 1 - 1 8 zum Ermitteln von Wirkstoffen gegen Zielproteine.1 9. Use of a saccharide library according to one of claims 1 - 1 8 for the determination of active substances against target proteins.
20. Verwendung nach Anspruch 1 9, wobei die Zielproteine Rezeptoren sind. 20. Use according to claim 1 9, wherein the target proteins are receptors.
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AP3396A (en) 2009-02-13 2015-08-31 Chem Inc X Methods of creating and screening DNA-encoded libraries
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