EP1626977A2 - Silanyl-n-alkanalverbindungen, verfahren zu deren herstellung und deren verwendung - Google Patents

Silanyl-n-alkanalverbindungen, verfahren zu deren herstellung und deren verwendung

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Publication number
EP1626977A2
EP1626977A2 EP04742596A EP04742596A EP1626977A2 EP 1626977 A2 EP1626977 A2 EP 1626977A2 EP 04742596 A EP04742596 A EP 04742596A EP 04742596 A EP04742596 A EP 04742596A EP 1626977 A2 EP1626977 A2 EP 1626977A2
Authority
EP
European Patent Office
Prior art keywords
formula
silanyl
compound
solid support
compounds
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Withdrawn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
EP04742596A
Other languages
English (en)
French (fr)
Inventor
Françoise Vinet
Gérard LANNEAU
Michel Granier
Franck Martin
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.)
Centre National de la Recherche Scientifique CNRS
Universite Montpellier 2 Sciences et Techniques
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Original Assignee
Centre National de la Recherche Scientifique CNRS
Commissariat a lEnergie Atomique CEA
Universite Montpellier 2 Sciences et Techniques
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
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 Centre National de la Recherche Scientifique CNRS, Commissariat a lEnergie Atomique CEA, Universite Montpellier 2 Sciences et Techniques, Commissariat a lEnergie Atomique et aux Energies Alternatives CEA filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP1626977A2 publication Critical patent/EP1626977A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0896—Compounds with a Si-H linkage
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54393—Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding

Definitions

  • the present invention relates to ⁇ -silanyl-n alkanals compounds, to their preparation process, to their use for the functionalization of solid supports, to the solid supports functionalized by these compounds, as well as to the use of solid supports as well functionalized for immobilization and / or synthesis of biological molecules of interest.
  • the synthetic scheme for grafting oligonucleotide molecules onto a solid support presupposes the pretreatment of surfaces (generally oxides or metals) with a coupling agent with a functional termination which is organized on the surface of the material.
  • SAMs Self-assembled monolayers
  • Self-Assembled Monolayers are defined as an assembly of molecules in which the molecules are organized, organization due to interactions between the chains of the molecules, giving rise to a stable anisotropic film, monomolecular and ordered (A. ULMAN, Chem. Rev., 1996, 96, 1533-1554). These self-assembled monolayers, which can be obtained in a reproducible manner (J.B. BROZSKA et al.
  • organosilicon compounds have therefore already been used as coupling agents for the functionalization of solid supports (LA CHRISEY et al., Nucleic Acids Research, 1996, 24, 15, 3031-3039, U. MASKOS et al, Nucleic Acids Research, 1992 , 20, 1, 1679-1684) for the purpose of immobilizing or in situ synthesizing oligonucleotides.
  • the organosilicon coupling agents used in this work form inhomogeneous films and very little resistant to subsequent chemical treatments of synthesis or immobilization of oligonucleotides.
  • the formation of films with these coupling agents is not reproducible.
  • the properties of the silane coupling agent depend on the nature of the organic group R, but they mainly depend on the method of attachment to the surface by means of X functions.
  • the polyfunctional silanes of RSiX 3 and R 2 type SiX that is to say comprising three or two bonding functions, not only cling to the surface of the solid support but can also react with one another to form a crosslinked layer.
  • the monofunctional silanes of type R 3 SiX that is to say comprising only one hooking function, only hang individually on the substrate.
  • organosilanes RSiX 3 and R 3 SiX have been the most studied in the literature, both from an academic and industrial point of view, the first because they lead to the formation of a three-dimensional network and the second because they allow know the number of silanol sites present on the surface.
  • the functions generally studied are the Si-Ci, Si-OMe, Si-OEt bonds and a classic example of surface modification with a trichlorosilane is given in Scheme A below: step 1
  • the inventors have in fact set themselves the aim of improving the fixing qualities of the surfaces currently used to effect the immobilization of biological molecules of interest and their resistance over time, by controlling the attachment functions and have developed new silane-type compounds meeting this objective.
  • the present invention therefore relates to ⁇ -silanyl-n alkanals compounds, characterized in that they correspond to the following formula (I):
  • n represents an integer between 7 and 20 inclusive and preferably between 1 1 and 18 inclusive.
  • These compounds are characterized by the fact that they comprise a terminal aldehyde function allowing the direct grafting of any chemical or biological molecule comprising a terminal amine function unlike all the compounds of the silane type currently available which require either a modification step (of activation) of the terminal chemical function of the silane after the grafting step on the surface of a support, ie the presence of an intermediate molecule such as glutaraldehyde for example in order to allow grafting.
  • an intermediate molecule such as glutaraldehyde for example in order to allow grafting.
  • the synthesis of these compounds requires special conditions which are developed below and which allow the integrity of the aldehyde function to be preserved.
  • the inventors have demonstrated that the compounds of formula (I) in accordance with the invention make it possible to functionalize the surface of solid supports comprising hydroxyl functions, and this in a single step, and lead to the formation of self-assembled monolayers whose density is maximum, unlike SAMs formed from organosilanes known from the prior art, for example the compounds of formula R- (CH 3 ) 2 Si-X generally used. Indeed, if we compare the steric hindrance of different silanes, the presence of hydrogen atoms bonded to silicon leads to the minimum possible space between two silane chains, as we can see in Diagram B ci - after:
  • the subject of the invention is also the process for preparing the compounds of formula (I) as defined above, characterized in that:
  • n is a number between 7 and 20 inclusive in solution in an alcoholic solvent, with ethyl orthoformate, at reflux and in the presence of a catalyst to obtain a compound of formula (III) below:
  • the term "mild" reducing agent is understood to mean any reducing agent capable of reducing the ethoxy groups carried by the silicon atom, thereby reducing the methoxy groups present in the compound of formula (IV). It is the judicious choice of this particular reducing agent which allows the synthesis of the compounds of formula (I) which directly comprise a terminal aldehyde function.
  • certain weakly reducing agents such as sodium borohydride are not capable of reducing the ethoxy groups carried by the compounds of formula (IV) while more strongly reducing agents such as lithium trihydroaluminate not only lead to reduction ethoxy groups but also to that of the methoxy groups of the compounds of formula (IV) thus prohibiting the subsequent formation of the aldehyde function during the fourth step.
  • the intermediate compounds of formulas (II) to (V), and the final compound of formula (I) at the end of the synthesis are preferably washed, isolated and purified according to the methods conventionally used for this purpose. .
  • the organic solvents used during the first step are preferably chosen from lower alcohols such as methanol and ethanol.
  • the reaction is preferably carried out at the reflux temperature of the solvent and the duration of the reaction is generally between 8 and 16 hours.
  • the catalyst used during the first step is preferably para-toluenesulfonic acid used in a catalytic amount, that is to say at about 0.5%.
  • the catalyst used during the second step is preferably chosen from catalysts based on transition metal in homogeneous phase; Karstet's catalyst being particularly preferred.
  • the anhydrous solvent is preferably chosen from ethers and cyclic oxides; ethyl ether being particularly preferred.
  • the "mild" reducing agent is preferably lithium tetrahydroaluminate.
  • the organic solvent used during the fourth is preferably chosen from chlorinated solvents; chloroform being particularly preferred.
  • the oxidizing agent is preferably chosen from strong carboxylic or mineral acids; trifluoroacetic acid (TFA) being particularly preferred.
  • TFA trifluoroacetic acid
  • the compounds of formula (I) in accordance with the invention can be used to form a self-assembled monolayer organized on the surface of a solid support.
  • the subject of the present invention is also the use of at least one compound of formula (I) as described above to form, on the surface of a solid support comprising hydroxyl functions, a self-assembled organized monolayer.
  • SAMs can be carried out conventionally for a person skilled in the art by bringing at least one hydroxylated surface of a solid support into contact with a solution of at least one compound of formula (I) in accordance with l 'Invention in an organic solvent such as for example trichlorethylene at a temperature between 2 and 10 ° C for about 12 to 24 hours.
  • organic solvent such as for example trichlorethylene
  • the substrate is then rinsed with different solvents, preferably and successively with trichlorethylene, ethanol, chloroform, pentane, then dried, preferably with nitrogen.
  • the surfaces thus obtained directly present a large number of aldehyde functions making it possible to covalently immobilize biological molecules of interest comprising a complementary amine function, without the need for prior activation of the support.
  • the compounds grafted onto the support give rise to strong covalent bonds, of the siloxane type, with the surface and develop a strong cohesion between their alkyl chains, result of a self-assembly of the molecules which protects the siloxane bonds.
  • the grafting is reproducible and the aldehyde function of the grafted compounds has a high chemical reactivity.
  • the roughness of the surfaces, measured by atomic force microscopy (AFM), of the support treated by thermal oxidation and after covalent coupling of the compounds of formula (I) in accordance with the invention are respectively 0.8 ⁇ and 2.3 ⁇ , which indicates the deposition of a homogeneous layer.
  • the thickness of the layer measured by ellipsometry after grafting an SAM with a compound of formula (I) in which n 11 is 19.9 ⁇ 2.6 ⁇ (for a refractive index equal to 1.45), while the theoretical value for a Cn carbon chain orthogonal to the surface is 18.15 ⁇ .
  • the by-product of the grafting reaction of the compounds of formula (I) in accordance with the invention on the hydroxylated surface of a solid support is a release of hydrogen, easy to remove, unlike anionic entities or protic compounds which are inherent in the processes of the prior art using chlorosilanes or alkoxysilanes.
  • the grafting reaction leads to the substitution of a single Si-H bond, that is to say that the compound of formula (I) in accordance with the invention behaves like a monofunctional organosilane.
  • the activation of the Si-H bonds corresponds to the organization of the long alkyl chains in the vicinity of the surface, which can allow the transient formation of hypercoordinated species of silicon, of the type [R-SiH 4 ] " or [ R-SiH 5 ] 2 " , known to be more reactive than tetrahedral species.
  • IR-RTA makes it possible to identify the presence on the surface of only RSiH -O- entities, showing that there was only monofixation.
  • the present invention also relates to a solid support of which at least one surface is modified by an organized self-assembled monolayer, characterized in that said monolayer comprises a network of at least one compound of formula (I) as defined above.
  • network is understood to mean an assembly of molecules in which the molecules are organized and in which the chains of the molecules interact with one another by non-covalent bonds (Van der Waals forces for example).
  • All the solid supports comprising at least one hydrated surface can be functionalized with the compounds of formula (I) in accordance with the invention.
  • said solid support is such that its surface has, before being modified, hydroxyl groups. It is advantageously selected from the group consisting of glasses, oxide type ceramics and plastics.
  • said monolayer in addition to compounds of general formula (I) according to the present invention, can also comprise any other type of compound capable of being grafted onto the solid support (obtaining a so-called “mixed” monolayer) , which makes it possible to reduce the density of the compounds of formula (I) on the support, when such an effect is sought.
  • the solid supports whose surface is modified by a self-assembled monolayer organized according to the present invention can advantageously be used, as supports for the synthesis or the covalent immobilization of biological or chemical molecules of interest comprising an amino function.
  • biological or chemical molecules of interest comprising an amino function.
  • nucleic acids such as DNA and oligonucleotides, proteins, cellular ligands, therapeutic target molecules and combinatorial chemistry ligands.
  • the subject of the present invention is also the use of a solid support as described above for the synthesis or immobilization of molecules by covalent bond (formation of an amide bond).
  • the present invention also relates to a process for synthesizing molecules on a solid support as described above, characterized in that said molecules consist of a series of repeating units and in that said process comprises successive steps for grafting said repeating units, the first grafting repeating unit carrying an amine function reactive with respect to the aldehyde functions of the compounds of formula (I) in accordance with the invention present on the solid support.
  • the present invention further relates to a method of immobilizing biomolecules on a solid support as described above, characterized in that it comprises a step of grafting said biomolecules, which carry reactive amino functions vis- with respect to the aldehyde functions of the compounds of formula (I) in accordance with the invention, on said solid support.
  • the subject of the invention is also the solid supports as described above on which biological molecules are immobilized or chemically covalently via an amide function (nucleic acid chips, protein chips, cell ligand chips, etc.).
  • the invention also comprises other arrangements which will emerge from the description which follows, which refers to an example of preparation of a compound of formula (I) according to the invention, to an example for functionalizing the surface of a solid support using a compound of formula (I), to an example of the use of a support functionalized with a compound of formula (I) for the manufacture of a chip DNA, as well as in Figures 1 and 2 attached, in which: - Figure 1 shows the image of the fluorescence obtained on an epifluorescence microscope, after grafting of the 1 1 -silanyl-undecanal on the surface of a support silicon, an oligonucleotide (manually deposited) and hybridization with a complementary target;
  • FIG. 2 shows the image of the fluorescence obtained on a scanner, after grafting of the 1 1 -silanyl-undecanal on the surface of a silicon support, of an oligonucleotide (deposited in the robot) and hybridization with a complementary target.
  • the hydroxylation of a silicon substrate covered with a 5000 ⁇ thermal oxide layer is carried out in a 3.5 M sodium hydroxide solution for 2 hours.
  • a solid support is obtained in accordance with the invention comprising a surface modified by a self-assembled monolayer formed from 1 1 -silanyl-undecanal.
  • Example 2 the modified solid support prepared above is used in Example 2.
  • oligonucleotides of the following sequence: 3 'ATG TCA CAT GCC AAA TAG 5' (SEQ ID No. 1) modified in position 5 'by an amine function are carried out on the modified solid support of the example 2, either manually at the rate of 1.5 ⁇ l, or using a piezoelectric ejection robot sold under the name Nano-Plotter® by the company GeSiM (Germany), at the rate of 300 ⁇ l.
  • the oligonucleotide concentration of the solution used is 10 ⁇ M in a 0.3 M Na PO 4 buffer.
  • the substrates are hybridized with a solution of complementary targets of the following sequence: 3 ′ TAG AGT GTA CGG TTT ATC 5 ′ of concentration 0.1 ⁇ M, marked with a fluorescent group Cy3.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • General Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Nanotechnology (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Organic Chemistry (AREA)
  • Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
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  • Analytical Chemistry (AREA)
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  • Materials Engineering (AREA)
  • Manufacturing & Machinery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP04742596A 2003-04-30 2004-04-28 Silanyl-n-alkanalverbindungen, verfahren zu deren herstellung und deren verwendung Withdrawn EP1626977A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0305391A FR2854400B1 (fr) 2003-04-30 2003-04-30 COMPOSES SILANYL-n ALCANAL, LEUR PROCEDE DE PREPARATION ET LEURS UTILISATIONS
PCT/FR2004/001030 WO2004099219A2 (fr) 2003-04-30 2004-04-28 Composes silanyl-n alcanal, leur procede de preparation et leurs utilisations

Publications (1)

Publication Number Publication Date
EP1626977A2 true EP1626977A2 (de) 2006-02-22

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EP04742596A Withdrawn EP1626977A2 (de) 2003-04-30 2004-04-28 Silanyl-n-alkanalverbindungen, verfahren zu deren herstellung und deren verwendung

Country Status (5)

Country Link
US (1) US7442823B2 (de)
EP (1) EP1626977A2 (de)
JP (1) JP4781261B2 (de)
FR (1) FR2854400B1 (de)
WO (1) WO2004099219A2 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010105938A1 (en) * 2009-03-18 2010-09-23 Basf Se Modified silica particles and dirt repellent polymer compositions comprising them

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
FR2818662B1 (fr) * 2000-12-22 2003-09-19 Commissariat Energie Atomique Procede d'immobilisation de sondes, en particulier pour realiser des puces biologiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004099219A2 *

Also Published As

Publication number Publication date
WO2004099219A3 (fr) 2005-12-01
US7442823B2 (en) 2008-10-28
US20070032672A1 (en) 2007-02-08
JP2006525979A (ja) 2006-11-16
FR2854400B1 (fr) 2007-04-20
FR2854400A1 (fr) 2004-11-05
WO2004099219A2 (fr) 2004-11-18
JP4781261B2 (ja) 2011-09-28

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