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WO1997032892A1 - Composite pour synthese organique combinatoire - Google Patents

Composite pour synthese organique combinatoire Download PDF

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Publication number
WO1997032892A1
WO1997032892A1 PCT/GB1997/000556 GB9700556W WO9732892A1 WO 1997032892 A1 WO1997032892 A1 WO 1997032892A1 GB 9700556 W GB9700556 W GB 9700556W WO 9732892 A1 WO9732892 A1 WO 9732892A1
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WO
WIPO (PCT)
Prior art keywords
support
composite
beads
readable
readable marking
Prior art date
Application number
PCT/GB1997/000556
Other languages
English (en)
Inventor
Anthony Gerard Martin Barrett
Original Assignee
Imperial College Of Science Technology And Medicine
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 Imperial College Of Science Technology And Medicine filed Critical Imperial College Of Science Technology And Medicine
Priority to GB9819477A priority Critical patent/GB2326152B/en
Priority to AU22227/97A priority patent/AU2222797A/en
Publication of WO1997032892A1 publication Critical patent/WO1997032892A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/045—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers using devices to improve synthesis, e.g. reactors, special vessels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/005—Beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00502—Particles of irregular geometry
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
    • B01J2219/00547—Bar codes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/0059—Sequential processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00592—Split-and-pool, mix-and-divide processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00596—Solid-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00725—Peptides
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes

Definitions

  • the present invention relates to a composite.
  • the present invention relates to a process of forming the composite.
  • the present invention also relates to the use of that composite to prepare products.
  • the composite of the present invention is useful in combinatorial chemistry, especially combinatorial organic synthesis of products.
  • Combinatorial chemistry is a valuable tool for synthetic chemistry. It allows extremely large numbers of products to be synthesised in a reasonable time frame. In short, the products are synthesised by a multi-step wise addition of materials (such as molecules) to another material (such as a molecule) or other materials (such as molecules) that have been already linked together. The synthesised products can then be screened to see if, for example, they show promising favourable biological activity.
  • an appropriately functionalized solid phase support is partitioned among a number of reactors and unique subunits are reacted with each pool of resin in each reactor.
  • the resin beads are then removed entirely from all reactors, combined and mixed until homogeneous. This mixture is then redistributed to the reactors and the process is repeated, usually with a different set of unique subunits. If there are no redundancies in the subunits, the number of compounds produced by such a scheme is the number of reactors expanded to the exponent of the number of steps in which subunits are coupled. Thus, three sequential reactions using twenty pools of resin and unique subunits affords 20 3 products.
  • Figure 1 presents a schematic diagram of the use of polymeric supports for solid phase organic combinatorial synthesis of products.
  • These supports which for example are magnetite- impregnated poly(vinylbenzene), are sometimes referred to as “beads” .
  • the synthetic steps using such beads are sometimes referred to as “split bead synthesis” or “split/mix synthesis”.
  • an ensemble of, for example 900, beads (wherein each bead will be referred to as 1 ' , but is not shown as such) is collectively shown as set (1) of beads.
  • the set (1) of beads is divided into three portions (3, 5, 7) of beads - each having for example 300 beads. This explains why set (1) of beads is schematically shown bigger than portions (3, 5, 7) of beads. Thus, each of the portions (3, 5 and 7) of beads will initially contain equal amounts of beads (1 ').
  • Material A - such as reactant molecule A - is then bound (also referred to as coupled) to each bead (V) of the portion (3) of beads, such as via a suitable linker group (not shown), by use of a suitable reaction medium or media (not shown).
  • a suitable linker group not shown
  • an excess of material A will be added to the portion (3) of beads to ensure the binding of at least one material A to each bead (V) of the portion (3) of beads.
  • Each bead in the portion (3) of beads having bound thereto the material A will be referred to as bead (3', but is not shown as such).
  • a similar operation is also performed for the beads (1 ') in portion (5) of beads with material B.
  • Each bead in the portion (5) of beads having bound thereto the material B will be referred to as bead (5', but is not shown as such).
  • each of the portions (3, 5 and 7, respectively) of beads is then extracted from each reaction medium by use of, for example, a magnet (not shown).
  • the beads (3', 5' and 7') are then recombined to form a mixture of different beads (not shown) - comprising for example 900 beads.
  • the beads (3'), the beads (5') and the beads (7') within the mixture of different beads are then thoroughly mixed to form a set (10) of beads in a homogeneous mixture.
  • the set (10) of beads is then divided into three portions (13, 15, 17) of beads - of for example 300 beads each. This explains why set (10) of beads is schematically shown bigger than the portions (13, 15, 17) of beads. On average, therefore, in each portion
  • Material A - such as reactant molecule A - is then linked (also referred to as coupled) to the material bound to each of the beads (3'), beads (5') and beads (7') in the portion (13) of beads, such as by a linking reaction of the materials in a suitable reaction medium or media (not shown).
  • a linking reaction of the materials in a suitable reaction medium or media (not shown).
  • This linking step also known as coupling step
  • Each of these particular beads in portion (13) of beads will be collectively referred to as bead (13', but is not shown as such).
  • the second A can be different from the first A.
  • A can be the same as or different from B which can be the same as or different from C
  • AB, BB and CB bound to individual beads in the portion (15) of beads.
  • Each of these particular beads in the portion (13) of beads will be collectively referred to as bead (13', but is not shown as such).
  • the second B can be different from the first B.
  • A can be the same as or different from B which can be the same as or different from C]
  • the second C can be different from the first C.
  • A can be the same as or different from B which can be the same as or different from Cl
  • the beads (13', 15' and 17') When the beads (13', 15' and 17') have been formed in the portions (13, 15 and 17, respectively) of beads, they are then extracted from each reaction medium by use of as a magnet (not shown). The beads (13'), the beads (15') and the beads (17') and are then recombined to form a set (18) of different beads - of which there may be for example 900 beads.
  • the steps of dividing, linking (also referred to as coupling) and recombining are then continued until a desired number of different products are formed.
  • the products can then be separated from the bead by application of a suitable cleavage step.
  • the products can then be screened for favourable biological activity using, for example, in vitro assays.
  • a further attempt to overcome the inherent problem of analysing the synthesised product include the use of tags associated with materials bound to the beads, which tags are individual to each type of material. Accordingly, the product of interest may be indirectly analysed by determining the presence of a number of individual tags. Examples of the use of tags have been proposed by Needels et al (PNAS, 1993, 90, 10700-10704) and J C Chabala (Perspectives in Drug Discovery and Design, 1994,
  • tags include "soft" tags such as oligopeptides and oligonucleotides.
  • tags include "hard” tags such as electrophoretic tags - such as the group -O-(CH 2 ) n -O-AR.
  • radio-frequency tag encoding Another example of a tag is radio-frequency tag encoding.
  • radio-frequency tagging has a problem in that it has a population limitation.
  • the present invention seeks to overcome the problems associated with the prior art analytical techniques for the analysis of materials, and products that have been formed therefrom.
  • a composite comprising (i) a support; (ii) at least a first material bound to the support; and (iii) at least a first readable marking present on and/or in the support, wherein the first readable marking is capable of indicating the presence of the first material.
  • a composite according to the present invention for the synthesis of a product, wherein the product is synthesised by reacting the first material of the composite with a second material.
  • a process of synthesising a product comprising reacting at least a first material with a second material, characterised in that the first material is bound to a support, wherein a first readable marking is present on and/or in the support which first readable marking is capable of indicating the presence of the first material; and wherein a second readable marking is present on and/or in the support which second readable marking is capable of indicating the presence of a second material.
  • a process of synthesising a product comprising reacting at least a first material with a second material, characterised in that the reaction comprises the following steps: forming a composite according to the present invention; introducing a readable marking in and/or on the support of the composite, which readable marking is capable of indicating the presence of the second material; and linking the first material with the second material.
  • a product obtained by a use according to the present invention or by a process according to the present invention is provided.
  • a product according to the present invention wherein the product is or is used in the production of a pharmaceutical.
  • a composite comprising: (i) a support; (ii) a product bound to the support, wherein the product has been synthesised by reacting at least a first material bound to the support with at least a second material; and (iii) a readable marking or a series of readable markings present in and/or on the support, wherein the readable marking or the series of readable markings is capable of indicating the synthetic history of the product.
  • One of the key advantages of the present invention is that it provides a means for determining more readily the synthetic history of a product of interest, rather than having to analyse the product itself.
  • a further key advantage is that libraries of products can be prepared on solid supports using automated robotic set-ups and wherein the synthetic history of those products can be readily determined - such as by a machine.
  • the composite of the present invention provides an alternative analytical tool to current soft or hard chemical tag strategies. Moreover, the composite of the present invention amplifies synthetic procedures that can be used in split bead synthesis simply because tagging and library synthesis must use reagents of orthogonal reactivity.
  • the term "capable of indicating the presence of” as used herein includes a readable marking that is indicative of the presence of a bound material and/or the number of the reaction step(s), which readable marking may be an optically readable code.
  • the term also includes the marking being a sensor on or of the support whose detectable characteristics change when different materials and/or number of materials are bound to the support.
  • the term means an optically readable marking - such as a code - that is indicative of at least the presence of a bound material. More preferably, the term a readable marking that is indicative of the presence of a bound material and the number of synthetic steps. More preferably, the marking is machine readable - thus synthesis, screening and analysis can be fully automated.
  • the composite may be separated from a reaction medium by, for example, filtration techniques.
  • the composite comprises a separating component, such as a magnetic separating component (e.g. magnetite).
  • a magnetic separating component e.g. magnetite
  • the use of a magnetic separating component is advantageous as it eases separation of the composite from a reaction medium by use of a magnet.
  • the use of a magnetic separating component is further advantageous in that it allows the composite to be held in a particular orientation to enable a marking to be read from and written onto the support with more ease.
  • the present invention there may be occasions when the products are to be assayed when bound to the support.
  • At least a second material is linked to the first material; and wherein at least a second readable marking is present on and/or in the support, wherein the second readable marking is capable of indicating the presence of the second material.
  • a third material may be linked to the second material; and wherein at least a third readable marking is present on and/or in the support, wherein the third readable marking is capable of indicating the presence of the third material.
  • an n* material may be linked to an n-l * material; and wherein at least an n" 1 readable marking and an n-l th readable marking are present on and/or in the support, wherein the n ⁇ readable marking is capable of indicating the presence of the n" 1 material, wherein the n-l lh readable marking is capable of indicating the presence of the n-l th material; and wherein n is an integer greater than 1.
  • one or more further readable markings are present on and/or in the support, wherein the or each further readable marking is capable of indicating the presence of each step of forming the composite.
  • each readable marking is an optically readable marking.
  • each readable marking is a visually readable code.
  • each readable marking is formed in and/or on the support.
  • the support comprises a semi-conductor component on and/or in which component is any one or more readable marking.
  • the support comprises silicon and/or silica.
  • the composite comprises (iv) a component that enables the composite to be separated from a reaction medium.
  • the component is magnetic
  • the component is magnetite.
  • the composite comprises (v) a polymeric surface to which the first material is bound.
  • the polymeric surface does not cover each readable marking.
  • the polymeric surface is polystyrene.
  • the first material is bound to the support via a cleavable linker group.
  • a plurality of first materials are bound to the support.
  • the composite is of a particulate structure.
  • the support is a bead.
  • each material is a molecule.
  • step ii precedes step iii.
  • the size of the support is in the order of 1mm x 1mm x 1 mm or less. Preferably, the size of the support is less than 1mm x 1mm x 1 mm.
  • a preferred suitable support for the present invention is a microparticle that has a thickness of from O. l ⁇ m to 50 ⁇ m, a length of from 0. l ⁇ m to 50 ⁇ m, and a width of from O. l ⁇ m to 50 ⁇ m.
  • the support of the present invention is a microparticle that has a thickness of about 10 ⁇ m, a length of about lO ⁇ m, and a width of about lO ⁇ m.
  • This support comprises a microparticle wafer that has a thickness of from O. l ⁇ m to 5 ⁇ m and a length of from 0.5 ⁇ m to 50 ⁇ m.
  • the readable marking is distinct from the material that is bound to the support.
  • the resultant product can be synthesised from a plurality of materials, all of which may be the same, some of which may be the same or all of which are different.
  • Each support can have bound thereto a plurality of products.
  • the synthetic process of the present invention is applicable to any chemical reaction, especially organic chemical transformation.
  • the present invention is applicable to any one or more of the following reactions: photochemical release (e.g. use of any one or more of ortho-nitro-benzyl linkers, HF/TFA scission of silane linkers, metal metathesis of alkene linkers with ethylene); organometallic methods to construct carbon-carbon skeletons (e.g. using any one or more of palladium and nickel [0] chemistry, alkene metathesis, asymmetric hydrogenation and hydro- formylation); iterative aldol reactions; cycloaddition reactions; heterocyclisations; redox chemistry; transacylations; and alkylations.
  • photochemical release e.g. use of any one or more of ortho-nitro-benzyl linkers, HF/TFA scission of silane linkers, metal metathesis of alkene linkers with ethylene
  • organometallic methods to construct carbon-carbon skeletons e.g
  • the support is a polymer-magnetite-silicon or magnetite-silicon-silica-silicone polymer composite, and wherein the readable marking is a bar code etched onto the support.
  • the magnetite core can be used in solution phase/solid phase separations and, at the same time, be used to align single beads for micro code writing/reading in the silicon face.
  • the combinatorial synthesis will be effected via phase methods using, for example, polystyrene supports with cleavable linkers.
  • linkers are those that are cleavable either via photochemically or via gas/solid phase reactions.
  • Possible cleavage techniques include laser-mediated thermal cycloelimination-recycloaddition with alkynes (eg in an ethyne atmosphere) followed by spontaneous loss of polymer-OL via aromatisation or via gas-solid phase protodesilylation reactions.
  • the preferred magnetite-silicon-silica-silicone composites may be employed with alkylsilane triol linkers attached to the silica modified silicon surface.
  • Such linkers could be subject to either photochemical or gas-solid phase cleavage.
  • the present invention provides a composite comprising (i) a support; (ii) at least a first material bound to the support; and (iii) at least a first readable marking present on and/or in the support, wherein the first readable marking is capable of indicating the presence of the first material.
  • the present invention also provides a composite comprising: (i) a support; (ii) a product bound to the support, wherein the product has been synthesised by reacting at least a first material bound to the support with at least a second material; and (iii) a readable marking or a series of readable markings present in and/or on the support, wherein the readable marking or the series of readable markings is capable of indicating the synthetic history of the product.
  • the present invention allows extremely large numbers of compounds to be synthesised and categorised in a reasonable time frame. It is believed that using the present invention it will be possible to fabricate, evaluate and archive up to 10,000, or even up to 1 ,000,000, compounds within 24 hours.
  • Figure 1 is a schematic diagram of a conventional split bead synthesis method
  • Figure 2 is an enlarged perspective view of a preferred support according to the present invention.
  • Figure 3 is an enlarged view of a preferred support according to the present invention showing the presence of a series of markings according to the present invention.
  • Figure 4 is a schematic diagram of a split bead synthesis process according to the present invention.
  • the support (20) comprises a polymeric outer layer
  • the support (20) also comprises a layer of magnetite (26), which aids the recovery of the composite material of the present invention from a reaction medium.
  • the support (20) also comprises a silicon/silica core (28), on to which can be etched a marking (or markings) (30) that is (are) indicative of the material(s) directly bound to the support and the material(s) that are linked to the material(s) bound to the support.
  • I (34) denotes the first material which marking, here a code, will be unique for the first material - such as reactant material C as shown in Figure 4
  • FIG. 4 is a schematic diagram of a combinatorial synthetic process according to the present invention.
  • an ensemble of, for example 900, beads (wherein each bead will be referred to as 101', but is not shown as such) is collectively shown as set (101) of beads.
  • the set (101) of beads is divided into three portions (103, 105, 107) of beads - each having for example 300 beads. This explains why set (101) of beads is schematically shown bigger than portions (103, 105, 107) of beads. Thus, each of the portions (103, 105 and 107) of beads will initially contain equal amounts of beads (101 ').
  • the beads (101 ') comprise the support (20) shown in Figures 2 and 3.
  • Each bead (101 ') in the portion (103) of beads is marked with a unique readable marking that is indicative of the number of the reaction step that is to be carried out (here the marking is ) and with a unique readable marking that is indicative of the material that is to be bound to the support (here the marking is (
  • that material is shown as reactant A.
  • Each bead (101 ') in the portion (105) of beads is also marked with a unique readable marking that is indicative of the number of the reaction step that is to be carried out (here the marking is ) and with a unique readable marking that is indicative of the material that is to be bound to the support (here the marking is (
  • that material is shown as reactant B.
  • Each bead (101') in the portion (107) of beads is also marked with a unique readable marking that is indicative of the number of the reaction step that is to be carried out (here the marking is ) and with a unique readable marking that is indicative of the material that is to be bound to the support (here the marking is (
  • that material is shown as reactant C.
  • the layer of magnetite (26) in each of beads (101 ') assists in the marking of the beads (101 '). In this regard, use of a magnet (not shown) will hold the areas of the silicon/silica core (28) in a certain orientation for the subsequent marking thereof and for the reading of the marking.
  • Reactant A is then bound (also referred to as coupled) to each bead (101 ') of the portion (103) of beads, such as via a suitable linker group (not shown), by use of a suitable reaction medium or media (not shown).
  • a suitable linker group not shown
  • an excess of material A will be added to the portion (103) of beads to ensure the binding of at least one material A to each bead in the portion (103) of beads.
  • Each bead in the portion (103) of beads having bound thereto the material A will be referred to as bead (103', but is not shown as such).
  • a similar operation is also performed for the beads (101 ') in the portion (105) of beads with material B.
  • Each bead in the portion (105) of beads having bound thereto the material B will be referred to as bead (105', but is not shown as such).
  • a similar operation is also performed for the beads (101') in the portion (107) of beads with material C.
  • Each bead in the portion (107) of beads having bound thereto the material C will be referred to as bead (107' , but is not shown as such).
  • the beads (103', 105' and 107') in the portions (103, 105 and 107, respectively) of beads are then extracted from each reaction medium by use of, for example, a magnet (not shown).
  • the beads (103' , 105' and 107') are then recombined to form a mixture of different beads (not shown) - which mixture may for example comprise 900 beads.
  • the beads (103'), the beads (105') and the beads (107') within the mixture of different beads are then thoroughly mixed to form a set (110) of beads in a homogeneous mixture.
  • the set (110) of beads is then divided into three portions (113, 115, 117) of beads - of for example 300 beads each. This explains why set (110) of beads is schematically shown bigger than portions (113, 115, 117) of beads. On average, in each portion (113, 115 and 117) of beads there should be an equal number of beads (103', 105' and 107').
  • Each bead in the portion (113) of beads is then marked with a unique readable marking that is indicative of the number of the reaction step that is to be carried out (here the marking is :) and with a unique readable marking that is indicative of the material that is to be linked to the bound material (here the marking is ( j ).
  • the marking is :
  • a unique readable marking that is indicative of the material that is to be linked to the bound material
  • Each bead in the portion (115) of beads is also marked with a unique readable marking that is indicative of the number of the reaction step that is to be carried out (here the marking is :) and with a unique readable marking that is indicative of the material that is to be linked to the bound material (here the marking is (
  • that material is shown as reactant B.
  • Each bead in the po ⁇ ion (117) of beads is also marked with a unique readable marking that is indicative of the number of the reaction step that is to be carried out
  • Material A - such as reactant molecule A - is then linked (also referred to as coupled) to the material bound to each of the marked beads in the portion (113) of beads, such as by a linking reaction of the materials in a suitable reaction medium or media (not shown).
  • a linking reaction of the materials in a suitable reaction medium or media (not shown).
  • an excess of material A will be added to the portion (113) of beads to ensure the linking of material A to the material bound to each bead in the portion (113) of beads.
  • This linking step also known as coupling step
  • Each of these particular beads in portion (113) of beads will collectively be referred to as bead (113', but is not shown as such).
  • This linking step also known as a coupling step
  • This linking step produces the products AB, BB and CB bound to individual beads in the portion (115) of beads.
  • Each of these particular beads in portion (115) will collectively be referred to as bead (115', but is not shown as such).
  • the beads (113', 115' and 117') When the beads (113', 115' and 117') have been formed in the portions (113, 115 and 117, respectively) of beads, they are then extracted from each reaction medium by use of as a magnet (not shown). The beads (113'), the beads (115') and the beads (117') and are then recombined to form a mixture (118) of a number of different beads - in which there may be for example 900 beads.
  • the synthetic process of the present invention produces products bound to supports, wherein the products have been formed by step wise synthetic stages which comprise successive linking of materials, which materials may be the same, partially the same or different, and wherein the supports have readable markings thereon and/ or therein which are indicative of the synthetic history of the products.
  • the products obtained and whilst still bound to the beads can then be screened for favourable biological activity using, for example, in vitro assays. This is sometimes referred to as "single bead assay" .
  • the products can then be separated from the bead by application of a suitable cleavage step.
  • the products can then be screened for favourable biological activity using, for example, in vitro assays.
  • markings shown in these examples are dots and lines, including combinations thereof, other suitable readable markings can be used.
  • reactant A in the second synthetic step could be the same as reactant A in the first synthetic step.
  • reactant A in the second synthetic step could different to reactant A in the first synthetic step.
  • reactant A in any of the synthetic steps could be the same as any one of the reactants B and C. The same is true of the other reactants.
  • beads can be split into any number of portions, which may be the same or different.
  • each bead can have bound to it a plurality of first materials.
  • the support is a polymer matrix comprising a markable surface.
  • An example of such a polymer matrix is modified polystyrene (e.g. a Link resin or a Wang resin).
  • Three portions of beads are formed during each synthesis step, however any number of portions can be formed.
  • the first material is a protected amino acid (first amino acid).
  • the first amino acids may be the same or different for each of the portions.
  • each first material can be an FMOC protected amino acid such as any one of Arg,
  • the second material is also a protected amino acid (second amino acid).
  • the second amino acids may be the same or different for each of the portions and/or the same as or different from any one or more of the first amino acids.
  • the second material can be an FMOC protected amino acid such as any one of Asp, Gly and Ser.
  • the third material, which links to the second material is also a protected amino acid (third amino acid).
  • the third amino acids may be the same or different for each of the portions and/or the same as or different from either any one or more of the first amino acids or any one or more of the second amino acids.
  • the third material can be an FMOC protected amino acid such as any one of Leu, Ala and Thr.
  • the first material binds to the polymer matrix via carbodiimide mediated coupling.
  • the second material links with the bound first material via carbodiimide mediated coupling.
  • the third material links with the bound second material via carbodiimide mediated coupling.
  • the readable markings are formed on the surface of the polymer matrix via photolithography.
  • the amino acid is deprotected via usage of piperidine in DMF.
  • the amino acid is deprotected via usage of piperidine in DMF.
  • the third material has linked to the bound second material the amino acid is deprotected via usage of piperidine in DMF.
  • the split bead synthesis of the present invention is also amenable for in situ assay with dye-conjugated soluble receptors or in single bead release/single cell assays.
  • the libraries can be screened with dye-conjugated soluble receptors, with macromolecules or even in single cell assays following release from the linker but with retention of spatial identity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)

Abstract

La présente invention concerne un composite. Ce composite comprend (i) un support (20); (ii) au moins un premier matériau lié au support (20); et (iii) au moins un premier marquage lisible (30) présent à l'intérieur et/ou en surface du support (20), le premier marquage lisible (30) étant capable d'indiquer la présence du premier matériau.
PCT/GB1997/000556 1996-03-07 1997-02-26 Composite pour synthese organique combinatoire WO1997032892A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB9819477A GB2326152B (en) 1996-03-07 1997-02-26 A composite for combinatorial organic synthesis
AU22227/97A AU2222797A (en) 1996-03-07 1997-02-26 A composite for combinatorial organic synthesis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9604858.2A GB9604858D0 (en) 1996-03-07 1996-03-07 A composite
GB9604858.2 1996-03-07

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WO1997032892A1 true WO1997032892A1 (fr) 1997-09-12

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GB (1) GB9604858D0 (fr)
WO (1) WO1997032892A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046550A1 (fr) * 1997-04-17 1998-10-22 Zeneca Limited Procede de preparation d'une banque chimique codee
EP1034183A1 (fr) * 1997-11-12 2000-09-13 The University of Queensland Ensemble support-billes de marquage
WO2003099843A3 (fr) * 2002-05-20 2004-07-01 Dow Corning Derives de peptides et utilisation de ces derives pour la synthese de materiaux composites a base de silicium
EP1495144A2 (fr) * 2002-03-21 2005-01-12 Aviva Biosciences Corporation Microdispositifs comprenant un axe preferentiel de magnetisation et utilisations de ces microdispositifs
US7811768B2 (en) 2001-01-26 2010-10-12 Aviva Biosciences Corporation Microdevice containing photorecognizable coding patterns and methods of using and producing the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008051A1 (fr) * 1992-10-01 1994-04-14 The Trustees Of Columbia University In The City Of New York Banques chimiques combinatoires complexes codees avec des etiquettes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008051A1 (fr) * 1992-10-01 1994-04-14 The Trustees Of Columbia University In The City Of New York Banques chimiques combinatoires complexes codees avec des etiquettes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J.J.BALDWIN ET AL.: "Synthesis of a Small Molecule Combinatorial Library Encoded with Molecular Tags", J.AM.CHEM.SOC., vol. 117, 1995, pages 5588 - 9, XP000652265 *
J.W.JACOBS ET AL.: "Combinarorial Chemistry- applications of light- directed chemical synthesis", TRENDS BIOTECHNOL., vol. 12, no. 1, 1994, pages 19 - 26, XP000652268 *
M.J.SZYMONIFKA ET AL.: "Magnetically Manipulable Polymeric Supports for Solid Phase Organic Synthesis", TERAHEDRON LETT., vol. 36, no. 10, 1995, pages 1597 - 1600, XP000654538 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046550A1 (fr) * 1997-04-17 1998-10-22 Zeneca Limited Procede de preparation d'une banque chimique codee
EP1034183A1 (fr) * 1997-11-12 2000-09-13 The University of Queensland Ensemble support-billes de marquage
EP1034183A4 (fr) * 1997-11-12 2001-07-18 Univ Queensland Ensemble support-billes de marquage
US7811768B2 (en) 2001-01-26 2010-10-12 Aviva Biosciences Corporation Microdevice containing photorecognizable coding patterns and methods of using and producing the same
EP1495144A2 (fr) * 2002-03-21 2005-01-12 Aviva Biosciences Corporation Microdispositifs comprenant un axe preferentiel de magnetisation et utilisations de ces microdispositifs
EP1495144A4 (fr) * 2002-03-21 2010-06-30 Aviva Biosciences Corp Microdispositifs comprenant un axe preferentiel de magnetisation et utilisations de ces microdispositifs
WO2003099843A3 (fr) * 2002-05-20 2004-07-01 Dow Corning Derives de peptides et utilisation de ces derives pour la synthese de materiaux composites a base de silicium
US7361731B2 (en) 2002-05-20 2008-04-22 Genencor International, Inc. Peptide derivatives, and their use for the synthesis of silicon-based composite materials

Also Published As

Publication number Publication date
AU2222797A (en) 1997-09-22
GB9604858D0 (en) 1996-05-08

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