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WO1997035198A1 - Techniques de synthese d'une bibliotheque combinatoire a distribution controlee dispersee dans l'espace - Google Patents

Techniques de synthese d'une bibliotheque combinatoire a distribution controlee dispersee dans l'espace Download PDF

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Publication number
WO1997035198A1
WO1997035198A1 PCT/US1997/004500 US9704500W WO9735198A1 WO 1997035198 A1 WO1997035198 A1 WO 1997035198A1 US 9704500 W US9704500 W US 9704500W WO 9735198 A1 WO9735198 A1 WO 9735198A1
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series
arrays
solid supports
array
supports
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PCT/US1997/004500
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English (en)
Inventor
Edmund J. Moran
John F. Cargill
Romaine R. Maiefski
Thomas J. Baiga
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Ontogen Corporation
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Priority to JP53370397A priority Critical patent/JP2001519763A/ja
Priority to EP97916869A priority patent/EP0904540A1/fr
Priority to AU25373/97A priority patent/AU2537397A/en
Publication of WO1997035198A1 publication Critical patent/WO1997035198A1/fr

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    • 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
    • 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
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • 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
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • 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
    • B01J2219/00452—Means for the recovery of reactants or products
    • B01J2219/00454—Means for the recovery of reactants or products by chemical cleavage from the solid support
    • 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
    • B01J2219/00457—Dispensing or evacuation of the solid phase support
    • B01J2219/0047—Pins
    • B01J2219/00472—Replaceable crowns
    • 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
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel 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
    • B01J2219/0059—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
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • 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
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
    • 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 method useful in combinatorial chemistry. More particularly, the present invention relates to methods for synthesizing spatially-dispersed positionally- encoded combinatorial chemistry libraries of oligomers whereby the synthesis is carried out on a plurality of solid supports which in turn are distributed in the form of a series of arrays. The position of each solid support in each array determines the exact identity of the oligomer.
  • a common feature to the spatially-addressable combinatorial library methods is that a unique combination of monomers is reacted to form a single oligomer or compound or, alternately, set of oligomers or compounds at a predefined unique physical location or address in the synthesis process.
  • An example of the spatially-addressable method is provided by Geysen et. al. 4 and involves the generation of peptide libraries on an array of immobilized polymeric pins (a solid support) that fit the dimensions of a 96-well microtiter plate. A two-dimensional matrix of combinations is generated in each microtiter plate experiment, where n x m unique oligomers or compounds are produced for a combination of n+ rn parallel monomer addition steps.
  • each of the individual library members is determined by analyzing the pin location and the monomers employed at that address during the sequence of reaction steps in the synthesis.
  • An advantage of this method is that individual oligomer or compound products can be released from the polymeric pin surface in a spatially-addressable manner to allow isolation and screening of each discrete member of the library.
  • Another advantage of this method is that the number of solid supports required is equal to, i.e. no larger than, the number of library members to be synthesized. Thus, relatively large quantities, i.e. micromolar quantities, of individual library members are synthesized in a practical manner using this method.
  • Related to the Geysen pin method are the parallel synthesis methods which use a reaction vessel system such as that practiced by Cody, et al.
  • This spatially-addressable method has advantages similar to that of Geysen, et. al. Thus, individual oligomer or compound products can be released from the solid support in a spatially-addressable manner to allow isolation and screening of each discrete member of the library.
  • the number of solid supports required is equal to, i.e. no larger than, the number of library members to be synthesized.
  • relatively large quantities, i.e. micromolar to millimolar quantities, of individual library members also are synthesized in a practical manner using this method.
  • Another example of a spatially-addressable method is the photolithographic method for synthesizing a collection oligomers or compounds on the chemically-derivatized surface of a chip (a solid support) provided by Fodor et. al. 6
  • a variety of masking strategies can be employed to selectively remove photochemically-labile protecting groups thus revealing reactive functional groups at defined spatial locations on the chip.
  • the functional groups are reacted with a monomer by exposing the chip surface to appropriate reagents.
  • the sequential masking and reaction steps are recorded, thus producing a pre-defined record of discrete oligomers or compounds at known spatial addresses in an experiment.
  • An advantage of this method is that binary masking strategies can be employed to produce 2" unique oligomers or compounds for n masking and monomer addition cycles.
  • Two important disadvantages of this method are that a) relatively minute quantities are produced on the surface of the chip and; b) release and isolation of individual library members is not technically feasible.
  • Split-pool combinatorial library methods differ from spatially- addressable methods in that the physical location of each unique oligomer or compound is not discrete. Instead, pools of library members are manipulated throughout the experiment.
  • solid support-based chemistry it is common in the practice to employ solid support-based chemistry for these methods.
  • a collection of solid supports are split into individual pools. These pools are then exposed to a series of reactive monomers, followed by a recombination step, in which the position of all solid supports is randomized.
  • the solid supports are then split into a new set of individual pools, exposed to a new series of reactive monomers, followed by a second recombination step. By repeating this split, react and recombine process all possible combinations of oligomers or compounds from the series of monomers employed are obtained, providing a large excess of solid supports are utilized.
  • the prior art split-pool methods produce pools of oligomers or compounds as a product of the experiment. Therefore, the identification of a specific member of the library is typically found by screening the pools for a desired activity, biological or otherwise.
  • the disadvantages of the deconvolution split-pool methods are that (a) the technique always requires that large mixtures of oligomers are screened in bioassays, (b) sequential rounds of resynthesis and bioassay are always required to deconvolute a library, and (c) since single oligomers are not produced a library is always stored as a mixture, requiring later deconvolution.
  • both categories of split-pool methods require a large excess of solid support beads to ensure with reasonable certainty (99% confidence level) that all possible oligomers are made when a random split-pool strategy is employed. 13 This is necessary because the exact identity of each bead (i.e. the identity of each oligomer) is lost due to the unstructured nature of the split-pool method. This presents a significant problem when scaling up these methods for the production of micromole or larger amounts of individual oligomers in the library.
  • a "monomer” is any atom or molecule capable of forming at least one chemical bond.
  • a “monomer” is any member of the set of atoms or molecules that can be joined together as single units in a multiple of sequential or concerted chemical or enzymatic reaction steps to form an oligomer.
  • Monomers may have one or a plurality of functional groups, which functional groups may be, but need not be, identical.
  • the set of monomers useful in the present invention includes, but is not restricted to, alkyl and aryl amines; alkyl and aryl mercaptans; alkyl and aryl ketones; alkyl and aryl carboxylic acids; alkyl and aryl esters; alkyl and aryl ethers; alkyl and aryl sulfoxides; alkyl and aryl sulfones; alkyl and aryl sulfonamides; phenols; alkyl alcohols; alkyl and aryl alkenes; alkyl and aryl lactams; alkyl and aryl lactones; alkyl and aryl di- and polyenes; alkyl and aryl alkynes; alkyl and aryl unsaturated ketones; alkyl and aryl aldehydes; heteroatomic compounds containing one or more of the atoms of: nitrogen, sulfur, phosphorous, oxygen, and other polyfunctional molecules
  • the monomers of the present invention may have groups protecting the functional groups within the monomer. Suitable protecting groups will depend on the functionality and particular chemistry used to construct the library. Examples of suitable functional protecting groups will be readily apparent to skilled artisans, and are described, for example, in Greene and Wuts, 14 which is incorporated herein by reference. As used herein, "monomer” refers to any member of a basis set for synthesis of an oligomer.
  • the dimers of 20 L-amino acids form a basis set of 400 "monomers" for synthesis of polypeptides.
  • Different basis sets of monomers may be used at successive steps in the synthesis of an oligomer.
  • an "oligomer” is any chemical structure that can be synthesized using the combinatorial library methods of this invention, including, for example, amides, esters, thioethers, ketones, ethers, sulfoxides, sulfonamides, sulfones, phosphates, alcohols, aldehydes, alkenes, alkynes, aromatics, polyaromatics, heterocyclic compounds containing one or more of the atoms of: nitrogen, sulfur, oxygen, and phosphorous, and the like; chemical entities having a common core structure such as, for example, terpenes, steroids, ⁇ -lactams, benzodiazepines, xanthates, indoles, indolones, lactones, lactams, hydantoins, quinones, hydroquinones, and the like; chains of repeating monomer units such as polysaccharides, phospholipids, polyurethanes
  • an "oligomer” of the present invention may be linear, branched, cyclic, or assume various other forms as will be apparent to those skilled in the art.
  • oligomer may be used synonymously or interchangeably with “compound” , thus describing any structure, organic or inorganic, which can be produced in a sequential fashion via the addition of monomeric units as described above.
  • Solid Support is a material, or combination of materials, having a rigid or semi-rigid surface and having functional groups or linkers, or that is capable of being chemically derivatized with functional groups or linkers, that are suitable for carrying out chemical synthesis reactions.
  • Such materials will preferably take the form of small beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, cellulose beads, pore-glass beads, silica gels, polystyrene beads cross-linked with divinylbenzene and optionally grafted with polyethylene glycol, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N'-bis- acryloyl ethylene diamine, polydimethylacrylamide beads crosslinked with polystyrene, glass particles coated with a hydrophobic polymer, or other convenient forms.
  • Solid supports may be constructed such that they are capable of being transferred mechanically from one support carrier to another support carrier.
  • Linker is a moiety, molecule, or group of molecules attached to a solid support and spacing a synthesized oligomer from the solid support.
  • a linker will be bi-functional, wherein said linker has a functional group at one end capable of attaching to a monomer, oligomer, or solid support, a series of spacer residues, and a functional group at another end capable of attaching to a monomer, oligomer, or solid support.
  • the functional groups may be, but need not be, identical.
  • said linker may be cleaved by a chemical transformation such that the synthesized oligomer, or part of the synthesized oligomer, or the synthesized oligomer and the linker, or the synthesized oligomer and part of the linker may be chemically separated from the solid support, linker, or both.
  • An object of the present invention is to provide a method for the synthesis of a spatially-dispersed combinatorial library of oligomers, in which the oligomers are distributed in a controlled manner.
  • oligomers are comprised of a series of monomers which are introduced into the oligomers in a sequential and stepwise fashion via chemical transformation steps (hereafter referred to as "steps").
  • steps chemical transformation steps
  • These monomers are comprised of subsets of monomers such that the first subset of monomers is introduced in the first step, the second set of monomers is introduced in the second step, etc.
  • the method further describes a means for introducing the monomers in a sequential and stepwise fashion on a series of solid supports. The number of supports equals the number of oligomers in the library.
  • a novel aspect of this process as distinguished from the prior art is that the supports are arranged in, and subsequently redistributed in a controlled manner between, a series of arrays.
  • This series of arrays provide a means for holding the supports in physically discrete locations such that the exact identity of each support is provided by its location.
  • the series of arrays of supports are placed in a further series of reaction vessels for the individual steps of an oligomer synthesis. After each step in the oligomer synthesis the supports are redistributed from one series of arrays to a next series of arrays.
  • a further novel aspect of this process is that between each step the redistribution of the supports is carried out in an controlled fashion, such that all possible combinations of possible oligomers are synthesized.
  • a further novel aspect of this process is that the positions of all supports are known during the synthesis experiment such that the identity of an oligomer is unequivocally established by its physical location.
  • the applied method achieves a geometric amplification in the number of library members synthesized relative to the number of synthetic steps required while providing individual library members in a spatially- dispersed format.
  • the use of a tagging system is eliminated for a split-pool synthesis experiment.
  • the method has utility in the production of oligomers which are available for screening in assays for novel biological, chemical, or physical properties which may have commercial value. Further, the structures of these oligomers are readily identifiable by virtue of their physical location. The method further provides a means for producing each oligomer in a discrete physical location which allows any pre-determined oligomer to be readily isolated from all other oligomers in the library. Yet another advantage of the invention is that no excess of solid supports is required, thus enabling a larger scale of synthesis.
  • the method described herein is suitable for the synthesis of a library of oligomers comprised of two, three, or more sets of oligomers. However, the method described is most suitable for the synthesis of a library of oligomers comprised of three monomer subsets. The sums of monomers in each of these subsets may be variable. However, conveyance of the methodology to those practiced in the art may be initially illustrated when the sum of all monomers in each subset is equal. The sum of monomers in each subset is defined by n in which n is a positive integer.
  • the solid supports are preferably arranged in a series of arrays of dimension nx n. There are a total of n such arrays required for the synthesis of such a library.
  • the n arrays of solid supports are preferably arranged in support carriers (hereafter referred to as "carriers").
  • carriers support carriers
  • Each carrier holds an n x n array of solid supports.
  • several carriers may be used to hold an n x n array of supports.
  • the carriers are of sufficient size to hold an entire n x n array of supports.
  • a further novel aspect of this process as distinguished from the prior art is the method by which the supports are redistributed from one series of arrays to the next series of arrays between chemical transformation steps.
  • the supports are arranged as arrays on the carriers and reacted with a first subset of monomers.
  • the columns of supports in the first series of arrays are redistributed such that the first column from the first array in the first series is transferred to the first column of the first array in the second series; the second column from first array in the first series is transferred to the first column of the second array in the second series; the third column from the first array in the first series is transferred to the first column of the third array in the second series.
  • the first, second and third columns of supports from the second and third arrays in the first series are redistributed to the second series of arrays for chemical transformation step #2 in a similar fashion. Having completed this redistribution process, the arrays of supports undergo chemical transformation step #2. After step #2 the arrays are redistributed again to a new series of arrays.
  • the method of redistribution is similar to that used after the chemical transformation step # 1 , however, it is the individual rows of each array that are redistributed rather than the columns described above.
  • the redistribution is shown in Figure 1.
  • the rows of supports in the second series of arrays are redistributed such that the first row from the first array in the second series is transferred to the first row of the first array in the third series; the second row from first array in the second series is transferred to the first row of the second array in the third series; the third row from the first array in the second series is transferred to the first row of the third array in the third series.
  • the first, second and third rows of supports from the second and third arrays in the second series are redistributed to the third series of arrays for chemical transformation step #3 in a similar fashion.
  • the redistribution of supports between the chemical transformation steps # 1 and #2 and between steps #2 and #3 is functionally identical if one simply reorients the arrays such that rows become columns and columns become rows (such as accomplished by a 90 degree rotation). If such a reorientation of the second series of arrays occurs then the columns from the second series of arrays are redistributed to columns in the third series of arrays. Following this second redistribution, chemical transformation step #3 is carried out on the supports.
  • this redistribution method uses this redistribution method to ensure all 27 possible combinations of monomers thus producing a combinatorial library of 27 oligomers. It may be appropriate to indelibly mark the carriers which hold the arrays using a means to ensure that rows are recognized as distinct from columns in each array. Additionally, each carrier may also be indelibly marked to distinguish the contents of its arrays uniquely from other carrier's arrays. Preferably, a barcode reading device may be used to query this information from a barcode placed across the top of the columns or beside the rows of each carrier. As appreciated by those familiar in the art, this redistribution method for an n x n x n library is efficient, transferring entire columns or entire rows of supports simultaneously.
  • reaction vessels can be employed to produce a library of one million members, all spatially-dispersed, individually identifiable and individually isolated.
  • spatially-dispersed techniques as previously practiced by Geysen, Cody, and Ellman 15 would have required 3 million reaction vessels to produce an identical resulting oligomer library.
  • the method described herein is also most suitable for the synthesis of a library of oligomers comprised of three monomer subsets.
  • the sums of monomers in each of these subsets may be variable.
  • the sum of monomers in each subset is defined by m, n, and p, respectively for the three subsets such that n, m, and p are positive integers.
  • the total number of unique oligomers produced in a three step synthesis is the product m n x p.
  • the solid supports are preferably arranged in a series of arrays of dimension n x p. Therefore, a total of m such arrays are required for the first step in the synthesis of such a library.
  • the m arrays of solid supports are preferably arranged in support carriers.
  • Each carrier holds an n x p array of solid supports.
  • several carriers may be used to hold an nx p array of supports.
  • the carriers are of sufficient size to hold an entire n x p array of supports.
  • there are m carriers which are placed in m reaction vessels for the first chemical transformation step such that each individual monomer from a subset of m monomers is reacted with the supports in each individual reaction vessel.
  • a further novel aspect of this process as distinguished from the prior art is the method by which the supports are redistributed from one series of arrays to the next series of arrays between chemical transformation steps. This novel method is illustrated in Figure 2 for a three-step combinatorial synthesis using three subsets of monomers.
  • the columns of supports in the first series of arrays are redistributed such that the first column from the first array in the first series is transferred to the first column of the first array in the second series; the second column from first array in the first series is transferred to the first column of the second array in the second series; the third column from the first array in the first series is transferred to the first column of the third array in the second series; the fourth column from the first array of the first series is transferred to the first column of the fourth array of the second series.
  • the first, second, third and fourth columns of supports from the second and third arrays in the first series are redistributed to the second series of arrays for chemical transformation step #2 in a similar fashion.
  • the arrays of supports undergo chemical transformation step #2.
  • step #2 the arrays are redistributed again to a new series of arrays.
  • the method of redistribution is similar to that used after the chemical transformation step # 1 , however, it is the individual rows of each array that are redistributed rather than the columns described above.
  • the redistribution is shown in Figure 2.
  • the rows of supports in the second series of arrays are redistributed such that the first row from the first array in the second series is transferred to the first row of the first array in the third series; the second row from first array in the second series is transferred to the first row of the second array in the third series.
  • the first and second rows of supports from the second, third, and fourth arrays in the second series are redistributed to the third series of arrays for chemical transformation step #3 in a similar fashion.
  • the arrays of supports undergo chemical transformation step #3. It is noted that the redistribution of supports between the chemical transformation steps #1 and #2 and between steps #2 and #3 is functionally identical if one simply reorients the arrays such that rows become columns and columns become rows (such as accomplished by a 90 degree rotation). If such a reorientation of the second series of arrays occurs then the columns from the second series of arrays are redistributed to columns in the third series of arrays.
  • this redistribution method Using this redistribution method, all possible combinations of monomers are ensured thus producing a combinatorial library of oligomers. As appreciated by those familiar in the art, this redistribution method for an m x n x p library is efficient, transferring entire columns or entire rows of supports simultaneously. Additionally, this redistribution method is amenable to automation via robotics.
  • the method described herein is also most suitable for the synthesis of a library of oligomers comprised of three monomer subsets.
  • the sums of monomers in each of these subsets may be variable.
  • the sum of monomers in each subset is defined by m, n, and p, respectively for the three subsets such that n, n, and p are positive integers.
  • the total number of unique oligomers produced in a three step synthesis is the product m x nx p.
  • the solid supports are may preferably arranged in a series of arrays of dimension n xp. Therefore, a total of m such arrays are required for the first step in the synthesis of such a library.
  • the m arrays of solid supports are preferably arranged in support carriers.
  • Each carrier holds an n x p array of solid supports.
  • several carriers may be used to hold an nx p array of supports.
  • the carriers are of sufficient size to hold an entire n x p array of supports.
  • there are m carriers which are placed in m reaction vessels for the first chemical transformation step such that each individual monomer from a subset of m monomers is reacted with the supports in each individual reaction vessel.
  • a further novel aspect of this process as distinguished from the prior art is the method by which the supports are redistributed from one series of arrays to the next series of arrays between chemical transformation steps.
  • This novel method is illustrated in Figure 3 for a three-step combinatorial synthesis using three subsets of monomers.
  • the supports are arranged as m-Z arrays of the dimension (2 x 4) on the carriers and reacted with a first subset of monomers.
  • the rows of supports in the first series of arrays are redistributed such that the first row from the first array in the first series is transferred to the first row of the first array in the second series; the second row from first array in the first series is transferred to the first row of the second array in the second series.
  • the first and second rows of supports from the second and third arrays in the first series are redistributed to the second series of arrays for chemical transformation step #2 in a similar fashion.
  • the method of redistribution is similar to that used after the chemical transformation step # 1 , however, it is the individual columns of each array that are redistributed rather than the rows described above.
  • the redistribution is shown in Figure 3.
  • the columns of supports in the second series of arrays are redistributed such that the first column from the first array in the second series is transferred to the first column of the first array in the third series; the second column from first array in the second series is transferred to the first column of the second array in the third series; the third column from the first array in the second series is transferred to the first column of the third array in the third series; the fourth column from the first array of the second series is transferred to the first column of the fourth array of the third series.
  • the first, second, third and fourth columns of supports from the second array in the second series are redistributed to the third series of arrays for chemical transformation step #3 in a similar fashion.
  • this redistribution method Using this redistribution method, all possible combinations of monomers are ensured thus producing a combinatorial library of oligomers. As appreciated by those familiar in the art, this redistribution method for an m x n x p library is efficient, transferring entire columns or entire rows of supports simultaneously. Additionally, this redistribution method is amenable to automation via robotics.
  • n x p are reacted with m monomers, then redistributed to p arrays of dimension (n x m) and reacted with p monomers, then redistributed to n arrays of dimension (p x m) and reacted with n monomers to produce a library of the quantity (m x n xp) oligomers; and Case 2.
  • m arrays of dimension (n x p) are reacted with m monomers, then redistributed to n arrays of dimension (m x p) and reacted with n monomers, then redistributed to p arrays of dimension (mx n) and reacted with p monomers.
  • the methods described heretofore provide for definitive ways by which rows or columns of organized arrays of solid supports can be manipulated to ensure the efficient chemical synthesis of all oligomers from a set of monomers. It is noted that the order of operations regarding the transfer of one series of arrays of solid supports to the next series of arrays of solid supports via the parallel movement of the supports from rows to rows, rows to columns, columns to columns, or columns to rows, may be varied to accomplish the necessary redistribution of arrays.
  • a general code relating the physical location of an oligomer to its monomer sequence can be developed.
  • M monomers ⁇ 1, 2,...m ⁇ , N monomers ⁇ 1, 2,...n) and P monomers ⁇ 1, 2,...p ⁇ used in a three-step, spatially-dispersed positionally-encoded library to produce a series of n arrays of dimension (p x m)
  • the sequence of any oligomer in any array can be defined by Mm - P P - N n , where m is both the column position number in the array and the monomer number in set M, p is both the row position number and monomer number in the set P, and n is both the array position number and the monomer number in the set N.
  • the sequence of any oligomer in any array can be defined by Mm - Nn - Pp , where m is both the row position number in the array and the monomer number in set M, n is both the column position number and monomer number in the set N, and p is both the array position number and the monomer number in the set P.
  • a computer algorithm can be designed which takes as input the goals of a synthetic experiment: namely, the desired number of combinatorial steps and the desired number of monomers used in each combinatorial step.
  • the algorithm can then generate a map of the protocol required to satisfy the experimental goal. This map would contain the same information as that given in the figures used herein. In the event that the experimental goal can not be satisfied the algorithm would suggest a protocol which would achieve a result as close as possible to the desired result.
  • the algorithm could be constructed to generate only those protocols that are consistent with a set of constraints imposed by an actual laboratory apparatus, for example, a fixed number of reaction vessels, carrier racks of a given dimension, and so forth. Such a computer algorithm would be useful for the practical application of the techniques disclosed herein. As a refinement of this method, such a computer algorithm could be designed to generate machine instructions for an automated synthetic apparatus which would perform the necessary chemical steps and positional transformations required to synthesize the desired combinatorial library.
  • the methods described above are very useful for the synthesis of a peptide library.
  • the preparation of a library of 512 trimeric peptides may be prepared on a series of polystyrene-grafted polyethylene crowns (Chiron Mimotopes Pty. LTD. , Victoria, Australia) which can serve as solid supports for the synthesis.
  • reaction vessels are used which are polypropylene or glass trays and are of a dimension sufficient to allow all crowns to be fully submerged in a reaction solvent. The following procedure is initiated:
  • Step 1 The crown holders are placed in a set of 8 individual reaction vessels.
  • the reaction vessels are filled with a solution of
  • reaction vessels labeled 1, 2, 3, ...through 8 are filled with a reaction mixture composed of the following: 200mM JV-hydroxybenzotriazole (HOBt), 200mM 2-(lH- hydroxybenzotriazole- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU), 100 mM fluorenylmethyloxycarbonyl -amino acid, and 250 mM diisopropylethylamine (DIEA) in a solution of NMP.
  • HOBt 200mM JV-hydroxybenzotriazole
  • HBTU 2-(lH- hydroxybenzotriazole- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate
  • DIEA diisopropylethylamine
  • Each reaction vessel receives a unique amino acid from the list of: 1. glycine; 2. alanine; 3. phenylalanine; 4. leucine; 5. lysine; 6. glutamic acid; 7. serine; and 8. threonine.
  • the crown holders are put into the appropriate vessels such that holder Sl. l is in vessel 1, holder S 1.2 is in vessel 2, etc. After three hours the arrays are removed from the reaction vessels and the crowns are washed liberally with 100 mL of NMP and 200 mL of dichloromethane. Step 3.
  • Eight individual crown holders are individually labeled as S2.1, S2.2, S2.3, S2.4, S2.5, S2.6, S2.7, S2.8. Additionally, the orientation of the crown holders is clearly marked such that the columns are defined as distinct from the rows.
  • the 8 columns from each of the 8 arrays of the Sl series of crown holders are transferred to the appropriate columns in the 8 arrays of the S2 series of crown holders in a manner such that each of the 8 amino acids are now represented on a column of crowns in each of the arrays in the S2 series.
  • Step 4 Repeat Step 1 on the S2 series of crown holders
  • Step 5 Repeat Step 2 on the S2 senes of crown holders whereby the crown holders are put into the appropnate vessels such that holder S2 1 is in vessel 1, holder S2.2 is in vessel 2, etc
  • Eight individual crown holders (carriers) are individually labeled as S3.1, S3.2, S3.3, S3 4, S3 5, S3.6, S3 7, S3.8 Additionally, the onentation of the crown holders is clearly marked such that the columns are defined as distinct from the rows
  • the 8 rows from each of the 8 arrays of the S2 senes of crown holders are transferred to the appropnate rows in the 8 arrays of the S3 senes of crown holders in a manner such that 64 unique dipeptides are now represented on the crowns m each of the arrays in the S3 senes
  • Step 7 Repeat Step 1 on the S3 senes of crown holders
  • Step 8 Repeat Step 2 on the S3 senes of crown holders whereby the crown holders are put into the appropnate vessels such that holder S3 1 is in vessel 1, holder S3 2 is in vessel 2, etc
  • Step 9 Repeat Step 1. on the S3 series of crown holders.
  • Step 10 The crown holders are positioned such that the crowns fit mto the wells of eight 96 2 mL-well polypropylene microtiter plates (available from Beckman Corp , Brea, CA), marked Plate 1, 2, 3, through 8 such that holder S3.1 is positioned with Plate 1, holder S3 2 is positioned with Plate 2, etc
  • the onentation is such that the columns (and therefore the rows) of the holders are aligned with the columns (and therefore the rows) of the plates
  • the dimensions of an array coverage in a plate would be from Rows A through H and from Columns 1 through 8 using the nomenclature common to the microtiter plate format
  • the crowns are treated with 5% tnfluoroacetic acid in dichloromethane for 30 m.
  • the crown holders are removed and the volatile contents of the microtiter plates evaporated under reduced pressure (20 mmHg)
  • any tnpeptide is readily identified by its location in the microtiter plates A code for deciphenng the identity is readily constructed.
  • M is the set of m ammo acids used in the first step
  • N is the set of n amino acids used in the second step
  • P is the set of p amino acids used in the third step
  • the methods described in the body of the invention may be used to produce non-peptide, low molecular weight organic compound libraries.
  • the synthetic chemistry protocols are more complex in the syntheses of many of these compounds than those utilized to construct peptide libraries. Additionally, there are no general methods available to directly sequence the structure of most of these compounds. Thus, the ease by which a library is de-coded using the method described herein renders it suitable for the svnthesis of low molecular weight compounds.
  • the synthesis of a heterocyclic library is demonstrated. The synthesis of 1,4- benzodiazapin-2-ones follows the procedure of Ellman et. al. 17 and is shown in the accompanying schematic.
  • the procedure combines 16 acid chlorides (defining the variability at the position R 1 ) and 24 amino acids (defining the variability at the position R 2 ) with 4 alkylating agents (defining the variability at the position R 3 ). These monomer groups are shown in the table below. Acid Chlorides
  • a collection of 1536 solid supports in the form of aminomethylated polystyrene-grafted polyethylene crowns (Chiron Mimotopes Pty. LTD., Victoria, Australia) are required for the synthesis.
  • a platform of crown holders to hold the necessary array sizes is constructed by ultrasonic welding four 96-position array crown holders on edge such that a 384-position platform of array dimension (16 x 24).
  • Sixteen crown platforms uniquely marked with row and column positions clearly designated will be used for the first step in the synthesis, 24 platforms for the second step, and 4 platforms for the third step.
  • the general method for redistributing arrays is followed as described for Case 1. in the Detailed Description of the Invention.
  • the crowns are prepared analogous to the method of Ellman
  • the arrays of crowns are washed with chloroform, exposed to a solution of 3% trifluoroacetic acid in dichloromethane for 5 min, then washed with dichloromethane and dried. The rearrangement of the arrays is then carried out as described.
  • the 24 arrays of crowns on 24 platforms are then coupled with the 24 fluorenylmethyloxycarbonyl-amino acid fluorides (lOOmM) using 4- methyl-2, 6-tert-butylpyridine (400mM) in dichloromethane in 24 reaction vessels for 12 hours.
  • the crowns are washed liberally with dichloromethane and then treated with a 20% solution of piperidine in dimethylformamide for 40 min, washed with dimethylformamide, then dichloromethane, and dried. The crowns are then warmed in a solution of 5% acetic acid in dimethylformamide at 60°C overnight to cyclize the benzodiazepine ring. After washing liberally with dimethylformamide and dichloromethane and drying, the 24 arrays of crowns are redistributed from the second set of crown platforms to the 4 crown platforms as described for the third step. The crown platforms are placed in 4 reaction vessels which are enveloped in dry argon in a glove box.
  • the vessels are half-filled with dry THF, cooled to -78°C, and filled with a 200mM solution of lithiated 5- (phenylmethyl)-2-oxazolidinone in THF. After 1 hour a solution of the appropriate alkyl halide (lOOmM) in THF is added to each reaction vessel. The vessels are allowed to warm to room temperature, the reaction continuing for another 5 hours. The crowns are washed with THF and dried.
  • lOOmM alkyl halide
  • a 16 x 24 array of benzodiazepines will be released from each of the 4 platforms of crowns.
  • an appropriately marked arrangement of 4 sets of four 96-well deep-well microtiter plates with 24 wells running across and 16 wells running down are positioned such that the individual crowns from each platform fit neatly into each well of the plates.
  • the crowns are treated with 85:5: 10 trifluoroacetic acid/ water /dimethylsulfide for 2 hours.
  • the crown holders are removed and the volatile contents of the microtiter plates evaporated under reduced pressure (20 mmHg).

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Abstract

La présente invention porte sur une technique utile en chimie combinatoire. Elle porte plus particulièrement sur des techniques de synthèse de bibliothèques d'oligomères dispersés dans l'espace, dont la position est codée et qui relèvent de la chimie combinatoire, synthèse effectuée sur divers supports solides eux-mêmes distribués sous forme d'une série de matrices. La position de chaque support solide dans chaque matrice détermine l'identité exacte de l'oligomère.
PCT/US1997/004500 1996-03-22 1997-03-21 Techniques de synthese d'une bibliotheque combinatoire a distribution controlee dispersee dans l'espace WO1997035198A1 (fr)

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925562A (en) * 1995-04-25 1999-07-20 Irori Remotely programmable matrices with memories
US5961923A (en) * 1995-04-25 1999-10-05 Irori Matrices with memories and uses thereof
WO1999063329A1 (fr) 1998-06-05 1999-12-09 The Regents Of The University Of California Amplification optique d'interactions moleculaires au moyen de cristaux liquides
WO2000023458A1 (fr) * 1998-10-19 2000-04-27 The Board Of Trustees Of The Leland Stanford Junior University Bibliotheque de chimie combinatoire a matrice d'adn
US6100026A (en) * 1995-04-25 2000-08-08 Irori Matrices with memories and uses thereof
WO2001001141A1 (fr) * 1999-06-30 2001-01-04 Amersham Pharmacia Biotech Ab Bibliotheque combinatoire avec categories de particules pouvant se distinguer par deux caracteristiques pouvant etre la taille, la densite, la couleur, etc.
US6284459B1 (en) 1995-04-25 2001-09-04 Discovery Partners International Solid support matrices with memories and combinatorial libraries therefrom
JP2002507617A (ja) * 1998-03-23 2002-03-12 プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ 化合物および化合物のライブラリの合成
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
EP1252126A1 (fr) * 2000-02-03 2002-10-30 Nanoscale Combinatorial Synthesis, Inc. Synthese non redondante partage/melange de bibliotheques combinatoires
JP2003514878A (ja) * 1999-11-24 2003-04-22 セレクタイド・コーポレイション コンビナトリアル・ライブラリーを合成するための装置および方法
WO2003040700A1 (fr) 2001-11-08 2003-05-15 Ciphergen Biosystems, Inc. Puce a surface hydrophobe
US6632641B1 (en) 1999-10-08 2003-10-14 Metrigen, Inc. Method and apparatus for performing large numbers of reactions using array assembly with releasable primers
WO2004038415A1 (fr) * 2002-10-24 2004-05-06 Biacore Ab Test avec des ligands co-immobilises
WO2004102197A1 (fr) * 2003-05-07 2004-11-25 Uop Llc Procédés d'assemblage de bibliothèques de particules
US6858423B1 (en) 1998-06-05 2005-02-22 The Regents Of The University Of California Optical Amplification of molecular interactions using liquid crystals
US7129326B2 (en) 2000-04-14 2006-10-31 Genencor International, Inc. Methods for selective targeting
US7341872B1 (en) 2004-04-29 2008-03-11 Uop Llc Multiautoclave with set of vessels for combinatorial synthesis of zeolites and other materials
US7413854B2 (en) 2002-03-15 2008-08-19 Nuevolution A/S Method for synthesising templated molecules
US7795007B2 (en) 2003-09-23 2010-09-14 Wisconsin Alumni Research Foundation Detection of post-translationally modified peptides with liquid crystals
US7935659B2 (en) 1995-04-25 2011-05-03 Nexus Biosystems, Inc. Multiplexed assays using encoded solid supports
US8133680B2 (en) 2003-09-23 2012-03-13 Wisconsin Alumni Research Foundation Using liquid crystals to detect affinity microcontact printed biomolecules
US8318640B2 (en) 2000-04-14 2012-11-27 Danisco Us Inc. Methods for selective targeting
US8932992B2 (en) 2001-06-20 2015-01-13 Nuevolution A/S Templated molecules and methods for using such molecules
US9096951B2 (en) 2003-02-21 2015-08-04 Nuevolution A/S Method for producing second-generation library
US9109248B2 (en) 2002-10-30 2015-08-18 Nuevolution A/S Method for the synthesis of a bifunctional complex
US9121110B2 (en) 2002-12-19 2015-09-01 Nuevolution A/S Quasirandom structure and function guided synthesis methods
US9574189B2 (en) 2005-12-01 2017-02-21 Nuevolution A/S Enzymatic encoding methods for efficient synthesis of large libraries
US10730906B2 (en) 2002-08-01 2020-08-04 Nuevolutions A/S Multi-step synthesis of templated molecules
US11118215B2 (en) 2003-09-18 2021-09-14 Nuevolution A/S Method for obtaining structural information concerning an encoded molecule and method for selecting compounds
US11225655B2 (en) 2010-04-16 2022-01-18 Nuevolution A/S Bi-functional complexes and methods for making and using such complexes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005394A1 (fr) * 1992-09-02 1994-03-17 Arris Pharmaceutical Corporation Procede et appareil destines a la systhese et au criblage de peptides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005394A1 (fr) * 1992-09-02 1994-03-17 Arris Pharmaceutical Corporation Procede et appareil destines a la systhese et au criblage de peptides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CURRENT OPINION IN BIOTECHNOLOGY, February 1992, Vol. 3, No. 1, BIRNBAUM et al., "Peptide Screening", pages 49-54. *
J. MED. CHEM., 29 April 1994, Vol. 37, No. 9, GALLOP et al., "Applications of Combinatorial Technologies to Drug Discovery. 1. Background and Peptide Combinatorial Libraries", pages 1233-1251. *

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US7935659B2 (en) 1995-04-25 2011-05-03 Nexus Biosystems, Inc. Multiplexed assays using encoded solid supports
US5961923A (en) * 1995-04-25 1999-10-05 Irori Matrices with memories and uses thereof
US5925562A (en) * 1995-04-25 1999-07-20 Irori Remotely programmable matrices with memories
US6284459B1 (en) 1995-04-25 2001-09-04 Discovery Partners International Solid support matrices with memories and combinatorial libraries therefrom
US6100026A (en) * 1995-04-25 2000-08-08 Irori Matrices with memories and uses thereof
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
JP2002507617A (ja) * 1998-03-23 2002-03-12 プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ 化合物および化合物のライブラリの合成
US6284197B1 (en) 1998-06-05 2001-09-04 The Regents Of The University Of California Optical amplification of molecular interactions using liquid crystals
US8246911B2 (en) 1998-06-05 2012-08-21 The Regents Of The University Of California Optical amplification of molecular interactions using liquid crystals
WO1999063329A1 (fr) 1998-06-05 1999-12-09 The Regents Of The University Of California Amplification optique d'interactions moleculaires au moyen de cristaux liquides
US6852285B2 (en) 1998-06-05 2005-02-08 The Regents Of The University Of California Optical amplification of molecular interactions using liquid crystals
US6858423B1 (en) 1998-06-05 2005-02-22 The Regents Of The University Of California Optical Amplification of molecular interactions using liquid crystals
WO2000023458A1 (fr) * 1998-10-19 2000-04-27 The Board Of Trustees Of The Leland Stanford Junior University Bibliotheque de chimie combinatoire a matrice d'adn
US7479472B1 (en) 1998-10-19 2009-01-20 The Board Of Trustees Of The Leland Stanford Junior University DNA-templated combinatorial library chemistry
WO2001001141A1 (fr) * 1999-06-30 2001-01-04 Amersham Pharmacia Biotech Ab Bibliotheque combinatoire avec categories de particules pouvant se distinguer par deux caracteristiques pouvant etre la taille, la densite, la couleur, etc.
US6632641B1 (en) 1999-10-08 2003-10-14 Metrigen, Inc. Method and apparatus for performing large numbers of reactions using array assembly with releasable primers
JP2003514878A (ja) * 1999-11-24 2003-04-22 セレクタイド・コーポレイション コンビナトリアル・ライブラリーを合成するための装置および方法
EP1252126A4 (fr) * 2000-02-03 2006-07-05 Nanoscale Combinatorial Synthe Synthese non redondante partage/melange de bibliotheques combinatoires
EP1252126A1 (fr) * 2000-02-03 2002-10-30 Nanoscale Combinatorial Synthesis, Inc. Synthese non redondante partage/melange de bibliotheques combinatoires
US7129326B2 (en) 2000-04-14 2006-10-31 Genencor International, Inc. Methods for selective targeting
US8318640B2 (en) 2000-04-14 2012-11-27 Danisco Us Inc. Methods for selective targeting
US8932992B2 (en) 2001-06-20 2015-01-13 Nuevolution A/S Templated molecules and methods for using such molecules
US10669538B2 (en) 2001-06-20 2020-06-02 Nuevolution A/S Templated molecules and methods for using such molecules
WO2003040700A1 (fr) 2001-11-08 2003-05-15 Ciphergen Biosystems, Inc. Puce a surface hydrophobe
US7413854B2 (en) 2002-03-15 2008-08-19 Nuevolution A/S Method for synthesising templated molecules
US10731151B2 (en) 2002-03-15 2020-08-04 Nuevolution A/S Method for synthesising templated molecules
US10730906B2 (en) 2002-08-01 2020-08-04 Nuevolutions A/S Multi-step synthesis of templated molecules
WO2004038415A1 (fr) * 2002-10-24 2004-05-06 Biacore Ab Test avec des ligands co-immobilises
US10077440B2 (en) 2002-10-30 2018-09-18 Nuevolution A/S Method for the synthesis of a bifunctional complex
US11001835B2 (en) 2002-10-30 2021-05-11 Nuevolution A/S Method for the synthesis of a bifunctional complex
US9109248B2 (en) 2002-10-30 2015-08-18 Nuevolution A/S Method for the synthesis of a bifunctional complex
US9284600B2 (en) 2002-10-30 2016-03-15 Neuvolution A/S Method for the synthesis of a bifunctional complex
US9121110B2 (en) 2002-12-19 2015-09-01 Nuevolution A/S Quasirandom structure and function guided synthesis methods
US9096951B2 (en) 2003-02-21 2015-08-04 Nuevolution A/S Method for producing second-generation library
WO2004102197A1 (fr) * 2003-05-07 2004-11-25 Uop Llc Procédés d'assemblage de bibliothèques de particules
US11118215B2 (en) 2003-09-18 2021-09-14 Nuevolution A/S Method for obtaining structural information concerning an encoded molecule and method for selecting compounds
US11965209B2 (en) 2003-09-18 2024-04-23 Nuevolution A/S Method for obtaining structural information concerning an encoded molecule and method for selecting compounds
US8569043B2 (en) 2003-09-23 2013-10-29 Wisconsin Alumni Research Foundation Detection of post-translationally modified peptides with liquid crystals
US8133680B2 (en) 2003-09-23 2012-03-13 Wisconsin Alumni Research Foundation Using liquid crystals to detect affinity microcontact printed biomolecules
US7795007B2 (en) 2003-09-23 2010-09-14 Wisconsin Alumni Research Foundation Detection of post-translationally modified peptides with liquid crystals
US7341872B1 (en) 2004-04-29 2008-03-11 Uop Llc Multiautoclave with set of vessels for combinatorial synthesis of zeolites and other materials
US9574189B2 (en) 2005-12-01 2017-02-21 Nuevolution A/S Enzymatic encoding methods for efficient synthesis of large libraries
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