WO1996003212A1 - Dispositif multidimensionnel a canaux destine a la synthese d'une banque combinatoire - Google Patents
Dispositif multidimensionnel a canaux destine a la synthese d'une banque combinatoire Download PDFInfo
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- WO1996003212A1 WO1996003212A1 PCT/IB1995/000626 IB9500626W WO9603212A1 WO 1996003212 A1 WO1996003212 A1 WO 1996003212A1 IB 9500626 W IB9500626 W IB 9500626W WO 9603212 A1 WO9603212 A1 WO 9603212A1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
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- 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
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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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- 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
- B01J2219/00281—Individual reactor vessels
- B01J2219/00286—Reactor vessels with top and bottom openings
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
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- B01J2219/00279—Features relating to reactor vessels
- B01J2219/00306—Reactor vessels in a multiple arrangement
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- 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
- B01J2219/00308—Reactor vessels in a multiple arrangement interchangeably mounted in racks or blocks
- B01J2219/0031—Reactor vessels in a multiple arrangement interchangeably mounted in racks or blocks the racks or blocks being mounted in stacked arrangements
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- 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
- B01J2219/00319—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks the blocks being mounted in stacked arrangements
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2219/00351—Means for dispensing and evacuation of reagents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- 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
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00423—Means for dispensing and evacuation of reagents using filtration, e.g. through porous frits
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- 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
- B01J2219/00479—Means for mixing reactants or products in the reaction vessels
- B01J2219/00484—Means for mixing reactants or products in the reaction vessels by shaking, vibrating or oscillating of the reaction vessels
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- 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
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- B01J2219/00479—Means for mixing reactants or products in the reaction vessels
- B01J2219/00488—Means for mixing reactants or products in the reaction vessels by rotation of the reaction vessels
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- 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
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- 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
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- B01J2219/00583—Features relative to the processes being carried out
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- 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
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- 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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- 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
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- 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
- B01J2219/00664—Three-dimensional arrays
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- 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
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- 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
Definitions
- This invention relates to combinatorial library synthesis devices used to generate combinatorial libraries of chemical compounds.
- the generation of combinatorial libraries of chemical compounds utilizing standard laboratory techniques of repetitively, separately reacting and mixing chemical compounds composing combinatorial libraries has been described in the art.
- Houghten et al., 354 Nature 84, 1991 and WO 92/09300 (PCT/US91/08694) , describe the generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. These libraries are composed of mixtures of free peptides which form a heterogenous library. Lam et al., 354 Nature 82, 1991, and WO 92/00091 (PCT/US91/04666) and Houghten et al. , 354 Nature 84, 1991 and WO 92/09300
- PCT/US91/08694 describe systematic synthesis and screening of peptide and other libraries of defined structure.
- the method used is based on a one bead one peptide approach in which a large peptide library consist- ing of millions of beads are screened. Each bead contains a single peptide.
- the library of beads was screened by a staining procedure and stained beads visualized using a microscope, and removed.
- the structure of the peptide is obtained by a chemical analysis of the material on the single bead. Lam et al. indicate:
- Dower et al . , WO 91/19818 (PCT/US91/04384) describes peptide libraries expressed as fusion proteins of bacteriophage coat proteins.
- Dower et al. , WO 93/06121 (PCT/US92/07815) describes a method for synthesizing random oligomers and the use of identification tags to identify oligomers with desired properties.
- Ellman United States Patent 5,288,514 describes the solid phase and combinatorial ynthesis of benzodiazepine compounds on a solid support .
- Ellman also discloses the use of a 96 pin block in which the pins act as a solid support for the sequential coupling of benzodiazepines.
- Each pin of the 96 pin block is configured to be lowered into a series of 96-well microtiter reaction plates.
- Winkler et al . WO93/09668 (PCT/US92/10183) discloses a method and device for forming large arrays of polymers on a substrate. The method and device relies on the use of thousands of channels to deliver compounds to a substrate on a surface and thereby generate molecular diversity. Photolithographic methods as are known in the art are also set forth in Winkler et al.
- This invention features methods and devices for rapidly, efficiently and conveniently synthesizing combinatorial libraries of chemical compounds.
- a "combinatorial library” is a collection of compounds in which the compounds comprising the collection are composed of one or more types of subunits.
- the subunits may be selected from natural or unnatural moieties, including dienes, dienophiles, amino acids, nucleotides, sugars, lipids, and carbohydrates.
- the compounds of the combinatorial library differ in one or more ways with respect to the number, order, type or types of or modifi ⁇ cations made to one or more of the subunits comprising the compounds.
- a combinatorial library may refer to a collection of "core molecules" which vary as to the number, type or position of R or functional groups they contain and/or identity of molecules composing the core molecule, for example, a diene and/or dienophile which react to form the core molecule.
- the collection of compounds is generated in a systematic way, for example by the method of Lam or Houghten, however, any method of systematically generating a collection of subunits differing from each other in one or more of the ways set forth above is a combinatorial library.
- a three-dimensional conduit synthesis device comprises a first array of cells that is aligned along one or more axes, a second array of cells aligned along one or more axes, and a means for communication between the first and second arrays of cells and to and from each cell in the arrays.
- the invention is useful for the efficient parallel synthesis of multi-milligram quantities of compounds.
- a cell is a compartment which can contain reactants and solvents utilized in the synthesis of compounds comprising a combinatorial library.
- the cell may have a porous disk bottom and an open top. The sides of the cell may be flanged.
- the cells may have a shape which allows one cell to be securely stacked on top of another by nesting the bottom of the upper cell into the open top of the bottom cell.
- the cell bottom may be any shape but is preferably cylindrical.
- the cells are arranged in arrays .
- An array is a set of two or more cells.
- the present invention may have at least two arrays of cells.
- the array of cells can be arranged in any geometric orientation, including planes, squares, cubes, spheres.
- the arrays may be connected by a means for communication among the arrays.
- a means for communication may also connect the cells within an array, and may connect certain cells from separate arrays.
- a preferred means of communication are conduits.
- the present invention also includes a means for moving substrates and reagents along the means for communication. Such means for moving substrates and reagents may include pressure differential, gravitational force, mechanical force and electromagnetic force.
- a preferred embodiment of the present invention features the arrays of cells on a planar surface, such as a tray.
- the cells may be regularly arranged in the tray.
- the trays may be stacked such that each cell in a particu ⁇ lar tray fits securely into a cell in the tray that is immediately below the particular tray.
- the upper most tray of the stacked tray may have conduits or channels which allow reagent and substrates to enter the stack of trays.
- the lower most tray may have conduits or channels that allow waste to be evacuated from the stack of trays.
- a system of conduits may allow reagents to flow among trays and among cells.
- Each tray may also contain one or more fiducial holes which allow the trays to be strung together and which serve as spatial reference points.
- a two- dimensional conduit synthesis device has a first array of cells aligned along a first axis and a second array of cells aligned along a second axis, wherein the first and second axes may be perpendicular to each other.
- a cell is a compartment which can contain reactants and solvents utilized in the synthesis of compounds comprising a combinatorial library.
- the two-dimensional conduit synthesis device is used to synthesize a dimer library of n x n dimers, wherein n corresponds to the number of cells in an array and n may vary from 2 to 100.
- the dimers are comprised of subunits which may be selected from but is not limited to the following chemical moieties, amino acids and amino acid analogs, nucleic acids and nucleic acid analogs, carbohydrates and carbohydrated analogs, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkylaryl, amide, thioamide, ester, amine, ether, thioether.
- alkyl refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups.
- the alkyl group has 1 to 12 carbons. More preferably it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons.
- alkenyl refers to an unsaturated hydrocarbon group containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups.
- the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, more preferably 1 to 4 carbons.
- alkynyl refers to an unsaturated hydrocar ⁇ bon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups.
- the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, more preferably 1 to 4 carbons.
- alkoxy group refers to an "-0-alkyl” group, where “alkyl” is defined as described above.
- aryl group refers to an aromatic group which has 'at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
- the preferred substituent (s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, N0 2 , amine, thioether, cyano, alkoxy, alkyl, and amino groups.
- alkylaryl group refers to an alkyl (as described above) , covalently joined to an aryl group (as described above) .
- Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted.
- Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.
- amide refers to an -C(0)-NH-R, where R is either alkyl, aryl, alklyaryl or hydrogen.
- a “thioamide” refers to -C(S)-NH-R, where R is either alkyl, aryl, alklyaryl or hydrogen.
- An “ester” refers to an -C(0)-OR', where R' is either alkyl, aryl, or alklyaryl.
- amine refers to a -N(R'')R''', where R' ' and R' ' ' , is independently either hydrogen, alkyl, aryl, or alklyaryl, provided that R' ' and R' ' ' are not both hydro- gen.
- ether refers to R-O-R, where R is either alkyl, aryl, or alkylaryl.
- a "thioether” refers to R-S-R, where R is either alkyl, aryl, or alkylaryl.
- the two-dimensional conduit synthesis device may be utilized in conjunction with s split synthesis, deconvolution method of generating a combinatorial li ⁇ brary. Briefly, the standard method is performed as follows. In one example, the method involves a first step of attaching ten different subunits A, B, C . . . J, to a solid support in ten separate vessels or columns.
- a portion or aliquot of the material synthesized at the first step is retained as separate columns, while the remainder (which is still attached to individual solid supports) is mixed or pooled, divided into ten new different columns, and ten further parallel syntheses carried out to provide the dimer XA 1 , XB 1 , XC 1 . . . XJ 1 , where X is any one of the original A-J, and A 1 , B 1 , C 1 . . . J 1 are ten different subunits which may be the same or different from A-J.
- fewer or more than ten syntheses can be used in this second step.
- step two a portion of the newly synthesized material of step two is again retained in separate columns, and the remainder mixed and divided into ten further columns so that the synthetic procedure can be repeated until the whole length of the desired polysubunit is synthesized.
- a series of vessels is formed at each step, differing from those in prior steps by the presence of an extra subunit.
- the final ten columns in the above example can be assayed using any standard assay format. That is, each of the ten mixtures is assayed to determine which mixture contains one or more active compounds.
- the column which is found to contain an active compound identifies the subunit required at the polysubunit terminus to be active in the assay.
- the column containing polysubunits of sequence XXXXJ 1 may be active in the assay. This indicates that J 1 is required at the terminus of a polysubunit in this assay.
- This subunit is now bonded to each of the columns retained in the previous synthetic step (in the example, the columns XXXA, XXXB, . . . XXXJ) .
- These ten newly synthesized series of compounds can then be assayed and the process repeated until the final polysubunit sequence is known.
- the advantage of utilizing the two-dimensional conduit synthesis method in conjunction with the standard method is as follows. Upon determination of the last two subunits of a compound of a library, by deconvolution as above, the appropriate dimer from the appropriate cell of the two-dimensional conduit synthesis device may be added to a combinatorial library generated by the standard split synthesis method allowing more rapid and convenient deconvolution of those libraries.
- dimer nl/n5 generated by the two-dimensional conduit synthesis device may be used to deconvolute the library, as opposed to first adding nl and then adding n5 to the preceding subunit stage of the library.
- An advantage of the present invention is that it allows for efficient synthesis and manipulation of combinatorial libraries of molecules.
- Another advantage of the present invention is that it allows synthesis of a great diversity of unique compounds in unlimited amounts.
- An additional advantage of the present invention is that each individual compound is synthesized in its own cell. The synthesized compounds can then be readily identified by its cell's position.
- a further advantage of the present invention is that it allows three-dimensional synthesis, which adds an additional dimension for combinatorial synthesis.
- Figure 1 shows a top perspective of a tray of cells, the edges of the tray having fiducial holes.
- Figure 2 shows a side view of stacked trays with guides threaded through the fiducial holes.
- Figure 3A shows a cross-section of two stacked trays, illustrating the nesting of one cell into another.
- Figure 3B shows a cross-section of a cell.
- Figure 4A is a top view of the bottom tray in a stack of trays, illustrating a possible layout of conduits or channels that allow the movement of reagents and substrates among the cells and the evacuation of reagents and substrates from the cells and trays.
- Figure 4B is a top view of the top tray in a stack of trays, illustrating a possible layout of conduits or channels that allow the entry of reagents and substrates into the stack of trays and into the cells of each tray.
- Figure 5A is a top view of the top tray or top layer in a stack of trays, illustrating a possible layout of conduits or channels.
- Figure 5B is a top view of the bottom tray or bottom layer in a stack of trays, illustrating a possible layout of conduits or channels.
- the present invention is an efficient method for synthesizing N 2 or N 3 compounds.
- Other compounds can be made by subunit extension, by sequential operation, or parallel synthesis in addition to the compounds generated by the invention.
- the method of the present invention may provide 0.1 mmoles of each compound. This amount is equivalent to 50 mg for a compound of molecular weight 500.
- the device is also simple and compact.
- the invention allows for parallel synthesis on a larger scale and with higher yields than those available by conventional methods.
- the invention also allows synthesis of combinatorial libraries with greater diversi- ty and in large quantities.
- the invention also allows for easy identification and manipulation of the synthesized compounds.
- Another advantage of the present invention is that it allows different chemical reagents to be routed to different cells.
- the invention also allows different cells to have different temperature conditions if the cells are insulated from each other.
- the three-dimensional conduit synthesis of the present invention is particularly useful for creating and identifying pharmacologically active and medicinally useful molecules and sets of molecules.
- the invention allows the rapid, efficient and convenient generation and screening of sets of pharmacologically active molecules . Once a pharmacologically active molecule or set of mole- cules has been identified, the present invention may then again be used to optimize the active molecule or set of molecules by making slight variations in the molecule or set of molecules.
- the present invention is also useful for the rapid generation of a large, highly diversified library of compounds.
- the high diversity of the library allows rapid and accurate experiments and assays to be performed on a large diversity of compounds.
- the present invention is also useful for the automated synthesis and automated screening of a large range of potentially biologically active compounds.
- Each compound is synthesized in its own cell. If N, the number of cells in an array, equals 10 then 10 3 or 1000 cells will be needed.
- the subunits may be synthesized on a solid support for example beads. One 100 ⁇ diameter bead carries approximately 100 pmoles of a compound.
- each bead is 10 6 ⁇ 3 .
- 10 6 beads occupy 10 12 femtoliters (1 ⁇ 3 is 1 femtoliter) , requiring i.e., 1 milliter.
- the cells may be accommodated in a cylindrical well, or cell, that is approximately, 1 cm in diameter and 1 cm deep.
- the cell may be a cylindrical well having a female flange at the top of the cell and a male flange at the bottom of the cell and a porous disk at the base of the cell. If teflon is used as the porous disc material of the present invention, for example, then the disk could have 50 ⁇ holes.
- the flanges may seal fairly tightly.
- the flanges may be straight and seal fairly tightly.
- the male and female flanges could be separate layers bonded to the main tray. It may also be possible to have seals between trays.
- the cells may make up part of a tray of, e . g.
- each tray could be 18 x 18 cm, extra space may be provided at the edges of the tray for fiducial holes.
- Each tray may have a series of fiducial holes along the outer edge of the tray.
- the invention may also be used with a separate device to place the first subunit in each cell. If N were 10, for example, then this separate device would consist of 10 columns, each with a capacity of 100 cc. The columns could be roughly 10 cm high and 10 0 > cm, i.e., 3.6 cm in diameter.
- the first subunit would be contained in each column.
- subunit A in column 1 and subunit B in column 2, and so on.
- the contents of each column may be added to one tray, filling all the cells.
- the trays may be stacked on top of each other, starting with a "base” and finishing with a "lid,” thread ⁇ ing the guides through the fiducial holes of each tray, and seating each tray into the tray below.
- the trays may then be assembled together so that a cube approximately 18 cm 3 is assembled.
- the base tray may contain conduits for the removal of waste.
- the top tray, or lid may contain the conduits for the entry of reagents.
- Reagents may be driven through the conduits by any suitable means, including gravitational, pressure differential, mechanical or electromagnetic.
- the trays may be made by machining successive sheets of plastic and then bonding them together. However, other suitable materials such as metal, glass or composites could be utilized. When bonded together, the trays may direct the fluid from column 1 of cells to a common outlet.
- the lid may contain conduits and entry ports to allow the addition of reagents: it may have the conduit built in.
- the conduits of the top tray may have a series of holes. The conduit allows the addition of A to the first row, B to the second, C to the third and so on. The holes allow the second member of the library compositions to be added to each row of stacked cells.
- the device may be dismantled as follows: Each tray may be put in a device that allowed the release of each reactant and collection of each reactant into a tray with, e . g. , glass vials. These could then be lyophi- lized, capped and held as stock.
- the entire cube could also be inverted or shaken, provided enough space is left inside each cell.
- the filling of the cell could also be automated (as in a fraction collector) and the other functions of the device could also be automated.
- Isolating the Compounds of the Synthesized Library may be purified by any of the techniques well known in the art. These techniques include, but are not limited to, precipitation, thin layer chromatography, column chromatography, high pressure liquid chromatography, crystallization, gel electrophoresis, and filtration.
- a combinatorial library synthesized by the three- dimensional conduit synthesis of the present invention may be screened by any method well known in the art . These methods include, but are not limited to, ELIZA plating, receptor binding, southern, western and northern blotting, and competitive binding.
- One method utilizing this approach that may be pursued in the isolation of such receptor-binding molecules would include the attachment of a combinatorial library molecule, or a portion thereof, to a solid matrix, such as agarose or plastic beads, microtiter wells, petri dishes, or membranes composed of, for example, nylon or nitrocellulose, and the subsequent incubation of the attached combinatorial library molecule in the presence of a potential combinatorial library molecule-binding com ⁇ pound or compounds. Attachment to said solid support may be direct or by means of a combinatorial-library-compound- specific antibody bound directly to the solid support. After incubation, unbound compounds are washed away, component-bound compounds are recovered. By utilizing this procedure, large numbers of types of molecules may be simultaneously screened for receptor-binding activity.
- the identified compound can be admin ⁇ istered to a patient alone, or in a pharmaceutical compo ⁇ sition comprising the identified active compound and a carrier or excipient.
- the compounds can be prepared as pharmaceutically acceptable salts (i.e. , non-toxic salts which do not prevent the compound from exerting its effect) .
- compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
- the pharmaceutical composi- tions of the present invention may be manufactured in a manner that is itself known, e . g. , by means of convention ⁇ al mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- compositions for oral use can be obtained, for example, by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl- cellulose, and/or polyvinylpyrrolidone (PVP) .
- PVP polyvinylpyrrolidone
- disintegrating agents may be added, such as the cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound is first dissolved in a suitable solvent such as an aqueous or aqueous-alcohol solution, containing the appropriate acid. The salt is then isolated by evaporat- ing the solution. In another example, the salt is prepared by reacting the free base and acid in an organic solven . Carriers or excipient can be used to facilitate administration of the compound, for example, to increase the solubility of the compound.
- Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physio ⁇ logically compatible solvents.
- the compounds or pharma ⁇ ceutical composition can be administered by different routes including intravenously, intraperitoneally, subcu- taneously, and intramuscularly; orally, topically, or transmucosally.
- the agents of the invention may be formulated in aqueous solutions, preferably in physiologi ⁇ cally compatible buffers, such as physiological saline buffer.
- physiologi ⁇ cally compatible buffers such as physiological saline buffer.
- penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
- compositions of the present invention in particular, those formulated as solutions, may be adminis ⁇ tered parenterally, such as by intravenous injection.
- the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
- Such carriers enable the compounds of the invention to be formulated as tab ⁇ lets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspen ⁇ sions of the active compounds may be prepared as 17 appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
- Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes, then administered as described above. Liposomes are spherical lipid bilayers with aqueous interiors. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external microenvironment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cyto ⁇ plasm.
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- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Clinical Laboratory Science (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
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Abstract
Procédés et dispositifs destinés à effectuer de manière rapide, efficace et pratique, la synthèse de banques combinatoires de composés chimiques, et procédé efficace de synthèse de composés N2 ou N3. On décrit notamment un dispositif de synthèse bi ou tridimensionnel à canaux.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU29905/95A AU2990595A (en) | 1994-07-26 | 1995-07-25 | Multidimensional conduit combinatorial library synthesis device |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28119494A | 1994-07-26 | 1994-07-26 | |
US08/281,194 | 1994-07-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996003212A1 true WO1996003212A1 (fr) | 1996-02-08 |
Family
ID=23076339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB1995/000626 WO1996003212A1 (fr) | 1994-07-26 | 1995-07-25 | Dispositif multidimensionnel a canaux destine a la synthese d'une banque combinatoire |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2990595A (fr) |
WO (1) | WO1996003212A1 (fr) |
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