WO1999048897A2 - Synthesis of compounds and libraries of compounds - Google Patents
Synthesis of compounds and libraries of compounds Download PDFInfo
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- WO1999048897A2 WO1999048897A2 PCT/US1999/006233 US9906233W WO9948897A2 WO 1999048897 A2 WO1999048897 A2 WO 1999048897A2 US 9906233 W US9906233 W US 9906233W WO 9948897 A2 WO9948897 A2 WO 9948897A2
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
Definitions
- peptides play as hormones, enzyme inhibitors, substrates, neurotransmitters, and neuromediators.
- peptides are able to influence cell-cell communication and control vital cell functions such as metabolism, immune defense and reproduction.
- Bobine et al., Chem. Rev. 1997, 9 ⁇ , 1359 Unfortunately, the utility of peptides as drugs is severely limited by several factors, including their rapid degradation by peptidases under physiological conditions, their poor cell permeability, and their lack of binding specificity resulting from conformational flexibility.
- peptidomimetics In response to these unfavorable characteristics of peptide drugs, many research groups have developed strategies for the design and synthesis of chemical compounds, known as "peptidomimetics", in which sensitive peptide moieties are removed and replaced with more robust functionalities.
- researchers have sought to improve peptide stability and cell permeability by replacing the amide functionality with groups such as hydroxyethylene, (E)-alkenes, carba groups and phosphonamide groups (Gante, J., Ange ⁇ v. Chem. Int. Ed. Engl 1994, 33, 1699-1720, and references cited therein). In most cases, these peptidomimetic compounds have been prepared one at a time.
- the present invention provides a system for the production of chemical compounds that are capable of mimicking structural and/or functional properties of peptides
- the inventive system allows simultaneous production of multiple complex compounds, and provides for significant stereochemical and regiochemical control, as well as functional group diversity While the prior art describes attempts to reproduce a particular peptide structure the present invention provides a broad new approach to the production of compounds with certain structural and/or functional properties characteristic of peptides
- the present invention teaches a broad new approach for the synthesis of libraries of compounds having stereochemistry as a diversity element
- both the structure replacing the peptide bond and that replacing the peptide functional group can be modified and diversified Furthermore, the present invention enables not only the diversification of chemical structure and the synthesis of compounds having peptide characteristics, but also enables the svnthesis of stereodiverse compounds
- the present invention therefore can be seen as providing methods and compounds that transform peptide functionalities into alternative chemical structures and stereoisomers of these chemical structures
- the invention constitutes a system for "morphing" peptides into other compounds
- the present invention provides methods for producing collections of peptidomimetic compounds
- these methods involve (1) providing two diversifiable monomers containing terminal reactive moieties, (2) reacting the monomers under conditions that allow for the control of stereochemistry as well as chemoselectivity, and (3) generating diversifiable, isolable compounds or libraries of compounds
- the methods involve (1) providing one diversifiable monomer containing terminal reactive moieties, (2) reacting the monomer with a reagent under conditions that allow for the control of stereochemistry as well as selectivity, and (3) generating diversifiable isolable compounds or hbra ⁇ es of compounds
- the present invention provides a system foi the stereochemical control of the svnthesis of compounds and libraries of compounds
- this aspect is not limited to the synthesis of libraries of peptide mimics Rather, the present invention encompasses the broader concept of providing any collection of chemical compounds having stereodiversity
- this aspect is not limited to the synthesis of libraries of peptide mimics Rather, the present invention encompasses the
- the invention provides various chemical compounds useful for production of complex peptidomimetic libraries
- These compounds may be diversified at the level of functional group units, monomer units, segment units, and biomolecule units
- each of these units may be diversified structurally, I e , by functional group diversification, or may be diversified stereochemically
- FIG. 1 depicts the Peptide Morphing strategy of the present invention
- Figure 2 depicts a retrosynthetic analysis of a preferred structure of the present invention
- Figure 3 depicts certain preferred monomers having a syn relationship between the allyhc alcohol and the functional group
- Figure 4 depicts bond construction through palladium coupling
- Figure 5 depicts bond construction through pinacol coupling
- Figure 6 depicts bond construction through tandem aldol reaction followed by Curtius rearrangement
- Figure 7 depicts hydrozirconation reactions
- Figure 8 depicts a nucleophihc addition reaction
- Figure 9 depicts Nozaki-Hiyama-Kishi coupling reactions
- Figure 10 depicts attachment of a morphed segment to the resin
- Figure 11 depicts synthesis of the C-terminal (first) monomer
- Figure 12 depicts the synthesis of the N-rerminal (second) monomer
- Figure 13 depicts a convergent and efficient synthesis of monomers
- Figure 14 depicts Hoffman, Lossen and Schmidt Rearrangements
- Figure 15 depicts intramolecular olefin metathesis
- Figure 16 depicts reaction of a dimethyldichlorosilane linker with preferred monomers of the invention
- Figure 17 depicts reaction of a dusopropyl amino chlorophosphoramidite linker with preferred monomers of the invention
- Figure 18 depicts intermolecular olefin cioss metathesis reactions
- Figure 19 depicts separation of two libraries generated from intermolecular olefin cross metathesis
- Figuie 20 depicts bond construction through cycJoaddition Figure 21 depicts a diversifiable core structure from the thesis of Ann Weber
- Figure 22 depicts a directed photolysis reaction using a silicon linker
- Figure 23 depicts modification of the olefin functionality
- Figure 24 depicts selective protection of a linking moiety on the resin
- Figure 25 depicts embedding morphed segment in an SH 2 binding peptide
- Figure 26 depicts a model structure of the binding of a morphed peptide to a SH 2 domain
- Figure 27 depicts a library of inhibitors of D A glycosylases
- Figure 28 depicts a library of synthetic transcriptional regulators
- Figure 29 depicts a use for the compounds and libraries of the present invention in the E6 E6-AP system
- Figure 30 depicts a use for the compounds and libraries of the present invention in the remn-angiotensin system
- Figure 31 depicts a use for the compounds and the libraries of the present invention as inhibitors of the proteasome.
- Figure 32 depicts the synthesis of compound 2
- Figure 33 depicts the synthesis of compound 3
- Figure 37 depicts the synthesis of compound 7
- Figure 38 depicts the synthesis of compound 8
- Figure 42 depicts the synthesis of compound 12
- Figure 43 depicts the synthesis of compound 13
- Figure 47 depicts the synthesis of compound 17
- Figure 48 depicts the synthesis of compound 18
- peptidomimetic refers to a chemical compound that, at least in part, mimics one or more structural or functional properties of a peptide
- the prior art definition of peptidomimetic focuses on compounds in which one or more of the characteristic chemical moieties of a peptide is substituted with alternative functional groups.
- the present invention provides a broader concept of peptidomimetic, describing a system for producing a wide variety of chemical compounds that may have one or more structural or functional aspects of biologically active peptides.
- a peptidomimetic does not necessarily refer to a compound that per se imitates the properties of a peptide, but can also refer to a compound in which a segment unit replacement of the amide functionality, which bears no structural relationship to a peptide functionality, is capable of interacting with a biological receptor or ligand with desired specificity.
- peptidomimetics include, but are not limited to, compounds in which the amide bond of a peptide is replaced with alkene, hydroxyethylene or carba functionalities.
- Peptidomimetics also include compounds in which the ⁇ -CH group is replaced with aza, C-alkyl, or bora functionalities, among others.
- Combinatorial Library refers to a collection of compounds produced in a manner that allows “segment units”, 'functionality units”, “monomer units”, “biomolecule units”., or any combination thereof, to be varied in a systematic fashion.
- the segment unit may be generated from any compatible reaction between monomers (or upon a monomer) that results in a replacement of the amide functionality with any other functionality.
- the functionality units may be varied on individual monomers, or after monomers have been joined together. These functionality units may be present within the segment unit of the joined monomers, or may be present at other sites within the monomers.
- Biomolecules refers to molecules (e.g., proteins, amino acids, nucleic acids, nucleotides, carbohydrates, sugars, lipids, etc.) that are found in living cells in nature.
- “Monomer unit” refers in one aspect to a molecule that can be joined together to form another molecule or set of molecules, such as a set of oligomers or polymers.
- “monomer unit”, as used herein, refers to a molecule that can be diversified at particular sites on the monomer unit. More particularly, the present invention refers to a monomer that is characterized in that it contains reactive moieties available for diversification and optionally is characterized by the presence of a reactive moiety that allows linkage of multiple individual monomers by way of a segment unit functionality
- the term “diversity element” refers to structural (1 e , functional group diversity), stereochemical, diastereochemical, and/or regiochemical diversity in a particular compound As will be appreciated by one of ordinary skill in the art, the present invention provides for the synthesis of compounds and libraries of compounds having any of these diversity elements alone or in combination with one or more of the other diversity elements "Stereoisomer”
- stereoisomer refers to a structure of the same constitution as another structure, differing only in the spatial arrangement Stereoisomers are described by specifying their topology and the nature of their relationship to other stereoisomers of the same constitution
- Enantiomer refers to a stereoisomer that is related to another stereoisomer as an object and its mirror image
- Diastereomer refers to a stereoisomer that is related to another stereoisomer in a manner other than as an object and its mirror image For example, one stereogenic center relative to another stereogenic center is different for diastereomers Diastereomers differ from one another both in phvsical properties and in chemical reactivities For example, different diasteriomers generally have different melting points, boiling points, and solubility characteristics
- stereoselective reaction refers to a chemical reaction in which one of the stereoisome ⁇ c products is formed in excess
- Enantioselective Reaction refers to a chemical reaction in which one of the enantiome ⁇ c products is formed in excess
- Diastereoselective reaction refers to a reaction in which only one of the diastereome ⁇ c products is formed in excess, or one m which the major product is diastereome ⁇ cally pure
- Regioselective Reaction refers to a reaction in which an unsymmetrical alkene gives a predominance of one of the two possible addition products. The reaction is regiospecific if one of the products is formed exclusively.
- the present invention provides methods and compounds related to production of complex libraries of chemical compounds with certain structural and/or functional characteristics of peptides.
- the present invention in a broader aspect, provides for the generation of chemical libraries of peptidomimetics and non- peptidomimetics alike, having stereoisomerism as a diversity element.
- the inventive reactions involve steps of (1) providing at least two monomer compounds, each of which has at least two terminal reactive moieties; and (2) reacting the monomers with one another, under conditions that allow for the control of stereochemistry as well as chemoselectivity, so that they become linked together at one of their reactive moieties and generate a segment unit, and (3) generating diversifiable isolable compounds or libraries of compounds.
- each monomer contains multiple reactive moieties, and additional reactions are performed to functionalize these moieties either before or after the monomers are linked to one another, so that highly complex libraries are produced.
- the inventive reactions involve steps of (1) providing at least one monomer compound, which has at least two terminal reactive moieties; (2) reacting the monomer with a reagent that allows for the control of stereochemistry as well as chemoselectivity, and (3) generating diversifiable isolable compounds or libraries of compounds with characteristics reminiscent of peptides.
- One advantage of the inventive synthetic system is that it allows simultaneous production of a large number of complex peptidomimetic compounds under conditions of controlled stereo- and regio-selectivity.
- Preferred peptidomimetic compounds produced according to the present invention contain both peptide bond and functional group substitutions when compared with peptides.
- the present invention represents a broadening of the conception of peptidomimetics
- another advantage of the present system is that these substitutions are not necessarily limited to compounds that represent structural mimics of peptides, as might be found in the prior art
- the inventive system through a segment unit replacement, enables the maximization of the diversification of structures
- the invention therefore enables the discovery of heretofore unanticipated interactions of compounds, that bear little or no structural relation with peptides, with biological receptors or hgands
- the present invention provides methods for the generation of compounds and libraries of compounds, peptidomimetics and non-peptidomimetics alike, having stereochemical diversity
- This method involves the steps of (1) selecting desired synthetic precursors having a predefined stereochemical relationship, (2) reacting the synthetic precursors so that a compound having a specific stereochemistry is obtained, and (3) repeating these steps of selecting and reacting until a desired library of compounds having stereochemical diversity is obtained
- a library of compounds having only diversity of stereochemistry is provided for these embodiments, it is particularly preferred that at least 4 stereoisomers are provided, more particularly preferred that at least 8 stereoisomers are provided, and most particularly preferred that at least 16 stereoisomers are provided
- a library of compounds having structural diversity and stereochemical diversity is provided
- FIG. 2 depicts the retrosynthetic analysis of a preferred diversifiable peptidomimetic core, in which two monomers are used to generate the desired structure.
- Each monomer is characterized either by the presence of a reactive moiety that facilitates the linkage of the monomers to one another by way of a segment unit, or by the presence of a reactive moiety that facilitates the reaction of the monomers with chemical reagents.
- Each monomer preferably also contains additional reactive moieties available for diversification, so that the peptidomimetic compounds produced according to the present invention can be diversified both at the level of the segment unit structure and at the level of functional groups.
- each monomer contains at least one terminal reactive moiety that allows the monomer to be linked to a biomolecule.
- each monomer contains a moiety available for linkage to a peptide, so that the inventive peptidomimetic compounds can readily be embedded within a peptide chain.
- each monomer is selected to react with the other monomer being employed.
- the chemical nature of the moiety on the first monomer that is available for linkage to the second monomer places constraints on the nature of the acceptable second monomer moiety and therefore limits the selection of the second monomer, and also limits the resulting stereoselectivity.
- at least one monomer contains a reactive moiety available for linkage to the solid phase. Such linkage may be direct or indirect.
- the monomer may be linked to another molecule, preferably a biomolecule (and most preferably a peptide) that is itself linked to the solid phase.
- a biomolecule and most preferably a peptide
- Methods of linking compounds to the solid phase are known in the art and a variety of methods may be employed in the present invention. (See, for example, Brown, "Recent Developments in Solid-Phase Organic Synthesis” Contemporary Organic Synthesis, 1997, p 216, Hiroshige et al , Eet lett 1995, 36, 4567, Rotella, D , J Am Chem Soc 1996, 118, 12246 and references cited therein )
- the monomers utilized in the present invention are preferably easily synthesized, in high yields with high diastereo- and enantioselectivity Examples of certain preferred monomers having a syn relationship between the allyhc alcohol and the functional (R) group are depicted in Figure 3 In addition to providing monomers having a svn relationship, the present invention provides monomers having an anti relationship as depicted in Examples 13-29 Thus, the ability to provide monomers having all possible stereoisomers enables the synthesis of compounds and libraries of compounds having significant stei eodiversity
- each monomer contains first (L n and L 21 ) and second (L 12 and L 22 ) terminal functionalities capable of either (1) linking to another monomer in an inter- or intramolecular fashion; (2) being immobilized on the solid support, or (3) attaching to other amino acids or peptides.
- Each monomer also contains an optional linking group binding site (X, or X 2 ) that can be employed to link the monomers together in an intramolecular fashion.
- any or all of the base monomer structures, the terminal functionalities, and the linking group binding sites may contain reactive sites available for further diversification, as is discussed in more detail below.
- first and second terminal functionalities may be employed in accordance with the present invention.
- Terminal functionalities include but are not limited to amines, carboxylic acids, halogenated aromatics for transition metal catalyzed cross coupling reactions, terminal aldehydes for pinacol couplings, terminal alkynes for hydrozirconation, and terminal alkenes for olefin metathesis and nucleophilic addition.
- Figures 4, 5, 6, 7, 8 and 9 show the preferred cross-coupling, pinacol coupling, tandem aldol/Curtius i ⁇ arrangement, hydrozirconization, nucleophilic addition, and N ⁇ K (Nozaki-Hiyama-Kishi (Furstrser et al., J. Am. Chem. Soc. 1996, 118, 12349)) coupling, respectively.
- the second terminal functionality (L 12 j of the first monomer and the first terminal functionality (L 21 ) of the second monomer are each alkenes, selected to be capable of reacting with one another.
- first terminal functionality (L ⁇ ) of the first monomer and the second terminal functionality (L 22 ) of the second monomer is either an amine or carboxylic acid capable of further reacting with amino acids.
- at least one of the first terminal functionality (L n ) of the first monomer and the second terminal functionality (L 22 ) of the second monomer is selected for linkage to a solid phase resin.
- linking group binding sites may be employed in accordance with the present invention, so long as the binding site can be reacted with a linking reagent to add a linking group to the monomer.
- the linking group then reacts to link the first and second monomers to one another.
- linking reagents include sulfonyl chloride, dimethyl dichlorosilane, diisopropylamino chlorophosphoramidite and metals (such as boron and titanium) that are capable of temporary binding as a linker.
- metals such as boron and titanium
- linking reagents can be employed to generate mixed carbonates (R and R'), carbamates, disulfides. ureas, acetals, ortho esters, phosphates and oxides as linking groups.
- Linking group binding sites can include any functionality capable of reaction with the selected linking reagent.
- the linking group binding site comprises a carbon, oxygen, nitrogen, or sulfur atom, for example a hydroxyl, amino, or thiol group, through which the linking group becomes attached to the monomer.
- L u and L 1 preferably each comprise the same or different terminal reactive moiety selected from the group consisting of hydrogen, protecting group, alkene, alkyne, amine, carboxylic acid, halogenated aromatic, aldehyde and vinyl halide;
- R,, R 2 and R 3 are preferably selected from the group consisting of hydrogen, alkyl, aryl, phenoxy, methoxy, halide, methylene cyclohexyl, benzyl, heteroaryl, aryloxy, heteroaryl, carboxyl, carboxalkyl, carboxaryl, arylalkyl, thio and hydroxyl;
- X preferably comprises a functional moiety selected from the group consisting of carboxyl, amino, gem-dialkyl, and methylene;
- X preferably comprises a functionality containing nitrogen, oxygen, sulfur or carbon;
- L preferably comprises a group, including but not limited to mixed carbonates
- Scheme 3 depicts the first monomer of Scheme 2 after linkage to a second monomer.
- the two monomers connected by the linking group are in a syn relationship to each other.
- L ⁇ , L 12 , L 21 , and L 22 each comprise the same or different terminal reactive moiety selected from the group consisting of hydrogen, protecting group, alkene, alkyne, amine, carboxylic acid, halogenated aromatic, aldehyde and vinyl halide;
- R 1; R 2 and R 3 are preferably selected from the group consisting of hydrogen, alkyl, aryl, phenoxy, methoxy, halide, methylene cyclohexyl, benzyl, heteroaryl, aryloxy, heteroaryl, carboxyl, carboxalkyl, carboxaryl, arylalkyl, thio and hydroxyl;
- X 3 and X. ⁇ each preferably comprises a functional moiety selected from the group consisting of carboxyl, amino, gem-dialky
- the first and second monomers are structurally related to one another so that the second monomer can be produced by chemical conversion of the first.
- Figures 1 1, 12 and 13 depict preferred embodiments of the present invention in which first and second monomers (depicted as C-terminal and N-terminal monomers, respectively) are synthesized convergently using known Evans' aldol chemistry (Evans et al.. J. Am. Chem. Soc. 1982, 104. 1737).
- R can be, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, phenoxy, methoxy, bromide, and methylene cyclohexyl, benzyl, chloride, carboxyalkyl, carboxyaryl, arylalkyl, thio, hydroxyl, and heteroaryl functionalities.
- R can be, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, cyclopentyl, phenoxy, methoxy, bromide, and methylene cyclohexyl, benzyl, chloride, carboxyalkyl, carboxyaryl, arylalkyl, thio, hydroxyl, and heteroaryl functionalities.
- Another important aspect of the monomers utilized in the present invention includes the ability to produce both syn and anti products. Specifically, Examples 1-12 present the synthesis of syn products, and examples 13-19 present the synthesis of anti products.
- Still another important aspect of the particular monomers produced according to Figures 1 1 and 12 is their ability to be converted into useful second monomers by utilizing the Curtius rearrangement as shown below in Figures 12 and 13.
- the Curtius rearrangement yields a stereochemically pure second monomer from the first monomer and thus under these reaction conditions, the stereocenters are rigidly set.
- stereochemically pure monomers can be obtained from other rearrangements such as the Hofmann, Lossen and Schmidt Rearrangements, as shown generally in Figure 14.
- the capability of controlling the stereochemistry of the present invention allows the development of peptidomimetics or libraries of peptidomimetics that may have certain desired conformational and binding properties.
- a first monomer may be reacted with a second monomer, or a sole monomer may be diversified.
- the reaction of the first and second monomers may occur inter-or intramolecularly. That is, if the monomers have already been linked to one another as described above (see for example, Scheme 3), their subsequent reaction is intramolecular; if they have not been so linked, their reaction is intermolecular. Whether the reaction employed is intermolecular or intramolecular, the monomers are selected to have terminal functional moieties L )2 and L 21 capable of reaction with one another so that the monomers become attached.
- L I2 and L 21 are both terminal alkenes.
- each of L 12 and L 21 may be selected from the group comprising but not limited to alkenes, alkynes, amines, carboxylic acids, halogenated aromatics, aldehydes, and vinyl halides.
- the first and second monomers each have a linking group binding site and are linked together by means of a crosslinking reagent as shown in Figure 15.
- the first and second monomers each have a heteroatom-containing linking group binding site and are linked together by means of a silicon crosslinker such as dimethyldichlorosilane as shown in Figure 16.
- the monomers each contain a hydroxyl or amine linking group binding site and diisopropylamino chlorophosphoramidite is utilized as a linking reagent as shown in Figure 17.
- these linked monomers comprise alkene terminal reactive moieties and thus are subjected to reaction conditions to effect an intramolecular metathesis reaction to generate an alkene moiety.
- the resultant linker provides a phosphorous moiety that can act as an additional site for functionalization. For example, oxidation can be employed to generate an oxide, which will enable further diversification.
- the generation of a phosphate is advantageous because phosphorylation of peptides is a key step in many intracellular processes, and therefore peptidomimetic structures containing a phosphate-like moiety might be expected to interact with signaling proteins.
- Other preferred linking reagents include, but are not limited to sulfonyl chloride and suitable reagents containing metals such as boron or titanium (e.g., TiCl 4 )
- Olefin metathesis is effected by using transition metal catalysts for ring closing metathesis reactions.
- transition metal catalysts for ring closing metathesis reactions.
- Grubbs' catalyst has been utilized for these types of reactions, however, recently, more efficient versions of this catalyst have been developed (see. Tet. Lett., 1999, 40, 2247) to effect ring closing metathesis reactions for more difficult substrates.
- the mixture of compounds obtained from the non-hydrogenated product can be separated by subsequent deprotection and cyclization, for example as shown in Figure 19.
- Preferred intermolecular embodiments of the present invention also include linking the first and second monomers in a transition metal mediated crosscoupling reaction, such as the palladium catalyzed Heck Reaction as shown in Scheme 4, in which a haloaromatic first monomer is reacted with a second monomer under palladium (0) catalysis to yield an aromatic backbone and olefin that can be further functionalized.
- a transition metal mediated crosscoupling reaction such as the palladium catalyzed Heck Reaction as shown in Scheme 4, in which a haloaromatic first monomer is reacted with a second monomer under palladium (0) catalysis to yield an aromatic backbone and olefin that can be further functionalized.
- the amine functionality can also be deprotected and peptide coupling continued.
- Preferred intermolecular embodiments of the present invention also include a pinacol coupling followed by elimination to yield an alkene, bond construction through tandem aldol reaction followed by Curtius rearrangement, hydrozirconization of terminal alkynes, and nucleophilic addition involving terminal alkenes, and NHK coupling, as shown in Figures 5, 6, 1, 8, and 9 respectively.
- the first monomer instead of being reacted with a second monomer as described above, is reacted with a reactive moiety to yield a molecule containing a diversifiable segment unit and diversifiable functional groups (R).
- ⁇ diastereoselective cycloaddition based upon the work of Carreira et al. (J. Am. Chem. Soc. 1997, 119, 8379), is shown in Figure 20, in which dipolarophiles are reacted with Me 3 SiCHN 2 to yield ⁇ 2 -pyazolines.
- Each of the structures shown in Figure 20 contain reactive moieties which may be further functionalized. Alternatively, these reactive moieties are capable of attachment of biomolecules. preferably peptides, to yield complex compounds and libraries of compounds.
- work from the thesis of Ann Weber is shown in Figure 21 in which a diversifiable monomer is generated which contains four points of diversity. This moiety is also capable of attachment of biomolecules, such as peptides, to yield complex compounds and libraries of compounds.
- each of the monomers utilized in the invention is capable of functionalization at one or more sites. That is, each monomer may contain functionalizable moieties as part of the base monomer structure, the terminal functionalities, and the linking group binding site. Where the monomers are linked together prior to attachment through an intramolecular reaction, the linking reagents and therefore the linker attaching the monomers, may also contain one or more functionalizable sites.
- These functionalizable sites may be diversified with any desirable moiety, including but not limited to hydrogen, alkyl, aryl, phenoxy, methoxy, halide, methylene cyclohexyl, benzyl, heteroaryl, aryloxy, carboxyl, carboxalkyl, carboxaryl, arylalkyl, thio, and hydroxyl.
- This functionalization is in general limited to those functionalities that will not participate in undesirable side reactions during the coupling reaction. For example, olefins, more particularly terminal olefins, interfere with the coupling process because of their ability to participate in undesirable side reactions.
- monomers and/or linking reagents can be functionalized either before or after being reacted, and thus the chemistry employed must be compatible with existing functionalities.
- the monomers are first reacted to produce a single core molecule that is subsequently functionalized and diversified.
- the diversification reactions are preferably performed according to combinatorial approaches such as split-and-pool or parallel synthesis.
- the reactions are performed to produce libraries having at least approximately 10 members, more preferably at least approximately 1,000 members, and most preferably 10,000 to about 1,000,000 or about 10,000,000 members.
- Scheme 4 represents one particular embodiment of a core molecule available for functionalization according to the present invention.
- L n and L 22 each comprise the same or different terminal reactive moiety selected from the group consisting of hydrogen, protecting group, alkene, alkyne. amine, carboxylic acid, halogenated aromatic, aldehyde and vinyl halide;
- R b R 2 and R 3 are preferably selected from the group consisting of hydrogen, alkyl, aryl, phenoxy, methoxy, halide, methylene cyclohexyl, benzyl, heteroaryl, aryloxy, heteroaryl, carboxyl, carboxalkyl, carboxaryl, arylalkyl, thio and hydroxyl;
- X 3 and X 4 each preferably comprises a functional moiety selected from the group consisting of carboxyl, amino, gem-dialkyl, and methylene;
- X, and X 2 preferably each comprise a functionality containing nitrogen, oxygen, sulfur or carbon;
- L preferably comprises a group, including but not limited to mixed carbonates (R and R'
- the structure depicted in Scheme 4 is available for randomization and diversification at several sites, allowing for the rapid synthesis of a library of compounds capable of emulating peptidic functions and structures, although these compounds are not necessarily required to emulate peptidic structure.
- diversification can be achieved through functionalization at the R groups, represented by R,, R 2 and R 3 as shown in Scheme 4.
- R groups represented by R,, R 2 and R 3 as shown in Scheme 4.
- various functionalities can be substituted including but not limited to hydrogen, alkyl, aryl, phenoxy, methoxy, halide, methylene cyclohexyl, benzyl, heteroaryl, aryloxy. carboxyl, carboxalkyl, carboxaryl, arylalkyl, thio, and hydroxyl.
- the segment unit replacement represented by A, may be diversified.
- a 2 + 2 addition to yield a cyclobutane segment unit can be initiated by photolysis ( Figure 21 ) or by the use of certain transition metal catalysts such as Ti(CH 2 Ph) .
- This segment unit can then be further diversified by cyclobutane ring opening reactions including but not limited to reactions with cuprates, radical type fragmentations and De Mayo fragmentations.
- the double bond product can be converted into a cyclopropane ( Figure 23) which also can be further diversified by reaction with a variety of nucleophiles, such as cuprates or organometallics. Additional diversification of the double bond may be achieved by hydrogenation, epoxidation, or dihydroxylation.
- the linking group can be removed to yield further diversifiable functionalities X, and X 2 , as shown in Scheme 5.
- These linking groups are preferably carbon, oxygen, sulfur or nitrogen containing functionalities such as hydroxy, thiol, or amine functionalities, which are capable of further reaction with electrophiles.
- the hydroxyl group depicted in Figure 24 is selectively protected via the Hoffman Rearrangement.
- L u and L 22 each comprise the same or different terminal reactive moiety selected from the group consisting of hydrogen, protecting group, alkene, alkyne, amine, carboxylic acid, halogenated aromatic, aldehyde and vinyl halide;
- R b R 2 and R 3 are preferably selected from the group consisting of hydrogen, alkyl, aryl, phenoxy, methoxy, halide, methylene cyclohexyl, benzyl, heteroaryl, aryloxy, heteroaryl, carboxyl, carboxalkyl.
- X 3 and X 4 each preferably comprises a functional moiety selected from the group consisting of carboxyl, amino, gem-dialkyl, and methylene; and X, and X 2 preferably each comprise a functionality containing nitrogen, oxygen, sulfur or carbon.
- the core functionality A is most preferably an alkene.
- the monomers may be diversified prior to or after reaction to generate core structures. Additionally, after their synthesis, the core structures can also be diversified.
- the synthesis of libraries from the above-described core structures and monomers can be performed using established combinatorial methods for solution phase, solid phase, or a combination of solution phase and solid phase synthesis techniques. The synthesis of combinatorial libraries is well known in the art and has been reviewed (see, e.g., "Combinatorial Chemistry", Chemical and Engineering News, Feb. 24, 1997, p. 43; Thompson, L.A., Ellman, J.A., Chem. Rev.
- the inventive libraries are generated using a solution phase technique.
- Traditional advantages of solution phase techniques for the synthesis of combinatorial libraries include the availability of a much wider range of organic reactions, and the relative ease with which products can be characterized.
- Notable disadvantages of solution phase techniques includes the inability to easily synthesize libraries of compounds containing very large numbers, such as one million or more library members, because one reaction vessel must be provided for each library member, and the inability to use excess reagents without time-consuming purification steps, such as chromatography.
- Recently, however, advances have been made in solution phase synthesis techniques such as the use of a "covalent scavenger" which selectively removes from solution via covalent bond formation.
- the "covalent scavenger” is essentially a solid phase bound nucleophile or electrophile that reacts with these excess reagents. (Kaldor, Eli Lilly, Frechet et al., Tetrahedron Lett., 21, 617 (1980)).
- a parallel synthesis technique is utilized, in which all of the products are assembled separately in their own reaction vessels.
- a microtitre plate containing n rows and m columns of tiny wells which are capable of holding a few milliliters of the solvent in which the reaction will occur, is utilized.
- n variants of reactant A such as a carboxylic acid
- m variants of reactant B such as an amide
- a solid phase synthesis technique is utilized, in which the desired scaffold structures are attached to the solid phase directly or though a linking unit, as discussed above.
- Advantages of solid phase techniques include the ability to more easily conduct multi-step reactions and the ability to drive reactions to completion because excess reagents can be utilized and the un reacted reagent washed away.
- One of the most significant advantages of solid phase synthesis is the ability to use a technique called "split and pool", in addition to the parallel synthesis technique, developed by Furka. (Furka et al., Abstr. 14th Int. Congr. Biochem., Prague, Czechoslovakia, 1988, 5. 47, Furka et al.. Int. J. Pept.
- a mixture of related compounds can be made in the same reaction vessel, thus substantially reducing the number of containers required for the synthesis of very large libraries, such as those containing as many as or more than one million library members.
- the core structures or monomers can be divided into n vessels, where n represents the number species of reagent A to be reacted with the core structures or monomers
- n represents the number species of reagent A to be reacted with the core structures or monomers
- m vessels represents the number of species of reagent B to be reacted with the core structures or monomers. This procedure is repeated until the desired number of reagents is reacted with the core structures or monomers to yield the inventive library.
- solid phase techniques in the present invention may also include the use of a specific encoding technique.
- Specific encoding techniques have been reviewed by Czarnik. (Czarnik, A.W., Current Opinion in Chemical Biology, 1997, 1, 60.)
- an encoding technique involves the use of a particular ' identifying agent attached to the solid support, which enables the determination of the structure of a specific library member without reference to its spatial coordinates
- a particular ' identifying agent attached to the solid support, which enables the determination of the structure of a specific library member without reference to its spatial coordinates
- the reaction history of these library members may also be identified by their spatial coordinates in the particular plate, and thus are spatially encoded It is most preferred, however for large combinatorial libraries, to use an alternative encoding technique to record the specific reaction history
- Examples of particular preferred alternative encoding techniques that can be utilized in the present invention include, but are not limited to, spatial encoding techniques, graphical encoding techniques, including the "tea bag” method, chemical encoding methods, and spectrophotomet ⁇ c encoding methods
- Spatial encoding refers to recording a reaction ' s history based on its location
- Graphical encoding techniques involve the coding of each svnthesis platform to permit the generation of a relational database
- Examples of preferred spectrophotomet ⁇ c encoding methods include the use of mass spectroscopy, fluorescence emission, and nuclear magnetic resonance spectroscopy
- chemical encoding methods are utilized, which uses the structure of the reaction product to code for its identity Decoding using this method can be performed on the solid phase or off of the solid phase
- one particular aspect of the present invention is the provision of methods and reagents for preparing and identifying chemical compounds that mimic certain desired structural and/or functional properties of a predetermined peptide
- a variety of techniques e g , alanine scanning mutagenesis, NMR, X-ray crystallography, etc ) are available for defining within a biologically active protein particular peptide sequences, or dispersed amino acids or small collections of amino acids, that are responsible for part or all of the protein's function
- the present invention provides a novel approach for preparing a non-peptide compound that captures the functionality of that sequence
- the methods discussed above provide libraries of chemical compounds that typically resemble of di- or tn-peptide moieties
- the libraries can be prepared in the context of an existing peptide structure, that functions as a biasing element for the library, or can be embedded within a peptide after their preparation
- the techniques described herein allow preparation of a library of peptide derivatives corresponding to a known active sequence except that two or three residues of the sequence are replaced with an inventive library
- This peptide derivative library can readilv be screened to identify those compounds within it that retain the peptide activity of interest In this way, a portion of the peptide is "morphed" into another compound that retains the peptide activity
- This morphing method is not limited to substitution of a single di- or tn-peptide unit within an active sequence
- a second unit within the peptide can be subjected to the same procedure, and so on Alternatively, two or more units may be morphed simultaneously
- two or more units may be morphed in parallel and the final morphed structures may subsequently be embedded within a single peptide
- the method, compounds, and libraries of the present invention can be utilized in various disciplines Any available method may be employed to screen the libraries produced according to the present invention to identify those with desirable characteristics for a selected application.
- the present invention can be utilized to produce peptidomimetic compounds that control (i.e., promote or inhibit) cell functions.
- Such compounds may be formulated and utilized as therapeutic pharmaceuticals.
- therapeutic pharmaceuticals through interactions with cellular receptors, can control HIV production, cell proliferation, viral replication, gene expression, or any other cell signaling process.
- a morphed segment produced according to the present invention can be embedded in a SH 2 binding peptide, as shown in Figure 25.
- Figure 26 depicts model studies showing the binding of a morphed peptide to a SH2 domain.
- a library of inhibitors of DNA Glycosylases as shown in Figure 27 can be synthesized according to the method of the present invention.
- a library of synthetic transcriptional regulators can be developed by the attachment of FK506 to the resin linked library of the present invention via an olefin linker as depicted in Figure 28.
- Figure 29 depicts a use for the inventive compounds and libraries in the E6 E6-.AP system.
- Figure 30 depicts a use for the inventive compounds and libraries in the renin-angiotensin system.
- Figure 3 1 depicts a use for the inventive compounds and libraries as inhibitors of the proteasome.
- Inventive peptidomimetic or stereodiverse compounds can alternatively or additionally be used for catalysis, either as a ligand for a transition metal capable of mimicking an important biological environment, or by acting in concert with a particular transition metal catalyst to effect a particular desired enantioselective chemical reaction.
- Inventive peptidomimetic or stereodiverse compounds are also useful in the area of materials science. Because of the reactive moieties present at the terminal ends of these compounds, molecules such as lipids and other polymeric molecules may be attached and thus generate potentially important biomaterials. It will be appreciated by one of ordinary skill in the art that the present invention is not intended to be limited to the abovementioned uses, but rather may be employed in many contexts and disciplines.
- Norephedrine (compound 1) was purchased from Aldrich (28,255-3, 31,750-0, both enantiomers available) and used as received. Norephedrine (32 g, 21 1 mmoles) was placed in a flame-dried 250 ml round bottom flask equipped with a stir bar. Diethyl carbonate (60 ml, 422 mmoles) (Aldrich D9.155-1) and K 2 CO 3 (2.5 g, 21 mmoles) were added and the resulting slurry was heated to 120°C under a Dean-Stark trap for 16 hours.
- Compound 2 (8.9 g, 50 mmoles) was placed in a 500 ml round bottom flame-dried flask equipped with a stir bar and then dissolved in 150 ml THF. The solution was then cooled to -78 ° C and to this solution was added dropwise over a period of five minutes 1.6 ml (50.5 mmoles) of 1.6 M solution of n-BuLi in hexanes (Aldrich 18,617-1). Upon complete addition, 4-methylvaleroyl chloride (Pfaltz & Bauer M30370) was added via syringe. The solution was stirred at -78 °C for 30 minutes and then allowed to warm up to room temperature over 15 minutes.
- Example 11 In a 50 ml Corning plastic test tube, compound 11 (166 mg, 0 25 mmoles) was dissolved in 1 ml of THF and cooled down to 0°C A solution of HF in pyridine (71 ml, 2.5 mmoles, Aldrich 18,422-5) was added dropwise, the reaction was allowed to warm up to room temperature and stirred for additional 30 minutes at room temperature After that time, the reaction was carefully quenched with 10 ml of 1 0M Na 2 CO 3 (vigorous foaming), extracted (3X) with EtOAc, dried with anhydrous MgSO , filtered and concentrated under vacuum The crude product was purified by flash chromatography (3 1 hexanes/EtOAc+1 0% MeOH) Yield 85 mg (50%) Note The low yield is most likely caused by the residual catalyst decomposition products increasing the weight of compound 11 before the deprotection
- Norephedrine (compound 1 ) was purchased from Aldrich (28,255-3, 31,750-0, both enantiomers available) and used as received Norephedrine (7 6g, 50 mmoles) was placed in a flame-dried 500ml round-bottom flask equipped with a stir bar, dissolved in 200 ml of freshly distilled methylene chloride and cooled down to 0°C Freshly distilled Et 3 N (8 3 ml, 60 mmoles) was added slowly over a period of 5 minutes and then 2-mes ⁇ tylenesulfonyl chloride (Aldrich M770-7, 11 0 g, 50 mmoles) dissolved in 25 ml of freshly distilled methylene chloride was added slowly via cannula over a period of 5 minutes The reaction mixture was allowed to warm to room temperature and stirred for another 4 hours After that time, the reaction mixture was extracted (3X) with EtOAc, dried with anhydrous
Abstract
Description
Claims
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HU0103260A HUP0103260A3 (en) | 1998-03-23 | 1999-03-22 | Peptidomimetic compounds and process for their synthesis |
CA002324016A CA2324016A1 (en) | 1998-03-23 | 1999-03-22 | Synthesis of compounds and libraries of compounds |
EP99912805A EP1066295A2 (en) | 1998-03-23 | 1999-03-22 | Synthesis of compounds and libraries of compounds |
IL13864799A IL138647A0 (en) | 1998-03-23 | 1999-03-22 | Synthesis of compounds and libraries of compounds |
AU31099/99A AU767185B2 (en) | 1998-03-23 | 1999-03-22 | Synthesis of compounds and libraries of compounds |
JP2000537880A JP2002507617A (en) | 1998-03-23 | 1999-03-22 | Synthesis of compounds and libraries of compounds |
IL138647A IL138647A (en) | 1998-03-23 | 2000-09-22 | Synthesis of compounds and libraries of compounds |
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WO2001094946A2 (en) * | 2000-06-05 | 2001-12-13 | Chiron Corporation | Microarrays for performing proteomic analyses |
WO2002086503A1 (en) * | 2001-04-18 | 2002-10-31 | Japan Science And Technology Corporation | Bacteriotoxin adsorbents and method of screening the same |
US7148058B2 (en) | 2000-06-05 | 2006-12-12 | Chiron Corporation | Protein microarrays on mirrored surfaces for performing proteomic analyses |
US7153682B2 (en) | 2000-06-05 | 2006-12-26 | Chiron Corporation | Microarrays on mirrored substrates for performing proteomic analyses |
US7381790B2 (en) | 2001-10-03 | 2008-06-03 | President And Fellows Of Harvard College | Copolymers for suppression of autoimmune diseases, and methods of use |
EP2359842A1 (en) | 2004-07-14 | 2011-08-24 | University of Utah Research Foundation | Netrin-related compositions and uses |
EP2796146A1 (en) | 2005-02-25 | 2014-10-29 | University of Utah Research Foundation | Tropoelastin for promoting endothelial cell adhesion or migration |
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DE69434998T2 (en) * | 1993-05-27 | 2008-03-13 | Aventis Pharmaceuticals Inc. | Topologically separated, encoding solid-phase libraries |
IL106106A0 (en) * | 1993-06-22 | 1993-10-20 | Interpharm Lab Ltd | Library of polymeric molecules and its preparation |
AU2537397A (en) * | 1996-03-22 | 1997-10-10 | Ontogen Corporation | Methods for spatially-dispersed positionally-encoded combinatorial library synthesis |
DE19619373A1 (en) * | 1996-05-14 | 1997-11-20 | Hoechst Ag | New substance library and the resulting supramolecular complexes |
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Cited By (8)
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WO2001094946A2 (en) * | 2000-06-05 | 2001-12-13 | Chiron Corporation | Microarrays for performing proteomic analyses |
WO2001094946A3 (en) * | 2000-06-05 | 2003-01-30 | Chiron Corp | Microarrays for performing proteomic analyses |
US7148058B2 (en) | 2000-06-05 | 2006-12-12 | Chiron Corporation | Protein microarrays on mirrored surfaces for performing proteomic analyses |
US7153682B2 (en) | 2000-06-05 | 2006-12-26 | Chiron Corporation | Microarrays on mirrored substrates for performing proteomic analyses |
WO2002086503A1 (en) * | 2001-04-18 | 2002-10-31 | Japan Science And Technology Corporation | Bacteriotoxin adsorbents and method of screening the same |
US7381790B2 (en) | 2001-10-03 | 2008-06-03 | President And Fellows Of Harvard College | Copolymers for suppression of autoimmune diseases, and methods of use |
EP2359842A1 (en) | 2004-07-14 | 2011-08-24 | University of Utah Research Foundation | Netrin-related compositions and uses |
EP2796146A1 (en) | 2005-02-25 | 2014-10-29 | University of Utah Research Foundation | Tropoelastin for promoting endothelial cell adhesion or migration |
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JP2002507617A (en) | 2002-03-12 |
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WO1999048897A3 (en) | 1999-11-11 |
HUP0103260A2 (en) | 2002-02-28 |
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