Classifications

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Definitions

• the present invention relates to a method for generating arrays of compounds having a common core structure through a combinatorial array synthesis using a multiple component combinatorial array (MCCA)
• MCCA multiple component combinatorial array
• the present invention also relates to arrays of organic compounds wherein each array is comprised of a group of structural analogues having a common core structure, the core structure being generated by a multiple component one pot synthesis.
• contours of a receptor's binding site or an enzyme's active site can be effectively analyzed by testing the binding affinity of several structural analogues to these sites.
• the rate limiting step in the analysis of structure-function relationships is the synthesis of the necessary structural analogues.
• the traditional strategy for evaluating structure-function relationships involves an iterative process whereby successive groups of compounds, all having a common core structure, are synthesized and assayed. After each iteration, the assay results are evaluated in order to design the next group of compounds to be synthesized and assayed. This process is repeated until the substituents or structural factors influencing biological activity are determined and/or optimal therapeutic agents are identified.
• the general approach for screening monoclonal antibodies to a specific antigen presents a useful model for how structure-function studies should be conducted.
• the monoclonal antibody producing B-cells of the host are immortalized and diluted over a large array of microtiter wells.
• biopolymer synthesis technology cannot be readily redirected to the production of structural analogues of organic compounds. Unlike biopolymer synthesis, the synthesis of structural analogues of organic compounds involves numerous
• the present invention relates to an array of compounds having a common core structure wherein the compounds of the array comprise the products of a multiple component combinatorial array synthesis having at least three reactive components.
• Each component of the multiple component combinatorial array synthesis comprises a group of reactants having a common
• the array synthesis is conducted under appropriate conditions such that the common functional group of each component in the reaction reacts with functional groups on the other components to form an array of compounds having a common core
• Each component of the combinatorial array synthesis can itself comprise an array of compounds having a common core structure, the array of component reactants being synthesized by a multiple component combinatorial array synthesis .
• Each component can also comprise a group of reactants wherein each reactant comprising a mixture of compounds having a common functional group.
• the array of compounds is formed while bound to a solid support.
• the present invention also relates to a method of making an array of compounds having a common core structure using a multiple component combinatorial array synthesis with at least three components.
• the component comprises a group of reactants having a common functional group.
• the method comprises organizing a series of reaction vessels in an n dimensional array wherein each reaction vessel is identifiable by its coordinates in the n dimensional array.
• Each axis in the n dimensional array corresponds to a different component in the array synthesis.
• Each position on each axis corresponds to a different reactant of the
• each component of the combinatorial array synthesis can itself comprise an array of compounds having a common core structure, the array of component reactants being synthesized by a multiple component combinatorial array synthesis.
• Each component can also comprise a group of reactants, each reactant comprising a mixture of compounds having a common functional group.
• a further embodiment of the present invention relates to solid phase multiple component array synthesis which comprises the further step of binding one of the
• the present invention also relates to a method of creating a combinatorial array of compounds with a common core structure by identifying the desired core structure, identifying a MCCA reaction capable of generating that core structure, followed by preparing an array of compounds using the identified MCCA reaction according to the aforementioned method.
• the present invention also relates to a method for conducting in vitro assays of biological material by adding biological material to an array of compounds, each member compound of the array having a common core structure and being bound to a solid support followed by measuring the effect each member compound of the array has on the biological material's biological activity.
• Figure la-p provides a summary of some of the common core structures synthetically accessible by MCCA reactions .
• Figure 2 depicts the synthesis of the core structures depicted in Figure 1, showing the
• Figure 2a depicts a synthesis described in Joucia, et al., J. Tetrahedron Lett., (1985) 26:1221.
• Figure 2b depicts a synthesis described in Kelly, et al., J. Am. Chem. Soc., (1985) 107:3879.
• Figure 2c depicts a synthesis described in Banville, et al. Can. J. Chem., (1974) 50:80; Cameron, et al., J. Chem. Soc. Chem.
• Figure 2e depicts a synthesis described in Posner, et al., Tetrahedron (1981) 37:3921.
• Figure 2f depicts a synthesis described in Davis, et al., J. Org. Chem., (1979) 44:3755.
• Figure 2g depicts a synthesis described in Bestmann, et al., Angew Chem. Int. Ed. Engl, (1985) 24.:790.
• Figure 2h depicts a synthesis described in Weis, et al., Tetrahedron Lett., (1981) 22:1453.
• Figure 2i depicts a synthesis described in Ugi, et al., Justus Lie ⁇ is Ann.
• Figure 2j depicts a synthesis described in Ugi, et al., Chem. Ber. (1961) 64:734.
• Figure 2k depicts a synthesis described in Sebti, et al., Synthesis (1983) 546.
• Figure 21 depicts a synthesis described in Isenring, et al., Synthesis (1981) 385 and Isnering, et al.,
• Figure 2n depicts a synthesis described in Boehm, et al., J. Org. Chem. (1986) 51:2307.
• Figure 2o depicts a synthesis described in Murakami, et al., J. Org. Achem., (1993) 58:1458.
• Figure 2p depicts a synthesis of a c-linked disaccharide wherein the
• stereochemistry of the first ring is determined by the sugar used in the synthesis and the stereochemistry of the second ring is determined by the oxidation catalyst.
• Figure 3 depicts the fact that MCCA array syntheses produce analogues on a geometric scale where the total number of analogues synthesized equals the product of the number of structural variants of each component of the MCCA array synthesis used.
• Figure 4 depicts the results of a two dimensional MCCA array synthesis using the Passerini reaction wherein the aldehyde and acid reaction
• Figure 5 depicts the mechanism of action for carzinophilin/azinomycin .
• Figure 6 depicts the cu-acyloxy amine core structure of the antitumor antibiotic
• Figure 7 depicts the Ugi reaction which, upon removal of the protecting groups, provides
• nonhydrolizable peptide analogues that mimic a natural peptide's structure.
• Figure 8 depicts the peptide backbone core structure of phosphotyrosine peptides and the synthesis of structural variants of phosphotyrosine by varying the first and second amino acids employed (aal and aa2) as well as the other components of the Ugi reaction.
• Figure 9 depicts the synthesis of a series of tyrosine-based peptide analogues.
• Figure 9a depicts the synthesis of pseudosubstrate peptide inhibitors.
• Figure 9b depicts the synthesis of low molecular weight
• Figure 9c depicts the synthesis of low molecular weight tyrosine-based peptide analogues where the tyrosine structural unit is intact.
• Figure 9d depicts the synthesis of additional low molecular weight tyrosine-based peptide analogues.
• Figure 10 depicts the synthesis of a support and linker system.
• Figure 11 depicts the solid phase synthesis of peptidomimetics by means of the Ugi reaction.
• the present invention relates to a simple and efficient method for synthesizing arrays of organic compounds having a common core structure. More
• the present invention relates to the use of multiple component combinatorial array (MCCA) syntheses to synthesize arrays of structurally related analogues having a common core structure.
• Multiple component combinatorial array (MCCA) syntheses correspond to reactions where the reactants combine synchronously or asynchronously in one reaction vessel to form the product.
• MCCA multiple component combinatorial array
• numerous MCCA reactions have been developed. In some cases, the reactions were developed in order to show an efficient synthesis of a known natural product.
• Cameron, et al., J. Chem. Soc. Chem. Comm., (1976) 275 synthesis of m-deoxygenated benzoquinones in the application of the total synthesis if anthraquinone insect pigments);
• Linear syntheses involve the sequential reaction of several separate reactants in order to achieve the final product.
• Linear syntheses are generally not one pot reactions, requiring the isolation and purification of intermediate products.
• MCCA reactions because they are one pot syntheses, do not require the isolation and purification of intermediate reaction products.
• MCCA reactions are simpler and more efficient to perform than multiple step linear syntheses. Products of MCCA reactions are therefore more accessible to those lacking a high level of skill in the synthetic organic chemical arts. Further, since no intermediate isolation and
• MCCA reactions when used in the form of an array synthesis, enable the synthesis of structural analogues on a geometric rather than linear scale.
• an MCCA array synthesis at least three reaction
• Each component comprises a group of reactants possessing a common functional group that participates in the MCCA reaction.
• the combinatorial array synthesis is conducted by reacting the different combinations of the various MCCA components.
• a MCCA array synthesis can be characterized by the number of reaction components involved and the number of variants of each reaction component employed.
• a MCCA array synthesis where the MCCA reaction has n components, an n dimensional array of structural
• analogues can be produced. Each array of analogues is equivalent to a library of analogues. When one reactant is held constant (or when a component is comprised of a group of one reactant), the n dimensional array
• n-1 array simplifies to an n-1 array and can be visualized as a sublibrary of a greater array where the reactant used for that component is held constant.
• synthesis is analogous to the multiplication of a series of one dimensional arrays. Each component of the array synthesis is represented by a different one dimensional array, the elements of the one dimensional array
• an n dimensional array is generated when n one dimensional arrays are multiplied.
• the reaction vessels are organized in an n dimensional array wherein each reaction vessel is identifiable by its coordinates in an n dimensional array.
• Each axis of the array of reaction vessels corresponds to a different component in the MCCA reaction.
• Each position on each axis corresponds to a different reactant of the corresponding component.
• the reactants of the n components are added to the n dimensional array of reaction vessels such that the same reactant is added to all of the reaction vessels in the array having a position on the array corresponding to that reactant.
• the reaction of the components in the array of reaction vessels is analogous to the multiplication of the n one dimensional arrays since the reaction of the various reactants in each reaction vessel in the n dimensional array results in the "product" of the reactants added to that reaction vessel.
• MCCA array syntheses have the advantage over linear syntheses in that they produce analogues on a geometric scale rather than a linear scale.
• the ability to synthesize structural analogues on a geometric scale significantly decreases the time and effort required to synthesize these compounds .
• the total number of analogues synthesized equals the product of the number of each reactant employed. For example, if 10 different variants of each component of a three component MCCA are employed, a 10x10x10 three dimensional array of
• the reactants of a component of a combinatorial array synthesis can themselves be the product of a combinatorial array synthesis.
• individual reactants of a component of an MCCA array synthesis can comprise mixtures of different compounds having a common functional group.
• the analogues produced by the synthesis are a mixture of compounds.
• the term "analogue,” as it is used in this application, can include more than one compound.
• cis, trans, exo, endo and diasteriometric isomers can also be produced by the array synthesis.
• MCCA array syntheses of the present invention encompass all type of chemical reactions including, but not limited to
• MCCA array syntheses involving the condensation of four or more components can also be conducted according to the present invention.
• a four component array synthesis it is simplest to view the reaction as a series of three dimensional (n-1) array syntheses where the only variable between the three dimensional arrays is the structure of the fourth component used in each array.
• n-1 array syntheses the only variable between the three dimensional arrays is the structure of the fourth component used in each array.
• Higher order MCCA array syntheses are also possible
• the present invention also relates to the arrays (libraries) of structural analogues that can be synthesized by an MCCA array synthesis. Assaying compounds requires very little time relative to the time presently required to synthesize compounds by linear syntheses.
• the present invention enables the rapid production of large libraries of structurally related analogues all having a common core structure. Given the speed with which compounds can be analyzed, access to libraries of compounds sharing a common core structure would be an invaluable tool for analyzing the structurefunction relationships governing a molecule's biological activity.
• combinatorial arrays of structural analogues would not need to contain large amounts of any given compound.
• combinatorial arrays containing small quantities of each compound would be capable of repeated use.
• the organizational sense of the combinatorial arrays of the present invention greatly simplifies the mental aspect of structure-function analysis.
• the organizational nature of the combinatorial arrays of the present invention needs to be explained.
• the combinatorial array of compounds generated by a MCCA synthesis is best thought of in terms of a geometric array having a dimension equal to the number of reaction components employed in the MCCA array synthesis. For example, a four component MCCA reaction would generate a four dimensional combinatorial array. Each element of the array is identifiable by its coordinate in the array which corresponds to the precise components used to synthesize that analogue. Hence the product of the second variant of each component of a three dimensional array would have an array coordinate of (2,2,2).
• Each n dimensional array can be envisioned as a series of (n-1) dimensional arrays or sublibraries wherein all of the members of each sublibrary share a common core structure formed by at least one common component.
• a three component condensation reaction can be broken down into a series of two dimensional arrays where one reactant is held constant.
• the present invention provides a systematic framework for evaluating MCCA arrays as multidimensional arrays that can be divided into sublibraries
• sublibrary independent of its size, corresponds to a class of compounds where one structural subunit is held constant, a finding of biological activity across a particular sublibrary would indicate that the unvaried functional subunit was significant to the biological activity realized for that group of compounds.
• the organizational sense created by the combinatorial arrays of the present invention provide an invaluable tool for evaluating the structure-function correlations of a very large number of compounds.
• the linear synthetic approach currently employed for the identification of new therapeutics is driven largely by evaluating the binding constants of the molecules assayed.
• the rational as to why certain analogues exhibit stronger binding is not necessarily readily apparent from those studies.
• the approach of the present invention provides an organizational framework whereby structure-function effects become readily apparent.
• the present invention provides a more effective means for evaluating
• the present invention also relates to the solid phase synthesis, storage and use of these MCCA arrays. Solid phase synthesis is valuable for
• reaction components to a solid support, for example, a microtiter well, it is possible to isolate the compounds synthesized in high purity.
• One of the disadvantages of any multiple step reaction is low yields.
• a three step synthesis having a 70% yield for each step only produces a product in a 35% yield.
• simplification of the purification process is highly desirable as a means for optimizing the resulting yield.
• purification and isolation of the product is greatly simplified. This is especially important when complex, lower yielding MCCA reactions are involved since all that is needed in the present invention is an adequate amount of each analogue to test for biological activity.
• Solid phase synthesis of the combinatorial arrays of the present invention improves the storage stability of these arrays by enabling these compounds to be isolated in high purity and in a solid state.
• storing the compounds while bound to a solid support prevents the spillage or mixing of the compounds in the combinatorial array.
• Solid phase synthesis also facilitates the use of these combinatorial arrays for conducting in vitro binding studies. Entire two dimensional arrays of compounds bound to microtiter trays can be assayed at one time for their ability to bind to a protein or cell. This enables entire arrays of analogues to be very rapidly assayed for binding to different biomolecules and cells.
• Solid phase synthesis of combinatorial arrays by MCCA reactions presents very few limitations on the different types of compounds that can be synthesized.
• the only limitation presented by the use of solid phase synthesis is the requirement that there be a means for attaching one of the reaction components to the solid support. This will generally involve the use of a functional group such as an alcohol, mercaptan, amine, carbonyl, carboxylate or selenide. No other limitations to the structure of the compound to be synthesized are created. Further, as new linkers are designed, the structural limitations presented will be further reduced.
• polyacrylamide-kieselguhr composites and controlled pore glass have all been commercialized with functional groups suitable for derivitization with various linkers.
• Linkers are used to couple a variety of monomers to the solid support for the solid phase polymeric synthesis of biomolecules such as DNA and peptides.
• the linkers of the present invention must be capable of binding to one of the components of the MCCA synthesis and must also be capable of later releasing the synthesized molecules by some specific, regulatable mechanism.
• Such regulatable methods include but are not limited to thermal, photochemical, electrochemical, acid, base, oxidation and reduction reactions.
• linkers which provide a variety of functional group coupling and cleavage strategies.
• acid labile linkers include the 4-hydroxy methyl phenoxy aliphatic acids which allow the coupling of ethers acetals and esters to the linker.
• Acid labile linkers bearing an amine such as the p-[2,4-dialkoxylaminobenzyl] phenoxy acetic acid, allow for coupling through functional groups such as amides, imines, carbonates or ureas.
• the extent of the alkoxyl substituents on the aromatic rings of these linkers influence the pH at which the organic compound is cleaved from the solid support. Trityl-based linkers can be cleaved under mildly acid conditions.
• Base labile linkers include [4-(2-bromopropionyl)phenoxy] acetic acid linkers.
• the ester coupling of these linkers can be cleaved by nucleophiles such as hydroxide, alkoxides, and amines to give the corresponding acid, ester and amide derivatives of the organic compounds.
• nucleophiles such as hydroxide, alkoxides, and amines
• the [4-(2-bromopropionyl)phenoxy] acetic acid linker as well as the ortho-nitro benzyl linkers enable the photochemical cleavage of an organic compound from solid support under neutral conditions.
• linker be capable of photochemically or thermally releasing the product since no decoupling reactants are required.
• linker having a thermal release mechanism is the most preferred
• thermal reactions provide greater control over the rate at which the compound is released. Further, thermally labile linkers are more stable than photochemically labile linkers.
• linkers useful in the present invention is not limited to the linkers described herein since additional suitable linkers may exist in the art or be later developed.
• linkers in the solid phase synthesis of an MCCA array is described in
• the present invention also relates to the use of solid support bound analogues in in vitro binding studies.
• whole arrays of compounds can be simultaneously, quickly and efficiently tested for their ability to bind to a biological molecule. This greatly accelerates the process of assaying large arrays of compounds for biological activity.
• Arrays of compounds bound to a solid support can also be used to study the effect of structural orientation on a compound's biological activity. This is accomplished by assaying combinatorial arrays of the same group of compounds where each array differs in that a different portion of the structural analogues in each array are used to bind the compounds to the solid support.
• the present invention provides a method for testing the binding affinity of different faces of the same array of compounds.
• the linear synthesis approach currently employed does not provide a means for obtaining this data short of obtaining crystal
• One of the limitations of using solid phase synthesis is the requirement that one of the components be attachable to the solid support and also be able to participate in the MCCA reaction. In order for a component to serve both these functions, the component must have two functional groups, one that participates in the reaction and the other which binds to the linker. The requirement that a component have two functional groups is not a significant problem when one does not seek to vary the structure of the component being bound to the solid support. However, the range of structural variants of a component that can be both bound to a linker and at the same time participate in the reaction is often limited.
• a method for isolating reaction products from solution chemistry reaction mixtures involves sequestering the unreacted components of the reaction.
• An example of the use of sequestering agents to isolate the products of an Ugi reaction is provided in Example 9.
• sequestering agents to sequester the unreacted components of the reaction, the products of the array synthesis can be isolated at sufficient purity to use in bioassays.
• the present invention also relates to a method for the automated production of structural analogues.
• the automated synthesis of MCCA arrays reduces the level of skill required for the preparation of arrays of structural analogues and thus enables the performance of structure-function studies without the assistance of synthetic organic chemists.
• the present invention enables researchers without a high level of skill in the synthetic chemical arts to generate combinatorial arrays of structural analogues.
• the automated synthesis of the combinatorial arrays of structural analogues of the present invention is made possible by the logical organization of the arrays synthesized.
• Automation of the present invention is facilitated by the fact that the present invention can be organized so that the same reaction component can be added to all of the reaction compartments in the same row, column or layer. Automated synthesis is also facilitated by the fact that the same MCCA reaction conditions can be used for the synthesis of all of the compounds within the MCCA array.
• the component of the reaction mixture is the product.
• the product can often be isolated by
• the automated combinatorial synthesis of MCCA arrays is preferably conducted in the solid phase because the purification and isolation of the synthesized compounds is greatly simplified.
• condensation reactions as well as the combinatorial arrays generated are illustrated in the following examples.
• the present invention through the use of MCCA reactions, provides a simple and efficient method for synthesizing large numbers of structural analogues for most of the known common core structures of biologically active molecules. Further objectives and advantages other than those set forth above will become apparent from the examples and accompanying drawings .
• the present invention takes advantage of the organic chemistry synthesis design theory known as the retrosynthetic approach.
• the retrosynthetic approach teaches one to dissect a target molecule into its smaller, simpler components by looking for bonds in the molecule that can be formed by known synthetic methods.
• the present invention takes an analogous approach, teaching one to evaluate the target molecule for the presence of one or more of the core structures known to be accessible by MCCA reactions.
• Figure 1 summarizes fourteen core structures that can be generated by known MCCA
• structural analogues of the target molecule can be prepared by varying the structure of the substituents of the various components of the MCCA reaction. This procedure is further described in Example 3 which describes the synthesis of carzinophilin/azinomycin structural analogues using a Passerini MCCA reaction.
• Passerini reaction involves the reaction of an aldehyde having the general structure RCHO with an isocyanide having the general structure R 1 NC and an acid having a general structure R 2 COOH.
• benzaldehyde, heptaldehyde, propanaldehyde , trans-2 -butenal , p-methoxybenzaldehyde , butyraldehyde, 4-N,N-dimethylaminobenzaldehyde, and cinnamaldehyde were prepared in 5 mL round bottom flasks such that each aldehyde represented 20 molar equivalents based on isocyanide.
• a shell vial box (Fisher, 1 dr, 15 ⁇ 45 mm, 72 vials) containing 64 glass vials (8X8) was used as the reaction chamber for the combinatorial array synthesis.
• the specific aldehyde used in the combinatorial array synthesis was varied by rows.
• the specific acid used in the combinatorial array synthesis was varied by columns. Row 1 :
• cyanomethylphosphonate was dispensed in 0.25 mL aliquots into 64 vials of the array using a gas tight syringe in a single process.
• each reaction vessel contained 2 molar equivalents of aldehyde, one molar equivalent of acid, and one molar equivalent of isocyanide in a total volume of 0.75 mL in CH 2 Cl 2 .
• the reaction vessels (vials) were all capped and no further precautions were taken to maintain an
• Analogue 3C N-[(1-diethylphosphono)methyl]-2-diphenylacetoylpentamide: This reaction mixture
• n-heptaldehyde 125 uL, 2 equiv.
• OCOCH OCOCH
• Carzinophilin (CZ) and Azinomycin B are antitumor/antibiotic compounds which function as a DNA bis-alkylating agent.
• the mechanism of action for CZ and Azinomycin B is depicted in Figure 5.
• Carzinophilin and Azinomycin B are structurally very similar. Given the structural
• Azinomycin B has also been produced by fermentation but in very low yields (2 mg/250 L). Given the difficulty associated with
• both CZ and Azinomycin B have ⁇ -acyloxy amine core structures.
• R 1 , R 2 and R 3 By labelling the substituents off of the ⁇ -acyloxy amine core structure R 1 , R 2 and R 3 , a Passerini reaction scheme for the synthesis of Carzinophilin, Azinomycin B and their structural analogues is identified.
• a Passerini multicomponent combinatorial array synthesis of Carzinophilin and Azinomycin B analogues can be designed by varying the R 1 , R 2 and R 3 substituents of the reaction components.
• One possible three dimensional Passerini-type MCCA array synthesis of Carzinophilin and Azinomycin B structural analogues is provided in
• the isocyanates used in the combinatorial array synthesis described in Table 2 were prepared according to the general reaction scheme provided below.
• Isocyanides 106E and 106Z were formed from a ⁇ -bromo-dehydroamino acids 71E and 71Z with retention of the olefin configuration by dehydrating the N-formyl groups with POCl 3 and Et 3 N in CH 2 Cl 2 at 0°C for 30 minutes.
• the corresponding vinyl aziridine compounds 107E and 107Z were formed from the isocyanates 106E and 106Z by adding ethyleneimine to the isocyanates in tetrahydrofuran and triethyl amine for 3-5 hours.
• azinomycin structural analogues may be produced
• Racemic 2-methylasiridine (210 ⁇ L, 2.91 mmol) was added to a r.t. THF (10 mL) solution of isocyanide bromide 106Z (0.88 mmol) and Et 3 N (125 ⁇ L, 0.97 mmol). The mixture was stirred for 2 hrs., after which the solvent and excess amines were removed under reduced pressure to afford a brown oil. The crude oil was extracted 3X with Et 2 O over H 2 O. The ether fractions were dried over MgSO 4 and rotoevaporated to afford a brown oil 108Z (198 mg, 93%) , which was sufficiently pure (>90%) for analytical data.
• Racemic 2-(methyl)-aziridine 250 ⁇ L, 3.0 mmol was added to a r.t. THF (5 mL) solution of
• 109Z/109E 5.1:1).
• SAR structural activity relationship
• Azinomycin analogs of Example 3 is provided in Table 3 below.
• HCT116/VM46 was selected for resistance to VM-26 and expresses the multidrug resistant (MDR) phenotype.
• HCT116/VP35 was selected for resistance to VP-16 and is resistant to topoisomerase II active drugs. The results of the
• Analogs 109E, 109Z, 110E and 110Z which all contain vinyl-aziridine, epoxide and naphthoate moieties displayed IC 50 's well within an order of magnitude of the natural product, Azinomycin B.
• the racemic 2-(methyl)-aziridine analogs 110E and 110Z behaved nearly identically in the in vi tro assays to the correspondingly unsubstituted aziridine analogs 109E and 109Z.
• a combinatorial array of peptidomimetic polymers having a non-hydrolyzable ethylenediamine core structure can be prepared using the Ugi reaction.
• the Ugi reaction is a four component condensation involving a first amino acid, a second amino acid having a Boc-protected alpha amino group, methylisocyanide and acetic acid.
• the Ugi reaction is conducted at room temperature in aqueous solvents.
• the Ugi reaction provides nonhydrolizable peptide analogues that mimic the structure of natural peptides.
• phosphotyrosine peptides have a peptide backbone core structure.
• Structural variants of phosphotyrosine can be synthesized by varying the first and second amino acids employed (aal and aa2) as well as the other components of the Ugi reaction.
• R 3 on the amine is an amino acid or derivative thereof.
• low molecular weight analogues of tyrosine that possess an intact tyrosine structural unit can be prepared wherein the R groups of the isocyanides, acids and amines employed are alkyl, aryl or acyl groups.
• low molecular weight derivatives of tyrosine where the tyrosine structural unit is also modified can be prepared by using different aldehydes.
• low molecular weight tyrosine derivatives can be prepared where the acid and amine are the same molecule. Further variations of these tyrosine-based peptide analogues can also be made according to the present invention by using different reaction components.
• the linker can be synthesized by condensing ethylene oxide with the lithium enolate of succinic anhydride. The resulting alcohol can then be converted to its mesylate and displaced with sodium azide to provide the azide
• This anhydride is then heated in the presence of the polymer in dimethylformamide to afford a free carboxylate linker.
• a solid phase MCCA array synthesis utilizing the Passerini reaction can be conducted using the linker described in Example 7.
• the carboxylic acid linker-resin system formed in Example 7 can be treated with dicyclohexylcarbodiimide and hydroxybenzotriazole in the presence of the methyl ester of alanine.
• the progress of the reaction can be monitored by nuclear magnetic resonance based on the disappearance of free alanine. Filtration of reactants and subsequent washing with fresh DMF should provide a purified resin-linker-amino acid system. Hydrolysis of the ester of alanine under base conditions should then provide the free carboxylic acid.
• reaction products of an Ugi-type reaction can be efficiently recovered from the reaction media by sequestering the unreacted components thereby yielding a substantially pure product.
• a mixed bed resin containing strongly acidic and basic resins can be used to remove the amine and acid respectively.
• the solvent is first removed by evaporation at reduced pressure. Distilled water is then added to the reaction mixture.
• a mixed bed resin containing Biorad AG 501-X8/Bio-Rex MSZ 501 a strongly basic anion exchange and strongly acidic cation exchange resin.
• exchange resins to sequester unreacted acids or amines can be extended to other unreacted components having different functional groups, such as esters, where the unreacted component is
• Metal sequestering agents can also be used where organometallic solution chemistry is employed in the MCCA reaction.
• organometallic solution chemistry is employed in the MCCA reaction.
• the addition of an EDTA molecule tethered to a polymer can be used to sequester palladium salts from the reaction mixture.
• Strongly acidic cation exchange resins can be used to remove boronic acids.
• the carbamate linkers 120 and 121 were then coupled to methylbenzhydrylamine (MBHA) Gly-resin 125 using HOBt in DMF to yield the polymer supported
• MBHA methylbenzhydrylamine
• photocleavable carbamates 126 and 127 respectively.
• butyraldehyde were added to the polymer supported acid 128 to yield the resin bound Passerini adduct 129.

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