Combinatorial libraries peptidomimetics

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

Design, Synthesis, Screening, and Decoding of Encoded One-Bead One-Compound Peptidomimetic and Small Molecule Combinatorial Libraries... 

Mixture-Based Combinatorial Libraries From Peptides and Peptidomimetics to Small Molecule Acyclic and Heterocyclic Compounds... 

This multigeneration strategy for the synthesis of pyrimidines combines efficiently a novel cyclocondensation reaction using the highly reactive acetylenic ketones 153215,218 to build the pyrimidine skeleton, with a multicomponent reaction, and a multidirectional cleavage procedure. The Ugi four component reaction is especially useful in the context of building peptidomimetic-derived combinatorial libraries as it affords directly dipeptide analogues of type 159. 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

Physicochemical and structural properties of known potent peptidomimetic and nonpeptidic HIV PR inhibitors and their building blocks used in the focusing of combinatorial libraries... 

Liu R, Marik J, Lam KS. A novel peptide-based encoding system for one-bead one-compound peptidomimetic and small molecule combinatorial libraries. J. Am. Chem. Soc. 2002 124 7678-7680. 

Lee, RE, Smith, M D, Pickering, L, Fleet, G W J, An approach to combinatorial library generation of galactofuranose mimics as potential inhibitors of mycobacterial cell wall biosynthesis Synthesis of a peptidomimetic of uridine 5 -diposphogalactofuranose (UDP-galf), Tetrahedron Lett., 40, 8689 8692, 1999. 

Peptides and Peptidomimetics from Combinatorial Libraries. Mixture-based combinatorial peptide libraries have been extensively explored by Houghten and coworkers and have led to the identification of a variety of peptides with affinity for opioid receptors (see Ref 946 for a review). Early hexapeptide libraries, deconvoluted by binding to p opioid receptors and either iterative deconvolution (947)or positional scanning (948 see Ref 946 for a description of these deconvolution techniques), identified sequences related to the enkephalins. Other nonacetylated peptide libraries have identified more varied peptides, some that resemble opioid peptides and some that do not. Iterative deconvolution of a hexapeptide library resulted in identification of both Tyr-Pro-Phe-Gly-Phe-XNH, (X = one of 20 natural amino acids), reminiscent of the... 

Peptidomimetic ligands for opioid receptors have also been identified from combinatorial libraries. Screening of an N-(substi-tuted)glycine peptoid library for affinity for ix opioid receptors yielded novel structures (251) with high affinity for these receptors (K = 6-46 nM) (953). A library of dipeptide amides with alkyl substituents on both the interior and C-terminal amides were prepared, and high affinity agonists for all three opioid receptors identified from the library (see Ref 946). Peptide libraries can also be further modified ["libraries from libraries" (954)] to yield new potential ligands for receptors. Thus an acety-... 

A further improvement of this approach, to create increased molecular diversity, was applied to the synthesis of a soluble peptidomimetic combinatorial library of about 60 000 compounds [22]. This library generated using the split and combine method is based on a dipeptide scaffold, which incorporates 50 different L-, D- and unnatural amino acids,... 

SE Blondelle, E Perez-Paya, CT Dooley, C Pinilla, RA Houghten. Soluble combinatorial libraries of organic, peptidomimetic and peptide diversities. Trends Anal Chem 14 83-92, 1995. 

Blondelle, S. E., Perezpaya, E., Dooley, C. T., Pinilla, C. Houghten, R. A. (1995) Soluble Combinatorial Libraries of Organic, Peptidomimetic and Peptide Diversities. Trac-Trends in Analytical Chemistry 14, 83-92. 

The synthesis of peptidomimetics based on a D-glucose or D-allose scaffold featured 2,3-di-0-alkyl-6-0-aryl-4-0-carboxymethyl-pyranose compounds/ while a muramic acid analogue has been used in the solid phase synthesis of peptido-glycan monomers for the generation of a combinatorial library/... 

Since the introduction of solid-phase peptide synthesis by Merrifield (1) nearly forty years ago, solid-phase techniques have been applied to the construction of a variety of biopolymers and extended into the field of small molecule synthesis. The last decade has seen the emergenee of solid-phase synthesis as the leading technique in the development and production of combinatorial libraries of diverse compounds of varying sizes and properties. Combinatorial libraries can be classified as biopolymer based (e.g., peptides, peptidomimetics, polyureas, and others [2,3]) or small moleeule based (e.g., heterocycles [4], natural product derivatives [5], and inorganie eomplexes [6,7]). Libraries synthesized by solid-phase techniques mainly use polystyrene-divinylbenzene (PS) derived solid supports. Owing to physieal and ehemical limitations of PS-derived resins, other resins have been developed (8,9). Most of these resins are prepared from PS by functionalizing the resin beads with oligomers to improve solvent compatibility and physical stability (8,9). 

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