Library mixture-based

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... 

The solid-phase technique of split and mix synthesis relies on the efficiency of mixture-based synthesis to provide very large libraries (millions) of discrete compounds (Figure 4).[161 In this approach, each resin bead is treated with a single building block for each synthesis step. Thus any single resin bead possesses identical copies of one library member, but the identity of the library member on any bead is lost due to the mix step of the process. Elegant strategies have been developed to chemically encode the syn-... 

Appel, J.R., Johnson, )., Narayanan, V.L., and Houghten, R.A. Identification of novel antitumor agents from mixture-based synthetic combinatorial libraries using cell-based assays. Mol Div. 1999, 4, 91-102. 

Advances in chemical synthesis have enabled considerable sophistication in the construction of diverse compound libraries to probe protein function [61, 62). However, few general techniques exist that can directly assess binding mechanisms and evaluate ligand afEnities in a multiplexed format. To realize the full potential of combinatorial chemistry in the drug discovery process, generic and efficient tools must be applied that combine mixture-based techniques to characterize protein-ligand interactions with the strengths of diversity-oriented chemical synthesis. 

Dooley, . T., Ny, P, Bidlack, J. M., Houghten, R. A. (1998) Selective ligands for the i, S, and opioid receptors identified from a single mixture based tetrapeptide positional scanning combinatorial library. / Biol Chem 273, 18848-18856. 

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

Preparation of Mixture-Based Synthetic Combinatorial Libraries... 

Two major techniques are generally employed in solid-phase chemistry to generate mixture-based synthetic combinatorial libraries (SCL) of millions of compounds. Multiple functionalities at diverse positions within the library are incorporated either by mixing multiple resins or by using mixtures of incoming reagents. 

Generally, when developing a mixture-based synthetic combinatorial library, reaction conditions for all the steps in the reaction scheme need to be optimized to achieve the widest possible breadth of diversity and... 

Using the DCR method, a mixture-based library of 95 mixtures of 48 benzothiazepine-5-ones 2 (Fig. 2) was produced in eight synthetic... 

Starting from resin-bound N-acylated dipeptides 11 having tryptophan or a tryptophan analog as the C-terminal amino acid, a mixture-based combinatorial library of 46,750 indolepyridoimidazoles 12 was synthesized by double cyclodehydration under Bischler-Napieralski conditions (POCl3, dioxane, 100°) (Fig. 4).23 Twenty-two tryptophan analogs, 25 amino acids, and 85 carboxylic acids were used for the library synthesis. 

This chapter is intended to provide an overview of the field of mixture-based combinatorial chemistry. It deals with reports of library preparation and utilization for the period from the beginning of 1995 to mid-1996. As this is the first Report in this planned series, some discussion of pre-1995 work will be included to set the proper context for the more recent work. The discussion will cover the methods of preparation of mixture-based libraries, the means of identifying actives from the mixtures, and the rationale for using mixtures. 

There have appeared a substantial number of reports on new organic syntheses being carried out on solid support. In general, these are important to mixture-based library production, but in a number of these reports the syntheses were not extended to produce actual libraries or were employed for the synthesis of arrays. For these reasons, these types of reports are beyond the scope of this chapter and will not be discussed. An effort has been made to include the important reports and patents describing actual libraries. 

The synthesis of mixture-based libraries in any of the various formats relies on the divide, couple, and recombine paradigm (Fig. 1) to assemble the mixture [13-15], In this method, the solid support is divided into appropriate portions, each portion is coupled... 

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