Introduction to Layout of Library

This proposal describes molecular libraries derived from imidazole-4,5-dicarboxylic acid (I45DA), an ideal scaffold for the design of bioactive compounds due to the structural and conformational features of derivatives that mimic bioactive structures such as peptides, proteins, and nucleic acid bases. In addition, the synthesis of I45DA derivatives is straightforward, requiring just three synthetic steps to give the target product for many library members in this proposal. Replenishing a supply of bioactive compound will therefore be easy. The imidazole ring in all compounds provides one site for derivatization with a bioassay probe. We have also included protected amines in substituents in order to yield a subset of the total library with another handle for derivatization with probes following deprotection. Likewise, I45DA derivatives with amino acid esters provide a different subset, albeit with partial overlap to the amines, and have a carboxylic acid for derivatization following deprotection. Secondary libraries to further probe structure-activity relationships or to identify exposed and tolerant sites for adding fluorescent probes, biotin, or other useful tags are easy to design for all compounds in the proposal. These derivatives will be equally uncomplicated to prepare as those highlighted in this work. The three specific aims describe the synthesis, purification, and characterization of distinct classes of I45DA derivatives to yield an approximate total of 1700 compounds. The success of these specific aims will result in valuable and informative small molecule libraries for the discovery of biological tools for the study of the cell and cellular pathways. These compounds will be submitted to the NIH repository for use in screening through the Molecular Libraries Screening Center Network (MLSCN).
The specific aims to advance this objective are detailed below.
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Specific Aim 1

We will synthesize, purify, and characterize 719 imidazole-4,5-dicarboxylic acid (I45DA) derivatives to include new monomeric, symmetrically N,N'-disubsituted (sI45DCs) and dissymetrically N,N'-disubstituted imidazole-4,5-dicarboxamides (dI45DC), I45DA-based ester-amide combinations (I45EA), and I45DA-based diesters (I45DE). These libraries represent those useful for identifying inhibitors of kinases, receptors, ion channels, cytoskeletal proteins, and enzymes.
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Specific Aim 2

We will synthesize, purify, and characterize a maximum of 44 imidazole ring alkylated derivatives, 322 deprotected amine and ester derivatives from specific aim 1, and up to 50 substituent derivatized compounds from a few selected bioactive derivatives. These ring alkylated analogs will be prepared from sI45DC members and a few (< 20) dissymmetrically disubstituted compounds of specific aim 1. The deprotected compounds will include all unique and singly protected derivatives from specific aim 1. The substituent derivatized compounds will be prepared from identified bioactive compounds in specific aim 1 or from those in our preliminary results, and will be modified to include groups such as biotin, fluorescent probes, or other labels in order to help develop the compound into a useful biochemical tool.
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Specific Aim 3

We will synthesize, purify, and characterize 63 bis- and tris-I45DCs, as well as 441 linear oligomers containing two I45DCs. These compounds are of sufficient size and have preferred conformations that help them to mimic small protein surfaces. As such, they will be the useful compounds for identifying inhibitors of protein-protein interactions in order to disrupt cellular signaling or processes.
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