This proposal aims to synthesize a library of compounds that are pre-disposed to inhibit peptidylarginine deiminases (PADs), enzymes that have recently been implicated in chromatin modification. In concert with the known small molecule inhibitors of histone deacetylaces (tubacin) and peptidylarginine methyl transferases, these compounds may enable the dissection of these epigenetic marks and their implications in gene regulation and oncogenesis. Enzymes that modify arginine generally accept the free amino acid as controlled by a guarded active site. Recent crystallographic evidence shows that PADs have a region around the active site that recognizes peptide substrates. It may be generalized that this binding surface is isoform specific, between PADs1-4, allowing the selective recognition of target proteins by small molecules. Having no known specific inhibitors, we wish to exploit diversity oriented synthesis to generate a library of compounds that explore binding interactions with this peptide recognition surface. Elaborating a novel Rh(ll) catalyzed folding pathway, six distinct molecular skeletons will be prepared.
We aim to exploit a Cu(l) catalyzed cycloaddition reaction to terminate these skeletons with arginine pharmacophores. For screening purposes, this collection of potential inhibitors will be synthesized on a platform capable of delivering up to 20 mg of compound, greatly expediting the process of validating their biological activity. ? ?
