Non-coding RNAs (ncRNAs) are essential in many important cellular processes and are highly misregulated in numerous diseases. One example, HOX antisense intergenic RNA (HOTAIR), is overexpressed in metastatic cancer, and overexpression in mouse models leads to a significant increase in metastasis. Despite the recent discovery of therapeutically relevant ncRNAs, there are no FDA-approved drugs that target RNA, excluding antimicrobials that recognize the ribosome. Currently, most RNA-based, small molecule screens utilize commercially available libraries, which are proposed to be biased to protein binding, leading to low hit rates and the identification of promiscuous ligands with limited efficacy in vivo. Therefore, we herein describe the design, synthesis, and evaluation of an RNA-targeted small molecule library based on the oxazolidinone core, a privileged RNA binding scaffold that has been shown to recognize the bulge motifs of ribosomal RNA and the T-box riboswitch. Two synthetic routes are being explored toward oxazolidinone-based scaffolds with the ability to be diversified at the N3, C4, and C5 positions. One synthesis begins with a mono-protected 3-butene-1,2-diol. After conversion to an azidoformate, iron-catalyzed cyclization yields a scaffold with three orthogonal functional groups for diversification—an amine at the N3, methylene chloride at the C4, and protected alcohol at the C5. The second synthesis incorporates Boc-protected chiral amino acid methyl esters that are cyclized via a brominated intermediate to form a tri-substitutable scaffold. The scaffold is diversified utilizing the amine at the N3, a methyl ester at the C4, and the side chain of the amino acid defines the C5. To date, five diversity-oriented oxazolidinone scaffolds have been synthesized and eleven small molecules have been characterized. The oxazolidinone library is currently being screened against established, bulge-containing targets, including the bacterial T-Box riboswitch, HIV-1 TAR and hepatitis C virus IRES, and an underexplored RNA target, HOTAIR. Once screening is complete, chemoinformatics will be used to identify chemical properties that lead to selective RNA recognition, non-specific RNA recognition, or inability to bind RNA. At the conclusion of this work, an RNA-targeted library will have been screened against multiple disease-relevant RNA molecules, which will facilitate the identification of chemical properties required to recognize RNA with small molecules.

Oxazolidinone-based small molecule libraries for the selective recognition of therapeutically relevant RNA

251st National Meeting (2016)

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