Despite the discovery of many therapeutically relevant RNAs, there are no FDA-approved drugs that target RNA, excluding selected antimicrobials, which recognize the most abundant RNA—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 for RNA and the identification of promiscuous ligands with limited efficacy <i>in vivo</i>. Therefore, the goal of this work is to identify RNA-privileged physicochemical and spatial properties, design an RNA-biased library, and synthesize RNA-targeted small molecules. To begin, a database of bioactive, RNA-binding ligands (RVD) was compiled from the literature with activity in cell culture and/or mouse models. Chemoinformatic parameters and principal moments of inertia vectors were calculated and compared to FDA-approved drugs, general RNA-binding ligands, and screening libraries to distinguish key two-dimensional properties and the molecular shape of the ligands, respectively. Three key guiding principals emerged for bioactive RNA ligands: i) compliance to medicinal chemistry rules; ii) an increase in nitrogen atom count and ligand rigidity; and iii) a statistically significant shift in rod-like character. To incorporate these properties into a synthetic combinatorial library, REtrosynthetic Combinatorial Analysis Procedure was used to fragment the RVD into building blocks, which inspired the selection and purchase of amine-based subunits. Using these subunits, a theoretical library of 2500 small molecules was generated based on a designed oxazolidinone scaffold, a RNA-privileged core with known biological activity. The small molecules that reflected the identified guiding principals were selected for synthesis. The novel scaffold was synthesized from 3-butene-1,2-diol, where the primary alcohol is first protected and the secondary alcohol is then converted to a trichloroacetyl carbamate. A copper-assisted palladium cyclization yields the oxazolidinone-based scaffold, where both protecting groups are removed under mild conditions. Utilizing the subunits, orthogonal substitution is achieved at two positions, as well as oxidation followed by amide coupling for synthesis of the selected library. The methodology developed in this work can be applied to additional RNA-privileged scaffolds to synthesize diverse RNA-targeted libraries for the discovery of novel RNA-based chemical probes and therapeutics.

Chemoinformatic-driven design and synthesis of an RNA-targeted small molecule library

254th National Meeting (2017)

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