Alkyne Activation in the Diversity Oriented Synthesis of sp2-Rich Scaffolds: A Biased Library Approach for Targeting Polynucleotides (DNA/RNA)

Polynucleotides, DNA and RNA (mRNA and non-coding RNAs) are critically involved in the molecular pathways of disease. Small molecule binding interactions with polynucleotides can modify functional polynucleotide topologies and/or their interactions with proteins. Current approaches to library design (lead-like or fragment-like libraries) are based on protein-ligand interactions and often include careful consideration of the 3-dimensional orientation of binding motifs and exclude pi-rich compounds (polyfused aromatics) to avoid off-target R/DNA interactions. In contrast to proteins, where pi,pi-interactions are weak, polynucleotides can form strong pi,pi-interactions with suitable pi-rich ligands. To assist in designing a polynucleotide-biased library, a scaffold-divergent synthesis approach to polyfused aromatic scaffolds has been undertaken. Initial screening hits that form moderately stable polynucleotide-ligand-protein ternary complexes can be further optimized through judicious incorporation of substituents on the scaffold to increase protein-ligand interactions. An example of this approach is given for topoisomerase-1 (TOP1), generating a novel TOP1 inhibitory chemotype.

Automated summary

Polynucleotides, DNA, and RNA are crucial in disease molecular pathways. Designing a polynucleotide-biased compound library can modify polynucleotide topology and protein interactions, contributing to disease treatment.