Alkyne Activation in the Diversity Oriented Synthesis of sp(2)‐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 π‐rich compounds (polyfused aromatics) to avoid off‐target R/DNA interactions. In contrast to proteins, where π,π‐interactions are weak, polynucleotides can form strong π,π‐interactions with suitable π‐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.