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

Shuqi Chen, Daniel L. Priebbenow, Julie Somkhit, Carmen V. Scullino, Keli Agama, Yves Pommier, Bernard L. Flynn

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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.

Original languageEnglish
Article numbere202201925
Number of pages11
JournalChemistry - A European Journal
Issue number71
Publication statusPublished - 20 Dec 2022


  • alkynes
  • electrophilic cyclization
  • polynucleotides
  • topoisomerase

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