Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Chemistry : a European journal, 2022-12, Vol.28 (71), p.e202201925-n/a

Ort / Verlag

Weinheim: Wiley Subscription Services, Inc

Erscheinungsjahr

2022

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• 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. The targeting of polynucleotide (RNA and DNA) topologies and their protein complexes by small molecules has enormous potential in the discovery of new therapeutics across a broad range of diseases (infectious, chronic and congenital). Polynucleotides are very different structures to proteins and have a much greater capacity to form strong π,π‐interactions with suitably π‐rich small molecules. To exploit this difference, we have developed a diversity‐oriented synthesis approach to π‐rich scaffolds from a common set of substrates. The utility of this approach has been exemplified in the discovery of a novel topoisomerase‐1 inhibitor.