Alkyne Activation in the Diversity Oriented Synthesis of sp2 -Rich Scaffolds: A Biased Library Approach for Targeting Polynucleotides (DNA/RNA).
Chemistry
; 28(71): e202201925, 2022 Dec 20.
Article
in En
| MEDLINE
| ID: mdl-36069042
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polynucleotides
/
RNA
Language:
En
Journal:
Chemistry
Year:
2022
Document type:
Article