Design and construction of a stereochemically diverse piperazine-based DNA-encoded chemical library

• Published in: Bioorganic & medicinal chemistry 2021-10, Vol.48, p.116387-116387, Article 116387
• Main Authors: Chamakuri, Srinivas, Chung, Mee-Kyung, Samuel, Errol L.G., Tran, Kevin A., Chen, Ying-Chu, Nyshadham, Pranavanand, Santini, Conrad, Matzuk, Martin M., Young, Damian W.
• Format: Article
• Language: English
• Subjects: Combinatorial Chemistry Techniques; DNA - drug effects; Drug Design; Encoded chemistry; Molecular Structure; Piperazines; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; sp3 rich compound collection; Stereochemical diversity; Stereogenic compounds; Stereoisomerism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116387

Here we report the successful construction of a novel, stereochemically diverse DNA-Encoded Chemical Library (DECL) by utilizing 24 enantiomerically pure trifunctional 2, 6- di-substituted piperazines as central cores. We introduce the concept of positional diversity by placing the DNA attachment at either of two possible sites on the piperazine scaffold. Using a wide range of building blocks, a diverse library of 77 million compounds was produced. Cheminformatic analysis demonstrates that this library occupies a wide swath of chemical space, and that the piperazine scaffolds confers different shape diversity compared to the commonly used triazine core. [Display omitted] Here we report the successful construction of a novel, stereochemically diverse DNA-Encoded Chemical Library (DECL) by utilizing 24 enantiomerically pure trifunctional 2, 6- di-substituted piperazines as central cores. We introduce the concept of positional diversity by placing the DNA attachment at either of two possible sites on the piperazine scaffold. Using a wide range of building blocks, a diverse library of 77 million compounds was produced. Cheminformatic analysis demonstrates that this library occupies a wide swath of chemical space, and that the piperazine scaffolds confers different shape diversity compared to the commonly used triazine core.