Expanding the scope of native chemical ligation - templated small molecule drug synthesis via benzanilide formation.

ABSTRACT: We describe a reaction system that enables the synthesis of Bcr-Abl tyrosine kinase inhibitors (TKI) via benzanilide formation in water. The reaction is based on native chemical ligation (NCL). In contrast to previous applications, we used the NCL chemistry to establish aromatic rather than aliphatic amide bonds in coupling reactions between benzoyl and o-mercaptoaniline fragments. The method was applied for the synthesis of thiolated ponatinib and GZD824 derivatives. Acid treatment provided benzothiazole structures, which opens opportunities for diversification. Thiolation affected the affinity for Abl1 kinase only moderately. Of note, a ponatinib-derived benzothiazole also showed nanomolar affinity. NCL-enabled benzanilide formation may prove useful for fragment-based drug

SUBMITTER: Houska R 

PROVIDER: S-EPMC8528049 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature