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 for¬mation in water. The reaction is based on the native chemical ligation (NCL). Contrary to previous applications, we used the NCL chemistry to establish aromatic rather than aliphatic amide bonds in coupling reactions between benzoyl and o mercapto¬aniline 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 benz¬anilide formation may prove useful for fragment-based drug discovery. To show that benzanilide synthesis can be put under the control of a template, we connected the benzoyl and o-mercaptoaniline fragments to DNA and peptide nucleic acid (PNA) oligomers. Complementary RNA templates enabled adjacent binding of reactive conjugates triggering a rapid benzoyl transfer from a thioester-linked DNA conjugate to an o-mercaptoaniline-DNA or -PNA conjugate. We evaluated the influence of linker length and unpaired spacer nucleotides within the RNA template on the product yield. The data suggest that nucleic acid-templated benzanilide formation could find application in the establishment of DNA-encoded combinatorial libraries (DEL).

Article information

Article type
Edge Article
Submitted
27 Jan 2021
Accepted
10 Sep 2021
First published
14 Sep 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021, Accepted Manuscript

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

R. Houska, M. B. Stutz and O. Seitz, Chem. Sci., 2021, Accepted Manuscript , DOI: 10.1039/D1SC00513H

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