A unified "top-down" approach for the synthesis of diverse lead-like molecular scaffolds

Chloe Townley; Lindsay McMurray; Stephen P Marsden; Adam Nelson

doi:10.1016/j.bmcl.2022.128631

A unified "top-down" approach for the synthesis of diverse lead-like molecular scaffolds

Bioorg Med Chem Lett. 2022 Apr 15:62:128631. doi: 10.1016/j.bmcl.2022.128631. Epub 2022 Feb 16.

Authors

Chloe Townley¹, Lindsay McMurray², Stephen P Marsden³, Adam Nelson⁴

Affiliations

¹ School of Chemistry, University of Leeds, Leeds LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
² Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK.
³ School of Chemistry, University of Leeds, Leeds LS2 9JT, UK. Electronic address: [email protected].
⁴ School of Chemistry, University of Leeds, Leeds LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. Electronic address: [email protected].

PMID: 35181466
DOI: 10.1016/j.bmcl.2022.128631

Abstract

A "top-down" synthetic approach enabled the step-efficient synthesis of 21 diverse novel molecular scaffolds. The scaffolds were derived from four complex intermediates that had been prepared using cycloaddition chemistry. Scaffold-hopping of these intermediates was achieved through attachment of an additional ring, ring cleavage, ring expansion and/or ring fusion. It was shown that the resulting scaffolds could be decorated to yield diverse lead-like screening compounds.

Keywords: Molecular diversity; Molecular scaffolds; Screening compounds.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cycloaddition Reaction
Molecular Structure*