Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition

J. P. Hilton-Proctor, O. Ilyichova, Z. Zheng, I. G. Jennings, R. W. Johnstone, J. Shortt, S. J. Mountford, M. J. Scanlon, P. E. Thompson

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N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.

Original languageEnglish
Article number115157
Number of pages9
JournalBioorganic & Medicinal Chemistry
Issue number24
Publication statusPublished - 15 Dec 2019


  • Acetyl-lysine
  • BRD4
  • Bromodomain
  • Fragment-based drug design
  • N-Methylpyrrolidone
  • NMP
  • Olinone

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