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Synthesis and Elaboration of N-methylpyrrolidone as an Acetamide Fragment Substitute in Bromodomain Inhibition

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

Bioorg Med Chem. 2019 Dec 15;27(24):115157.

PMID: 31727451

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4244413	Olinone			Price

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