Journal article

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

JP Hilton-Proctor, O Ilyichova, Z Zheng, IG Jennings, RW Johnstone, J Shortt, SJ Mountford, MJ Scanlon, PE Thompson

Bioorganic & Medicinal Chemistry | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2019

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 an..

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Grants

Funding Acknowledgements

This work was supported by a Research Training Program scholarship from the Monash Institute of Pharmaceutical Sciences, NHMRC project, program and fellowship grants, and a Cancer Council Victoria Venture Grant. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and the Australian Cancer Research Foundation (ACRF) detector. Initial crystallisation screens were carried out at the CSIRO Collaborative Crystallisation Centre (www.csiro.au/C3) in Melbourne, Australia.