Substituted 1-methyl-4-phenylpyrrolidin-2-ones - Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors
JP Hilton-Proctor, O Ilyichova, Z Zheng, IG Jennings, RW Johnstone, J Shortt, SJ Mountford, MJ Scanlon, PE Thompson
European Journal of Medicinal Chemistry | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Published : 2020
N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue - 1-methyl-4-phenylpyrrolidin-2-one - and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.
This work was supported by a Research Training Program scholarship from the Monash Institute of Pharmaceutical Sciences 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 made use of the Australian Cancer Research Foundation (ACRF) detector. We thank Mr Ali Noor for technical assistance in the conduct of BRD4 binding assays.