ABSTRACT
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.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Drug Design , Pyrrolidinones/pharmacology , Transcription Factors/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Fluorescence Resonance Energy Transfer , Humans , Models, Molecular , Molecular Structure , Pyrrolidinones/chemistry , Structure-Activity Relationship , Transcription Factors/metabolismABSTRACT
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.
Subject(s)
Cell Cycle Proteins/chemistry , Drug Design , Pyrrolidinones/chemical synthesis , Transcription Factors/chemistry , Binding Sites , Cell Cycle Proteins/metabolism , Crystallography, X-Ray , Fluorescence Resonance Energy Transfer , Gene Expression Regulation/drug effects , Humans , Models, Molecular , Molecular Structure , Protein Binding , Protein Conformation , Pyrrolidinones/chemistry , Structure-Activity Relationship , Transcription Factors/metabolismABSTRACT
Kisspeptin analogues with improved metabolic stability may represent important ligands in the study of the kisspeptin/KISS1R system and have therapeutic potential. In this paper we assess the activity of known and novel kisspeptin analogues utilising a dual luciferase reporter assay in KISS1R-transfected HEK293T cells. In general terms the results reflect the outcomes of other assay formats and a number of potent agonists were identified among the analogues, including ß(2) -hTyr-modified and fluorescently labelled forms. We also showed, by assaying kisspeptin in the presence of protease inhibitors, that proteolysis of kisspeptin activity within the reporter assay itself may diminish the agonist outputs. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.