8-Triazolylpurines: Towards Fluorescent Inhibitors of the MDM2/p53 Interaction
Journal article, 2015

Small molecule nonpeptidic mimics of alpha-helices are widely recognised as protein-protein interaction (PPIs) inhibitors. Protein-protein interactions mediate virtually all important regulatory pathways in a cell, and the ability to control and modulate PPIs is therefore of great significance to basic biology, where controlled disruption of protein networks is key to understanding network connectivity and function. We have designed and synthesised two series of 2,6,9-substituted 8-triazolylpurines as alpha-helix mimetics. The first series was designed based on low energy conformations but did not display any biological activity in a biochemical fluorescence polarisation assay targeting MDM2/p53. Although solution NMR conformation studies demonstrated that such molecules could mimic the topography of an alpha-helix, docking studies indicated that the same compounds were not optimal as inhibitors for the MDM2/p53 interaction. A new series of 8-triazolylpurines was designed based on a combination of docking studies and analysis of recently published inhibitors. The best compound displayed low micromolar inhibitory activity towards MDM2/p53 in a biochemical fluorescence polarisation assay. In order to evaluate the applicability of these compounds as biologically active and intrinsically fluorescent probes, their absorption/emission properties were measured. The compounds display fluorescent properties with quantum yields up to 50%.

Author

Mariell Pettersson

University of Gothenburg

David Bliman

University of Gothenburg

Jimmy Jacobsson

University of Gothenburg

Jesper Nilsson

Chalmers, Chemistry and Chemical Engineering, Chemistry and Biochemistry, Physical Chemistry

J. Min

St. Jude Children Research Hospital

L. Iconaru

St. Jude Children Research Hospital

R. K. Guy

St. Jude Children Research Hospital

R. W. Kriwacki

St. Jude Children Research Hospital

Joakim Andreasson

Chalmers, Chemistry and Chemical Engineering, Chemistry and Biochemistry, Physical Chemistry

Morten Grötli

University of Gothenburg

PLoS ONE

1932-6203 (ISSN)

Vol. 10 5 e0124423- e0124423

Subject Categories

Chemical Sciences

DOI

10.1371/journal.pone.0124423

More information

Latest update

4/18/2018