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Synthesis, Enzyme Assays and Molecular Docking Studies of Fluorina ted Bioisosteres of Santacruzamate A as Potential HDAC Tracers

[ Vol. 14 , Issue. 7 ]

Author(s):

Muneer Ahamed, Koen Vermeulen, Michael Schnekenburger, Lise Roman Moltzau, Finn Olav Levy, Janos Marton, Mathy Froeyen, Dag Erlend Olberg, Marc Diederich and Guy Bormans   Pages 787 - 797 ( 11 )

Abstract:


Background: Histone deacetylases (HDACs) emerged as important epigenetic regulators of gene expression.

Method: In order to identify potential positron emission tomography (PET) tracers for imaging HDACs, we evaluated in vitro and in cellulo activities of some compounds that were reported as potent HDAC2-selective inhibitors. We observed marked differences between reported activity values and the values obtained in our assays for some of the compounds. To understand the structural basis of the activity of some of these inhibitors, we also performed molecular docking studies to understand their interaction patterns and binding modes with HDAC2.

Results and Conclusion: We observed the low affinity compounds 4, 6 and 7 did not showed equal number of key π-π interactions and hydrogen bonding when compared to high affinity compounds, and could be the possible reason for poor inhibition as reflected in in vitro assays. These preliminary experimental and computational results will help to interpret the HDAC affinity values of these key compounds with caution.

Keywords:

HDAC inhibitors, enzyme assays, molecular docking, PET tracers, HDAC, in vitro.

Affiliation:

Laboratory of Radiopharmaceutical Research, KU Leuven, Leuven, Laboratory of Radiopharmaceutical Research, KU Leuven, Leuven, Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, ABX advanced biochemical compounds, Biomedizinische Forschungsreagenzien GmbH, Radeberg, Laboratory for Medicinal Chemistry, Rega Institute of Medical Research, KU Leuven, Leuven, School of Pharmacy, University of Oslo and Norwegian Medical Cyclotron Centre, Oslo, Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea and Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Laboratory of Radiopharmaceutical Research, KU Leuven, Leuven

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