3-Halo-3-nitro-aza/thioflavanones: DNMT inhibitors with a two-site binding mode in the hDNMT3A catalytic pocket

Alexandra Serhouni; Francesco Calzaferri; Yannick Bessina; Arie van der Lee; Paola B Arimondo; Maxime Louet; Jean-Yves Winum; Marie Lopez

doi:10.1016/j.bmc.2024.117988

3-Halo-3-nitro-aza/thioflavanones: DNMT inhibitors with a two-site binding mode in the hDNMT3A catalytic pocket

Bioorg Med Chem. 2024 Nov 28:118:117988. doi: 10.1016/j.bmc.2024.117988. Online ahead of print.

Authors

Alexandra Serhouni¹, Francesco Calzaferri¹, Yannick Bessina¹, Arie van der Lee², Paola B Arimondo³, Maxime Louet¹, Jean-Yves Winum¹, Marie Lopez⁴

Affiliations

¹ Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS-Université de Montpellier-ENSCM, 1919 route de Mende, 34296 Montpellier cedex 5, France.
² Institut Européen des Membranes (IEM), UMR 5635 CNRS-Université de Montpellier, 300 avenue du Prof. E. Jeanbrau, 34296 Montpellier cedex 5, France.
³ Institut Pasteur, Université Paris Cité, CNRS UMR 3523 Chem4Life, Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, 75015 Paris, France.
⁴ Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS-Université de Montpellier-ENSCM, 1919 route de Mende, 34296 Montpellier cedex 5, France. Electronic address: [email protected].

PMID: 39689413
DOI: 10.1016/j.bmc.2024.117988

Abstract

Flavonoid derivatives are natural product analogues that have shown great interest for therapeutic applications as modulators of DNA methylation. In this article we report new synthesis pathways to access ten novel flavonoid derivatives (i.e. 3-halo-3-nitro-aza/thioflavanones) to be used as potential DNA methyltransferase inhibitors. These compounds have a micromolar inhibition against human DNA methyltransferase 3A in our in vitro fluorescence-based assay. Importantly, a docking study of representative compounds of this series in the enzyme pocket highlights a mode of interaction in the catalytic pocket of hDNMT3A that has never been described.

Keywords: Binding modes; DNA methylation; DNMT inhibitors; Epigenetics.