Work

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

Year: 2024

Type: article

Abstract: • Synthesis pathways were established for the synthesis of 3-halo-3-nitro-aza/thioflavanones and a series of ten compounds was synthesised. • Enzyme assays showed a micromolar activities of 3-halo-3-nitro-aza/thioflavanones against DNMT3A-c. • A two-site binding mode of interaction was evidenced by molecular docking. 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 h DNMT3A that has never been described.

Source: Bioorganic & Medicinal Chemistry

DOI: 10.1016/j.bmc.2024.117988