Rational Design and Synthesis of Highly Stable Haloflavanone DNA Methyltransferase Inhibitors Inducing Tumor Suppressor Gene Re-expression in Cancer Cells

DNA methylation is
an epigenetic modification involved in cancer.
The clinically approved nucleoside DNA methyltransferase (DNMT) inhibitors
5-azacytidine and 5-aza-2′-deoxycytidine lack selectivity and
stability, resulting in high toxicity. Previously, we discovered 3-halo-3-nitroflavanones
as non-nucleoside DNMT inhibitors. Here, we designed and synthesized
a new series of 2-substituted haloflavanones to increase compound
chemical stability. Moreover, replacement of the nitro by an additional
halogen enhanced compound potency. Indeed, compound 34b (anti-3-bromo-3-chloro-2-methoxyflavanone) exhibited
submicromolar DNMT3A inhibitory activity, upregulated the expression
of DNMT-targeted genes, and impaired cell proliferation. Importantly, 34b triggered a critical cell cycle arrest in the G1/S transition,
notably in p53-depleted HCT-116 colorectal cancer cells, which paves
the way for novel therapeutic opportunities. 34b competes
for the same DNMT catalytic pocket as confirmed by saturation transfer
difference-nuclear magnetic resonance, but assuming different docking
poses as shown by computational studies. Overall, the high stability
and activity of 34b make it a promising DNMT inhibitor
for anticancer research and therapy.