Synthesis of NSC 106084 and NSC 14778 and evaluation of their DNMT inhibitory activity

Maxime Leroy (1) , Léa Mélin (1) , Steven R. Laplante (2) , José L. Medina-Franco (3) , Alexandre Gagnon (4, 1)

1 Département de Chimie [Montréal]
2 INRS-IAF - Institut Armand Frappier
3 UNAM - Universidad Nacional Autónoma de México = National Autonomous University of Mexico
4 UQAM - Université du Québec à Montréal = University of Québec in Montréal

DNA methylation is an epigenetic modification that is performed by DNA methyltransferases (DNMTs) and that leads to the transfer of a methyl group from S-adenosylmethionine (SAM) to the C5 position of cytosine. This transformation results in hypermethylation and silencing of genes such as tumor suppressor genes. Aberrant DNA methylation has been associated with the development of many diseases, including cancer. Inhibition of DNMTs promotes the demethylation and reactivation of epigenetically silenced genes. NSC 106084 and 14778 have been reported to inhibit DNMTs in the micromolar range. We report herein the synthesis of NSC 106084 and 14778 and the evaluation of their DNMT inhibitory activity. Our results indicate that while commercial NSC 14778 is moderately active against DNMT1, 3A/3L and 3B/3L, resynthesized NSC 14778 is inactive under our assay conditions. Resynthesized 106084 was also found to be inactive.

Keywords: DNA methylation; DNA methyltransferase Inhibitors (DNMTi); DNA methyltransferases (DNMTs); NSC 106084; NSC 14778

Domains: Life Sciences [q-bio]

Maxime Leroy, Léa Mélin, Steven R. Laplante, José L. Medina-Franco, Alexandre Gagnon. Synthesis of NSC 106084 and NSC 14778 and evaluation of their DNMT inhibitory activity. Bioorganic and Medicinal Chemistry Letters, 2019, 29 (6), pp.826-831. ⟨10.1016/j.bmcl.2019.01.022⟩. ⟨pasteur-02136075⟩