Rapid synthesis of new DNMT inhibitors derivatives of procainamide.

Ludovic Halby , Christine Champion , Catherine Sénamaud-Beaufort , Sophie Ajjan , Thierry Drujon (1) , Arumugam Rajavelu , Alexandre Ceccaldi , Renata Jurkowska , Olivier Lequin (2) , William G Nelson , Alain Guy , Albert Jeltsch , Dominique Guianvarc'H (1, 2, 3) , Clotilde Ferroud , Paola B Arimondo

1 UPMC - Université Pierre et Marie Curie - Paris 6
2 SSFMB - Synthèse, Structure et Fonction de Molécules Bioactives
3 LCMCP (site Paris VI) - Laboratoire de Chimie de la Matière Condensée de Paris (site Paris VI)

DNA methyltransferases (DNMTs) are responsible for DNA methylation, an epigenetic modification involved in gene regulation. Families of conjugates of procainamide, an inhibitor of DNMT1, were conceived and produced by rapid synthetic pathways. Six compounds resulted in potent inhibitors of the murine catalytic Dnmt3A/3L complex and of human DNMT1, at least 50 times greater than that of the parent compounds. The inhibitors showed selectivity for C5 DNA methyltransferases. The cytotoxicity of the inhibitors was validated on two tumour cell lines (DU145 and HCT116) and correlated with the DNMT inhibitory potency. The inhibition potency of procainamide conjugated to phthalimide through alkyl linkers depended on the length of the linker; the dodecane linker was the best.

Domaines: Chimie organique

Ludovic Halby, Christine Champion, Catherine Sénamaud-Beaufort, Sophie Ajjan, Thierry Drujon, et al.. Rapid synthesis of new DNMT inhibitors derivatives of procainamide.. ChemBioChem, 2012, 13 ((1)), pp.157-65. ⟨10.1002/cbic.201100522⟩. ⟨hal-00680950⟩