title: Rapid synthesis of new DNMT inhibitors derivatives of procainamide.
abstract: 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.
authors.affiliation: CNRS-MNHN UMR 7196 INSERM U565, Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Halby
authors.forename: Christine
authors.initials: C
authors.lastname: Champion
authors.forename: Catherine
authors.initials: C
authors.lastname: Sénamaud-Beaufort
authors.forename: Sophie
authors.initials: S
authors.lastname: Ajjan
authors.forename: Thierry
authors.initials: T
authors.lastname: Drujon
authors.forename: Arumugam
authors.initials: A
authors.lastname: Rajavelu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ceccaldi
authors.forename: Renata
authors.initials: R
authors.lastname: Jurkowska
authors.forename: Olivier
authors.initials: O
authors.lastname: Lequin
authors.forename: William G
authors.initials: WG
authors.lastname: Nelson
authors.forename: Alain
authors.initials: A
authors.lastname: Guy
authors.forename: Albert
authors.initials: A
authors.lastname: Jeltsch
authors.forename: Dominique
authors.initials: D
authors.lastname: Guianvarc'h
authors.forename: Clotilde
authors.initials: C
authors.lastname: Ferroud
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011342:Procainamide / Q000031:analogs & derivatives* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004248:DNA (Cytosine-5-)-Methyltransferases; D011342:Procainamide