title: Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors.
abstract: The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N-benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT-dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure-activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L-glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration-dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy. davide.garella@unito.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Garella
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Atlante
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
authors.forename: Emily
authors.initials: E
authors.lastname: Borretto
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Cocco
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Giorgis
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Costale
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Stevanato
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Miglio
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cencioni
authors.affiliation: Facultad de Química , Departamento de Farmacia, Universidad Nacional Autónoma de México, Mexico City, México.
authors.forename: Eli
authors.initials: E
authors.lastname: Fernández-de Gortari
authors.affiliation: Facultad de Química , Departamento de Farmacia, Universidad Nacional Autónoma de México, Mexico City, México.
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Spallotta
authors.affiliation: Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany. gaetano@em.uni-frankfurt.de.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bertinaria
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D018698:Glutamic Acid; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: DNA methylation; DNMT inhibitors; docking; epigenetics; structure-activity relationships