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. © 2016 John Wiley & Sons A/S.

Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors / Garella, Davide; Atlante, Sandra; Borretto, Emily; Cocco, Mattia; Giorgis, Marta; Costale, Annalisa; Stevanato, Livio; Miglio, Gianluca; Cencioni, Chiara; Fernández-de Gortari, Eli; L Medina-Franco, José; Spallotta, Francesco; Gaetano, Carlo; Bertinaria, Massimo. - In: CHEMICAL BIOLOGY & DRUG DESIGN. - ISSN 1747-0285. - 88:(2016), pp. 664-676. [10.1111/cbdd.12794]

Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors

Francesco Spallotta;
2016

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. © 2016 John Wiley & Sons A/S.
2016
DNA methylation; DNMT inhibitors; docking; epigenetics; structure–activity relationships
01 Pubblicazione su rivista::01a Articolo in rivista
Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors / Garella, Davide; Atlante, Sandra; Borretto, Emily; Cocco, Mattia; Giorgis, Marta; Costale, Annalisa; Stevanato, Livio; Miglio, Gianluca; Cencioni, Chiara; Fernández-de Gortari, Eli; L Medina-Franco, José; Spallotta, Francesco; Gaetano, Carlo; Bertinaria, Massimo. - In: CHEMICAL BIOLOGY & DRUG DESIGN. - ISSN 1747-0285. - 88:(2016), pp. 664-676. [10.1111/cbdd.12794]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1680074
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