Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors.
Chem Biol Drug Des
; 88(5): 664-676, 2016 11.
Article
em En
| MEDLINE
| ID: mdl-27225604
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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DNA (Citosina-5-)-Metiltransferases
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Inibidores Enzimáticos
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Aminoácidos
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article