Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 3; pp. 1124 - 1127
• Main Authors: Suzuki, Takayoshi, Tanaka, Rikako, Hamada, Shohei, Nakagawa, Hidehiko, Miyata, Naoki
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.02.2010; Elsevier
• Subjects: Antineoplastic agents; Biological and medical sciences; Crystallography, X-Ray; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methyltransferase; Drug Design; General aspects; Humans; Indoles - chemistry; Indoles - metabolism; Inhibitor; Maleimides - chemical synthesis; Maleimides - metabolism; Medical sciences; Non-nucleoside; Pharmacology. Drug treatments; Phthalimides; Propionates - chemistry; Propionates - metabolism; Protein Binding - physiology; Tryptophan - analogs & derivatives; Non-nucleoside; DNA methyltransferase; Inhibitor; Enzyme; Transferases; Non nucleoside compound; Active site; DNA (cytosine-5-)-methyltransferase; Biological activity; Imide; Methyltransferases; Carboxylic acid; Binding mode; Indole derivatives; Chemical synthesis; Conformation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.12.016

To identify novel non-nucleoside DNA methyltransferase (DNMT) inhibitors, we designed and synthesized a series of maleimide derivatives. Among this series, compounds 5– 8 were found to be more potent DNMT1 inhibitors than RG108, a DNMT1 inhibitor reported previously by Siedlecki et al. To identify novel non-nucleoside DNA methyltransferase (DNMT) inhibitors, we designed and synthesized a series of maleimide derivatives. Among this series, compounds 5– 8 were found to be more potent DNMT1 inhibitors than RG108, a DNMT1 inhibitor reported previously by Siedlecki et al. The binding mode analysis of compound 5 is also reported.