Synthesis and Biochemical Evaluation of 螖2-Isoxazoline Derivatives as DNA Methyltransferase 1 Inhibitors

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• 作者：Sabrina Castellano ; Dirk Kuck ; Monica Viviano ; Jakyung Yoo ; Fabian L贸pez-Vallejo ; Paola Conti ; Lucia Tamborini ; Andrea Pinto ; Jos茅 L. Medina-Franco ; Gianluca Sbardella
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7663-7677
• 全文大小：1219K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

A series of 螖²-isoxazoline constrained analogues of procaine/procainamide (7a鈥?b>k and 8a鈥?b>k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC₅₀ = 150 渭M) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.