Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5鈥?Monophosphate Decarboxylase

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• 作者：Melissa Lewis ; Maria Elena Meza-Avina ; Lianhu Wei ; Ian E. Crandall ; Angelica Mara Bello ; Ewa Poduch ; Yan Liu ; Christopher J. Paige ; Kevin C. Kain ; Emil F. Pai ; Lakshmi P. Kotra
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2891-2901
• 全文大小：1149K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

Fluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists because of their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2鈥?deoxy-2鈥?fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine 5鈥?monophosphate decarboxylase (ODCase or OMPDCase). These compounds were synthesized from the key intermediate, fully protected 2鈥?deoxy-2鈥?fluorouridine. Among the synthesized compounds, 2鈥?deoxy-2鈥?fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 卤 0.02 M^鈭? s^鈭?. Interestingly, the 6-cyano-2鈥?fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2鈥?fluoro moiety influences the chemistry at the C6 position of the nucleotides and thus interactions in the active site of ODCase. Molecular interactions of the 2鈥?fluorinated nucleotides are compared to those with the 3鈥?fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations.