A Practical Synthesis of Zanamivir Phosphonate Congeners with Potent Anti-influenza Activity

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• 作者：Jiun-Jie Shie ; Jim-Min Fang ; Po-Ting Lai ; Wen-Hsien Wen ; Shi-Yun Wang ; Yih-Shyun E. Cheng ; Keng-Chang Tsai ; An-Suei Yang ; Chi-Huey Wong
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：November 9, 2011
• 年：2011
• 卷：133
• 期：44
• 页码：17959-17965
• 全文大小：875K
• 年卷期：v.133,no.44(November 9, 2011)
• ISSN：1520-5126

文摘

Two phosphonate compounds 1a (4-amino-1-phosphono-DANA) and 1b (phosphono-zanamivir) are synthesized and shown more potent than zanamivir against the neuraminidases of avian and human influenza viruses, including the oseltamivir-resistant strains. For the first time, the practical synthesis of these phosphonate compounds is realized by conversion of sialic acid to peracetylated phosphono-DANA diethyl ester (5) as a key intermediate in three steps by a novel approach. In comparison with zanamivir, the high affinity of 1a and 1b can be partly attributable to the strong electrostatic interactions of their phosphonate groups with the three arginine residues (Arg118, Arg292, and Arg371) in the active site of neuraminidases. These phosphonates are nontoxic to the human 293T cells; they protect cells from influenza virus infection with EC₅₀ values in low-nanomolar range, including the wild-type WSN (H1N1), the 2009 pandemic (H1N1), the oseltamivir-resistant H274Y (H1N1), RG14 (H5N1), and Udorn (H3N2) influenza strains.