The Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
J Am Chem Soc. 2011 Nov 9;133(44):17959-65. doi: 10.1021/ja207892q. Epub 2011 Oct 14.
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 EC(50) 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.
合成了两种膦酸酯化合物 1a（4-氨基-1-膦酸-DANA）和 1b（膦酸扎那米韦），并证明它们比扎那米韦对禽源和人流感病毒的神经氨酸酶更有效，包括奥司他韦耐药株。首次通过一种新方法，将唾液酸转化为三乙酰基膦酸-DANA 二乙酯（5）作为关键中间体，在三步中实现了这些膦酸酯化合物的实际合成。与扎那米韦相比，1a 和 1b 的高亲和力部分归因于其膦酸基团与神经氨酸酶活性位点中的三个精氨酸残基（Arg118、Arg292 和 Arg371）之间的强静电相互作用。这些膦酸酯对人 293T 细胞没有毒性；它们能以低纳摩尔浓度的 EC50 值保护细胞免受流感病毒感染，包括野生型 WSN（H1N1）、2009 年大流行（H1N1）、奥司他韦耐药的 H274Y（H1N1）、RG14（H5N1）和 Udorn（H3N2）流感株。
