title: A practical synthesis of zanamivir phosphonate congeners with potent anti-influenza activity.
abstract: 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.
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Jiun-Jie
authors.initials: JJ
authors.lastname: Shie
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Lai
authors.forename: Wen-Hsien
authors.initials: WH
authors.lastname: Wen
authors.forename: Shi-Yun
authors.initials: SY
authors.lastname: Wang
authors.forename: Yih-Shyun E
authors.initials: YS
authors.lastname: Cheng
authors.forename: Keng-Chang
authors.initials: KC
authors.lastname: Tsai
authors.forename: An-Suei
authors.initials: AS
authors.lastname: Yang
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053243:Zanamivir / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D009439:Neuraminidase; D053243:Zanamivir