tetano
Editor, Senior Moderator
J Am Chem Soc. 2011 Sep 26. [Epub ahead of print]
A Practical Synthesis of Zanamivir Phosphonate Congeners with Potent Anti-influenza Activity.
Shie JJ, Fang JM, Lai PT, Wen WH, Wang SY, Cheng YS, Tsai KC, Yang AS, Wong CH.
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 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.
PMID:
21942552
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/21942552
A Practical Synthesis of Zanamivir Phosphonate Congeners with Potent Anti-influenza Activity.
Shie JJ, Fang JM, Lai PT, Wen WH, Wang SY, Cheng YS, Tsai KC, Yang AS, Wong CH.
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 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.
PMID:
21942552
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/21942552