| Summary: | 碩士 === 國立臺灣大學 === 化學研究所 === 105 === Abstract
Influenza viruses cause yearly epidemics and occasionally more severe pandemics, which lead to high fatality The worldwide death toll of influenza epidemics is in the range of 250,000 to 500,000 each year.
Influenza A virus is characterized as different subtypes according to neuraminidase (NA) and hemagglutinin (HA). The anti-influenza drugs Tamiflu and Relenza act as NA inhibitors. Formation of ribonucleoprotein complexes (RNPs) in the nucleus of the host cell is one of the main causes of influenza A virus pathogenesis. RNPs are composed of RNA polymerase, RNA fragment and nucleoprotein (NP). Because NP is substantially more conserved, we chose to develop the anti-influenza drugs by disrupting the NP–NP interaction.
E339A...R416A salt bridge interaction between NP monomers is essential. A research team in Academia Sinica has previously conducted a high-throughput screening of the chemical library to identify some small molecules as anti-influenza agents by disrupting the NP–NP interaction. Based on the structure of compound A, we thus designed and synthesized small molecules that may disrupt the salt bridge interaction, and further impose on other interactions, including hydrogen bonding, hydrophobic interaction and π–π stacking interaction, to increase their inhibitory activities against influenza viruses. To verify the binding sites between NP monomers, we further synthesized the aryl azide derivatives for photoaffinity labeling experiments.
In this study, we first synthesized (1,1-diphenylmethyl)amino derivatives 13a and 13b replacing the morpholine group in the compound A. The benzylamino derivatives 22a and 22b were also synthesized. We further synthesized the 4-azidobenzylamino derivative 30, 1-phenyl-1-(4-azidophenyl)methylamino derivative 36 and 1,1-bis(4-azidophenyl)methylamino derivative 42 for photoaffinity labeling experiments. The MTS bioassay indicated that compound 13a had anti-influenza activity similar to compound A. The azido compounds 36 and 42 had good anti-influenza activity to serve as potential photoaffinity labeling probes. Nevertheless, the compounds 22a and 30 showed lower anti-influenza activity, and compound 13b and 22b were too hydrophobic to do bioassay.
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