期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 16, 期 15, 页码 4533-4540出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.200902048
关键词
carbohydrates; cell secretion; inhibitors; tamiflu; total synthesis
资金
- Nanyang Technological University [RG 50/08]
- Ministry of Education, Singapore [T206B3220]
Tamiflu is currently the most effective drug for the treatment of influenza, but the insufficient supply and side-effects of this drug demand urgent solutions. We present a practical synthesis of Tamiflu by using novel synthetic routes, cheap reagents, and the abundantly available starting material D-glucal. The strategy features a Claisen rearrangement of hexose to obtain the cyclohexene backbone and introduction of diamino groups through tandem intramolecular aziridination and ring opening. In addition, this synthetic protocol allows late-stage functionalization for the flexible synthesis of Tamiflu analogues. By using the synthesized Tamiflu and its active metabolite (oseltamivir carboxylate), we investigated their influences on neuroendocrine PC12 cells in various aspects. It was discovered that oseltamivir carboxylate significantly inhibits the vesicular exocytosis (regulated secretion) of PC12 cells, and suggests a mechanism underlying the Tamiflu side-effects. in particular its possible adverse influences on neurotransmitter release in the central nervous system.
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