Sugar-based synthesis of Tamiflu and its inhibitory effects on cell secretion.
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.
Ma
Jimei
J
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Fax: (+65) 67911961.
Zhao
Yanying
Y
Ng
Simon
S
Zhang
Jing
J
Zeng
Jing
J
Than
Aung
A
Chen
Peng
P
Liu
Xue-Wei
XW
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002125:Calcium Gluconate / Q000737:chemistry*; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy*; D053139:Oseltamivir / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects
D000998:Antiviral Agents; D053139:Oseltamivir; C535162:oseltamivir carboxylate; D002125:Calcium Gluconate