Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Fax: (+65) 67911961.
Chemistry. 2010 Apr 19;16(15):4533-40. doi: 10.1002/chem.200902048. Epub 2010 Mar 9.
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.
达菲（Tamiflu）目前是治疗流感最有效的药物，但该药供应不足且存在副作用，这需要紧急解决。我们采用新型合成路线、廉价试剂和丰富易得的起始原料 D-葡萄糖醛酸，提出了一种达菲的实用合成方法。该策略的特点是通过糖的克莱森重排获得环己烯骨架，并通过串联的分子内氮丙啶化和开环反应引入二氨基。此外，该合成方案允许进行后期的官能团化，以灵活合成达菲类似物。通过使用合成的达菲及其活性代谢物（奥司他韦羧酸），我们从多个方面研究了它们对神经内分泌 PC12 细胞的影响。结果发现，奥司他韦羧酸能显著抑制 PC12 细胞的囊泡胞吐（调节分泌），这提示了达菲副作用的作用机制，特别是其对中枢神经系统神经递质释放的潜在不良影响。
