Departments of Chemistry and Immunology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bioorg Med Chem. 2010 Feb;18(3):1280-7. doi: 10.1016/j.bmc.2009.12.030. Epub 2009 Dec 22.
Botulinum neurotoxins (BoNTs) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. The natural product toosendanin, a limonoid, is a traditional Chinese medicine that has reported anti-botulinum properties in animal models. Toosendanin effectively inhibits the biological activity of BoNT/A in neuronal cells at concentrations of 200 nM, and partial inhibition can be observed with concentrations as low as 8 nM. Mechanistically, toosendanin's inhibition is due to prevention of transduction of the BoNT LC through the HC channel. Intriguing questions as to the molecular architecture of toosendanin as related to its anti-botulinum properties have focused our attention on a synthesis of toosendanin's unusual AB-ring, containing a unique bridged hemi-acetal. Within the current work, a synthetic strategy allowing access to the AB-fragment of toosendanin was achieved from a trans-decalin system. In addition, this fragment was examined for its modulation of BoNT/A intoxication in a rat spinal cord cellular assay.
肉毒神经毒素（BoNTs）是引起肉毒中毒的病原体，该病的特征是外周神经肌肉阻滞和人类典型的弛缓性瘫痪。天然产物川楝素是一种柠檬苦素，是一种中药，在动物模型中报告具有抗肉毒毒素的特性。川楝素在 200nM 的浓度下能有效抑制神经元细胞中 BoNT/A 的生物活性，在低至 8nM 的浓度下即可观察到部分抑制。从机制上讲，川楝素的抑制作用是由于阻止了 BoNT LC 通过 HC 通道的转导。关于川楝素作为抗肉毒毒素特性的分子结构的有趣问题引起了我们对其不寻常的 AB-环的合成的关注，其中包含独特的桥接半缩醛。在目前的工作中，从反式十氢萘系统中实现了一种合成策略，从而获得了川楝素的 AB-片段。此外，还在大鼠脊髓细胞测定中检查了该片段对 BoNT/A 中毒的调节作用。
