Total synthesis of pinnatoxins A and G and revision of the mode of action of pinnatoxin A.
Total synthesis of pinnatoxins A and G and revision of the mode of action of pinnatoxin A.
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DOI：
10.1021/ja201254c
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发表时间：
2011-07-13
影响因子：
15
通讯作者：
Zakarian, Armen
中科院分区：
文献类型：
--
作者：
Araoz, Romulo;Servent, Denis;Molgo, Jordi;Iorga, Bogdan I.;Fruchart-Gaillard, Carole;Benoit, Evelyne;Gu, Zhenhua;Stivala, Craig;Zakarian, Armen
海松毒素属于一类新兴的环状亚胺类强效海洋毒素。由于无法从天然来源获得这种复杂的天然产品，因此阻碍了对其生物效应的详细研究。这项工作描述了一个强大的，可扩展的合成序列的发展依赖于一个收敛的策略，提供了足够量的毒素详细的生物学研究和商业化使用的其他研究小组和监管机构。合成中的一个中心转变是复杂的α，α-二取代烯丙基酯的高度非对映选择性的Ireland-Claisen重排，其基于通过底物和氨基锂碱之间的手性匹配进行立体选择性烯醇化的独特模式。对合成的羽叶毒素A进行了详细的研究，为它作为对人类神经元α7亚型具有选择性的烟碱乙酰胆碱受体的强效抑制剂的作用模式提供了确凿的证据。全面的电生理学，生物化学和计算研究支持的观点，即螺亚胺亚基的pinnatoxins是至关重要的阻断烟碱乙酰胆碱受体亚型，证明了分析的效果的合成类似物的pinnatoxin A含有开放形式的亚胺环。我们的研究为生产用于海洋基质中这些毒素的质谱测定的认证标准和开发检测受污染贝类中这些毒素的测试铺平了道路。
Pinnatoxins belong to an emerging class of potent marine toxins of the cyclic imine group. Detailed studies of their biological effects have been impeded by unavailability of the complex natural product from natural sources. This work describes the development of a robust, scalable synthetic sequence relying on a convergent strategy that delivered a sufficient amount of the toxin for detailed biological studies and its commercialization for use by other research groups and regulatory agencies. A central transformation in the synthesis is the highly diastereoselective Ireland–Claisen rearrangement of a complex α,α-disubstituted allylic ester based on a unique mode for stereoselective enolization through a chirality match between the substrate and the lithium amide base. With synthetic pinnatoxin A, a detailed study has been performed that provides conclusive evidence for its mode of action as a potent inhibitor of nicotinic acetylcholine receptors selective for the human neuronal α7 subtype. The comprehensive electrophysiological, biochemical, and computational studies support the view that the spiroimine subunit of pinnatoxins is critical for blocking nicotinic acetylcholine receptor subtypes, as evidenced by analyzing the effect of a synthetic analogue of pinnatoxin A containing an open form of the imine ring. Our studies have paved the way for the production of certified standards to be used for mass-spectrometric determination of these toxins in marine matrices and for the development of tests to detect these toxins in contaminated shellfish.
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