A practical synthesis of the Chinese "nootropic" agent huperzine A: a possible lead in the treatment of Alzheimer's disease
A practical synthesis of the Chinese "nootropic" agent huperzine A: a possible lead in the treatment of Alzheimer's disease
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DOI：
10.1021/ja00193a062
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发表时间：
1989-05
影响因子：
15
通讯作者：
Yan Xia;A. Kozikowski
中科院分区：
文献类型：
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作者：
Yan Xia;A. Kozikowski
本文报道了生物碱石杉碱甲的首次全合成。[1]这种三环系统代表了自然界对人类的促智剂的贡献之一。2在中国进行的研究中，石杉碱甲被发现可以改善动物模型的记忆和学习。[3]实际上，石杉碱甲可以改善患有各种形式记忆障碍的老年人的记忆。4药理学上，石杉碱甲是一种有效的降解酶乙酰胆碱酯酶抑制剂，对红细胞膜乙酰胆碱酯酶的PI 50为7.2。5在分子图形比较中，乙酰胆碱在完全伸展的180，180）构象中的杂原子与石杉碱甲的杂原子重叠得很好。这种延伸构象被认为是在乙酰胆碱酯酶水解过程中起作用的构象。[6]石杉碱甲的活性实际上比其他已被证实的乙酰胆碱酯酶抑制剂，如毒扁豆碱和新斯的明更强。此外，石杉碱甲在高等灵长类动物中的记忆促进作用已在美国和瑞士的研究中得到证实。乙酰胆碱在我们的计划中，旨在改善自然界对一种促智剂的原始贡献，我们设计了一种短而实用的途径来获得这种分子。下面描述的这种途径足够灵活，可以生产各种结构类似物。7
In this article we report the first total synthesis of the alkaloid huperzine A. 1 This tricyclic system represents one of nature’s own contributions of a nootropic agent to mankind. 2 In studies carried out in China, huperzine A was found to improve memory and learning in animal models. 3 Of substantial interest was the finding that huperzine A could, in fact, improve memory in aged individuals suffering from various forms of memory impairment. 4 Pharmacologically, huperzine A functions as a potent inhibitor of the degradative enzyme, acetylcholinesterase, with a PI50 on acetylcholinesterase from erythrocyte membrane of 7.2. 5 In molecular graphics comparisons, the heteroatoms of acetylcholine in its completely extended¡ 180, 180) conformation overlay well with those of huperzine A. This extended conformation is believed to be the one which is operative during hydrolysis by acetyl-cholinesterase. 6 Huperzine A is, in fact, more active than other well-documented acetylcholinesterase inhibitors such as physo-stigmine and neostigmine. Furthermore, the memory facilitating effects of huperzine A in higher order primates havebeen con-firmed in studies carried out in the US and Switzerland.Acetylcholine In our program aimed at improving upon nature’s original contribution of a nootropic agent, we have designed a short and practical route to this molecule. This route described below is sufficiently flexible to allow for the production of a variety of structural analogues. 7