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科学家发现白果内酯的合成方法
作者:小柯机器人 发布时间:2019/10/17 14:00:44

美国斯克里普斯研究所Ryan A. Shenvi和Masaki Ohtawa等研究人员报道了不对称合成白果内酯的简单方法。2019年10月16日,《自然》在线发表了这项成果。

研究人员利用白果内酯的异常反应性来影响后期氧化,该后期氧化使分子核对称,并使氧化态嵌入到起始材料中。这种报道的总体策略可能适用于银杏同系物,包括银杏内酯,其中一些是甘氨酸受体(GlyR)选择性拮抗剂。总之,现在可以通过化学合成来质疑白果内酯的治疗潜力及其尚未完全理解的作用。

据介绍,银杏代谢产物白果内酯被人类广泛摄入,但其对哺乳动物中枢神经系统的作用尚不完全清楚。白果内酯对γ-氨基丁酸A受体(GABAAR)的拮抗作用与唐氏综合症小鼠模型认知功能障碍的挽救有关系。惊厥活动与这些神经保护作用的认知缺乏已导致一些人提出了另一种无法确定的靶标。然而,空间拥挤以及白果内酯的不稳定妨碍了除GABAAR以外的生物靶标的钓取。一种简洁而灵活的白果内酯合成方法将提供一个平台,以产生用于鉴定潜在新靶标的探针、在昆虫和人的GABAAR之间具有不同选择性的类似物,以及具有增强的血清半衰期的稳定类似物。

附:英文原文

Title: Concise asymmetric synthesis of (−)-bilobalide

Author: Meghan A. Baker, Robert M. Demoret, Masaki Ohtawa, Ryan A. Shenvi

Issue&Volume: 2019-10-16

Abstract: 

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood1–4. Antagonism of gamma-aminobutyric acid A receptors (GABAARs) by bilobalide has been tied to rescue of cognitive deficits in mouse models of Down syndrome5. A lack of convulsant activity coupled with these neuroprotective effects have led some to postulate an alternative, unidentified target.4 However, steric congestion and the instability of bilobalide1,2,6 have prevented pull-down of biological targets other than the GABAΑRs. A concise and flexible synthesis of bilobalide would provide a platform to generate probes for identification of potential new targets; analogs with differential selectivity between insect and human GABAΑRs; and stabilized analogs with enhanced serum half-life7. Here we exploit the unusual reactivity of bilobalide to affect a late-stage oxidation that symmetrizes the molecular core and allows oxidation states to be embedded in the starting material. The same overall strategy disclosed here may be applicable to G. biloba congeners including the ginkgolides, some of which are glycine receptor (GlyR)-selective antagonists8. The therapeutic potential of bilobalide and its incompletely understood effects can now be interrogated through chemical synthesis.

DOI: 10.1038/s41586-019-1690-5

Source:https://www.nature.com/articles/s41586-019-1690-5

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html