Enantiomerically Pure and Highly Substituted Alicyclic α,α-Difluoro Ketones: Potential Inhibitors for Malarial Aspartic Proteases, the Plasmepsins
Enantiomerically Pure and Highly Substituted Alicyclic α,α-Difluoro Ketones: Potential Inhibitors for Malarial Aspartic Proteases, the Plasmepsins
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DOI：
10.1002/ejoc.201000712
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发表时间：
2010-08-01
影响因子：
2.8
通讯作者：
Diederich, Francois
中科院分区：
文献类型：
--
作者：
Faeh, Christoph;Mathys, Roland;Diederich, Francois
新型氟化结构单元的设计和合成在新药和农用化学品的开发中具有重要意义。蛋白质数据库（PDB）中的定量检索表明使用二水合物和三氟水合物结合亲水性酶活性位点。水合脂环族α，α-二氟化酮引起关注，因为它们提供合适的官能团用于在天冬氨酸蛋白酶的活性位点处结合到催化活性天冬氨酸（Asp）侧链对。本文扩展了这类新的结合元件的合成可用性。对映体纯的脂环族α，α-二氟酮通过涉及非对映异构体Mosher酯的分离的直接路线有效地获得。转化成Mosher酯还能够确定对映体α，α-二氟酮的绝对构型。合成方案进一步扩展到制备高度取代的基于环己基的α，α-二氟酮，其具有两个出口载体以填充疟疾天冬氨酸蛋白酶（plasmepsin）中的相应侧袋。测定了对这些酶的中等生物活性，IC 50（中位抑制浓度）值在较低的微摩尔范围内。
The design and synthesis of novel fluorinated building blocks is of major interest in the development of new pharmaceuticals and agrochemicals. A quantitative search in the Protein Data Bank (PDB) manifests the use of di- and trifluoro hydrates for binding to hydrophilic enzyme active sites. Hydrated alicyclic alpha,alpha-difluorinated ketones attract attention since they provide suitable functionalities for binding to the pair of catalytically active aspartate (Asp) side chains at the active site of aspartic proteases. This article expands the synthetic availability of this novel class of binding elements. Enantiomerically pure alicyclic alpha,alpha-difluoro ketones are efficiently accessed by a straightforward route involving the separation of diastereoisomeric Mosher esters. The transformation into Mosher esters also enables the determination of the absolute configuration of the enantiomeric alpha,alpha-difluoro ketones. The synthetic protocol was further expanded to the preparation of highly substituted cyclohexyl-based alpha,alpha-difluoro ketones bearing two exit vectors to fill the corresponding side pockets in the malarial aspartic proteases, the plasmepsins. Moderate biological activities toward these enzymes were determined, with IC50 (median inhibitory concentration) values in the lower micromolar range.