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首页> 外文期刊>Chemistry: A European journal >Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation
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Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation

机译：ProM-2的设计和立体选择性合成：具有聚脯氨酸II（PPII）螺旋构象的螺环双脯氨酸模拟物

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摘要

With the aim of developing polyproline type II helix (PPII) secondary-structure mimetics for the modulation of prolin-rich-mediated protein-protein interactions, the novel diproline mimetic ProM-2 was designed by bridging the two pyrrolidine rings of a diproline (Pro-Pro) unit through a Z-vinylidene moiety. This scaffold, which closely resembles a section of a PPII helix, was then stereoselectively synthesized by exploiting a ruthenium-catalyzed ring-closing metathesis (RCM) as a late key step. The required vinylproline building blocks, that is, (R)-N-Boc-2-vinylproline (Boc=tert-butyloxycarbonyl) and (S,S)-5-vinylproline-tert-butyl ester, were prepared on a gram scale as pure stereoisomers. The difficult peptide coupling of the sterically demanding building blocks was achieved in good yield and without epimerization by using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIPEA). The RCM proceeded smoothly in the presence of the GrubbsII catalyst. Stereostructural assignments for several intermediates were secured by X-ray crystallography. As a proof of concept, it was shown that certain peptides containing ProM-2 exhibited improved (canonical) binding towards the Ena/VASP homology 1 (EVH1) domain as a relevant protein interaction target.
机译：为了开发II型螺旋脯氨酸（PPII）二级结构模拟物，以调节富含脯氨酸的介导的蛋白质-蛋白质相互作用，通过桥接双脯氨酸的两个吡咯烷环（Pro -Pro）单元通过Z-亚乙烯基部分。然后，通过利用钌催化的闭环复分解（RCM）作为后期关键步骤，立体选择性地合成了该支架，该支架与PPII螺旋​​的一部分非常相似。所需的乙烯基脯氨酸结构单元，即（R）-N-Boc-2-乙烯基脯氨酸（Boc =叔丁氧基羰基）和（S，S）-5-乙烯基脯氨酸叔丁酯，按克级制备纯立体异构体。通过使用2-（1H-7-氮杂苯并三唑-1-基）-1,1,3,3-四甲基铀六氟磷酸盐（HATU）/ N，可以实现高收率且没有差向异构的困难的立体构架的肽偶联， N-二异丙基乙胺（DIPEA）。在GrubbsII催化剂存在下，RCM顺利进行。通过X射线晶体学确定了几种中间体的立体结构分配。作为概念的证明，已表明某些含有ProM-2的肽对作为相关蛋白质相互作用靶标的Ena / VASP同源1（EVH1）域表现出改善的（规范的）结合。

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