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首页> 外文期刊>Chemistry: A European journal >Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT
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Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

机译：新的长链HPA-12类似物作为神经酰胺转移蛋白CERT的强配体的不对称合成和结合研究

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摘要

A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.
机译：由关键的手性含氧氨基酸制备了具有长脂族链的一系列12种Cer转移蛋白（CERT）拮抗剂HPA-12类似物，作为其（1R，3S）-syn和（1R，3R）-抗立体异构体。对这些中间体的对映选择性及其随后的转化取决于实际的结晶诱导不对称转化（CIAT）过程。然后实施Sonogashira偶联，然后进行三键还原和噻吩环加氢脱硫（HDS），形成相应的烷烃部分，以完成合成路线，从而以简明的4至6步反应顺序递送目标HPA-12类似物。通过使用最近开发的基于时间分辨的基于FRET的均相（HTR-FRET）结合测定法，评估了十种化合物与CERT START域结合的能力。在苯基部分上引入亲脂性附件会导致蛋白质结合的整体增强10到1000倍，对于间位的正己基残基观察到最高的效果。 3-脱氧植物神经酰胺脂族类似物的效力降低表明了苯环对于活性的重要性。 1,3-syn立体异构体在系统上比其1,3-anti类似物更有效。通过计算机研究将这些趋势合理化，从而形成了一种蛋白质识别模型，该模型与（1R，3S）-syn HPA的更强结合相一致。

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