Stereospecific Synthesis and Biological Evaluation of KRN7000 Analogues with Thio-modifications at the Acyl Moiety

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-06-05 DOI:10.1021/acsmedchemlett.4c00199

Tianhui Hao, Tian Mi, Qinyu Chu, Wenjing Ma, Xi Cheng*, Yi Zang*, Jia Li* and Tiehai Li*,

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Abstract

α-Galactosylceramide (KRN7000 or α-GalCer) analogues terminated with phenyl (Ph) groups at the acyl moiety possess more potency than KRN7000 to activate invariant natural killer T (iNKT) cells for inducing a T helper 1 (Th1)-biased immune response. However, biological activities of phenyl glycolipids with thio-modifications at the acyl moiety remain unknown, and facile approaches for highly stereoselective synthesis of KRN7000 and its analogues are rather scarce. Herein, we exploited 4,6-di-O-tert-butylsilylene (DTBS)-directed stereospecific galactosylation to efficiently synthesize various α-GalCer analogues bearing thioamide, terminal thiophenyl and dual modifications at the acyl moiety. Biological evaluations suggest that a new analogue S34 featuring a terminal Ph-S-Ph-F group exhibits a more superior Th1-biased immune response in mice. Molecular docking analysis revealed that the introduction of a sulfur atom influences vital hydrogen bonding interactions between glycolipids and the cluster of differentiation 1d (CDld), thus adjusting the stability of the glycolipid-CDld complex.

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在酰基上进行硫代修饰的 KRN7000 类似物的立体特异性合成和生物学评价

与 KRN7000 相比，以酰基上的苯基（Ph）基团为端基的 α-半乳糖基甘油酰胺（KRN7000 或 α-GalCer）类似物在激活不变自然杀伤 T（iNKT）细胞以诱导 T 辅助细胞 1（Th1）偏向免疫反应方面具有更强的效力。然而，酰基上具有硫代修饰的苯基糖脂的生物活性仍不为人知，而且高度立体选择性合成 KRN7000 及其类似物的简便方法也相当匮乏。在此，我们利用 4,6-二-O-叔丁基硅烷基（DTBS）定向立体特异性半乳糖基化，高效地合成了各种α-GalCer 类似物，其酰基具有硫代酰胺、末端硫代苯基和双重修饰。生物学评估表明，具有末端 Ph-S-Ph-F 基团的新类似物 S34 在小鼠体内表现出更优越的 Th1 偏向免疫反应。分子对接分析表明，硫原子的引入会影响糖脂与分化簇 1d（CDld）之间重要的氢键相互作用，从而调整糖脂-CDld 复合物的稳定性。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.