Uridine Bisphosphonate-Carbagalactose: A Stabilized α-1,4-Galactosyltransferase Inhibitor

IF 4.7 1区化学 Q1 CHEMISTRY, ORGANIC

Organic Letters Pub Date : 2026-10-16 Epub Date: 2026-10-02 DOI:10.1021/acs.orglett.6c03808

Jianyun Guo, Nicky de Koster, Bob van Puffelen, Roy Steneker, Vincent Verhoeks, Tim P. Ofman, Herman S. Overkleeft, Marta Artola, Dmitri V. Filippov, Jeroen D. C. Codée

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引用次数: 0

Abstract

Methylene and difluoromethylene uridine bisphosphonate carbagalactose were designed and synthesized as stable uridine diphosphate-galactose (UDP-Gal) mimics for probing α-1,4-galactosyltransferase (A4GALT). In these analogues, the labile glycosidic and pyrophosphate linkages of UDP-Gal are replaced by chemically and enzymatically stable motifs, yielding compounds that retain key structural features essential for biological recognition. This work demonstrates the first successful nucleophilic substitution of a secondary triflate with a difluoromethylene bisphosphonate, providing a methodology that should enable efficient access to a range of sugar nucleotide mimics. The CH₂ and CF₂ UDP-Gal analogues 5 and 6 inhibited A4GALT, displaying IC₅₀ values of 249 and 217 μM, respectively, in the presence of 500 μM UDP-Gal, consistent with efficient recognition by the A4GALT donor-binding site.

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一种稳定的α-1,4-半乳糖转移酶抑制剂

摘要设计并合成了二氟亚甲基尿苷二磷酸半乳糖（UDP-Gal）模拟物，用于探测α-1,4-半乳糖转移酶（A4GALT）。在这些类似物中，UDP-Gal的不稳定的糖苷和焦磷酸键被化学和酶稳定的基序所取代，产生的化合物保留了生物识别所必需的关键结构特征。这项工作首次成功地用二氟亚甲基二膦酸盐取代了仲三氟酸盐的亲核性，提供了一种能够有效获取一系列糖核苷酸模拟物的方法。CH2和CF2 UDP-Gal类似物5和6抑制A4GALT，在500 μM UDP-Gal存在下，IC50值分别为249 μM和217 μM，与A4GALT供体结合位点的有效识别一致。

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来源期刊

Organic Letters 化学-有机化学

CiteScore

9.30

自引率

11.50%

发文量

1607

审稿时长

1.5 months

期刊介绍： Organic Letters invites original reports of fundamental research in all branches of the theory and practice of organic, physical organic, organometallic,medicinal, and bioorganic chemistry. Organic Letters provides rapid disclosure of the key elements of significant studies that are of interest to a large portion of the organic community. In selecting manuscripts for publication, the Editors place emphasis on the originality, quality and wide interest of the work. Authors should provide enough background information to place the new disclosure in context and to justify the rapid publication format. Back-to-back Letters will be considered. Full details should be reserved for an Article, which should appear in due course.