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Sulfones as surrogates of phosphates to mimic sugar nucleotide donors.

机译：砜作为磷酸盐的替代物，模仿糖核苷酸供体。

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摘要

Sialyltransferases, fucosyltransferases and CMP-sialic acid synthetases play a crucial role in the construction of cell surface glycoconjugates. These proteins also have a pivotal role to play in a number of diseases, including cancer. When these proteins function in an abnormal way, hyperfucosylation and hypersialylation results. Hypersialylation also leads to the detachment of primary tumor cells due to an increase in the level of overall negative charge, causing repulsion between the cancer cells. Sialyltransferase enzymes, the fucosyltransferase enzymes and CMP-sialic acid synthetases are involved in the metastatic cascade associated with cancer.;The recent spurt of interest in glycosyltransferases has brought into focus concern for identifying potent inhibitors for these glycosyltransferase enzymes. We here report the synthesis and biochemical evaluation of sulfones as neutral phosphate mimics for CSS. We use a unique disulfone/diphosphonate and monosulfone/diphosphonate reagent in order to synthesize a large number of highly-functionalized geminal monosulfone/disulfone-containing compounds through Horner-Emmons-Wadsworth (HEW) olefination chemistry. The idea comes from using a methylene unit as a replacement for the phosphate bridging oxygen atom, thus rendering the phosphate isostere nonhydrolyzable, replacing the phosphorous atom with a sulfur and oxidizing it to the sulfone to increase metallophilicity. Taken together, these design principles maintain the correct bond distance found in a phosphate backbone, remove chirality and provide a similarly metallophilic group.;Oxidation of the 5'-hydroxymethylene of nucleosides to 5'-aldehyde is an essential step in the preparation of these biologically active molecules. There are relatively few methods in the literature describing the general preparation of such nucleosides-5'-aldehyde. Herein, we also report a mild procedure for the oxidation of 2',3'-isopropylidene-protected purine and pyrimidine-containing nucleosides to their respective 5'-aldehydes, using Dess-Martin oxidation. This method involves simple isolation and results in high yields, remarkable solubility in organic solvents and greater stability for purine 5'-aldehydes as they are very sensitive to moisture.
机译：唾液酸转移酶，岩藻糖基转移酶和CMP-唾液酸合成酶在细胞表面糖缀合物的构建中起关键作用。这些蛋白质在包括癌症在内的许多疾病中也起着关键作用。当这些蛋白质以异常方式起作用时，会导致岩藻糖基化和唾液酸化过多。高唾液酸化作用还由于总负电荷水平的增加而导致原发肿瘤细胞的分离，从而导致癌细胞之间的排斥。唾液酸转移酶，岩藻糖基转移酶和CMP-唾液酸合成酶参与了与癌症相关的转移级联反应。最近对糖基转移酶的关注引起了人们的关注，以鉴定这些糖基转移酶的有效抑制剂。我们在这里报告了作为CSS的中性磷酸酯模拟物的砜的合成和生化评估。我们使用独特的二砜/二膦酸酯和单砜/二膦酸酯试剂，以便通过霍纳-埃蒙斯-沃兹沃思（HEW）烯化化学反应合成大量高度官能化的含双磺砜/二砜的化合物。这个想法来自于使用亚甲基单元代替桥接磷酸盐的氧原子，从而使磷酸等排酯不可水解，用硫取代磷原子并将其氧化为砜，从而提高了金属亲和性。综上所述，这些设计原理可维持在磷酸酯骨架中发现的正确键距，消除手性并提供类似的嗜金属基团。核苷的5'-羟基亚甲基氧化为5'-醛是制备这些化合物的必不可少的步骤生物活性分子。文献中描述这种核苷5'-醛的一般制备方法相对较少。在这里，我们还报道了使用Dess-Martin氧化法将2'，3'-异亚丙基保护的嘌呤和含嘧啶的核苷氧化为各自5'-醛的温和程序。该方法涉及简单的分离，并导致高收率，在有机溶剂中的显着溶解度以及嘌呤5'-醛对水分非常敏感的更高的稳定性。

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  • 作者

    Sahni, Urvashi.;

  • 作者单位

    University of California, Davis.;

  • 授予单位 University of California, Davis.;
  • 学科 Chemistry General.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 226 p.
  • 总页数 226
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 化学;生物化学;
  • 关键词

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