2-(乙酰氨基)-2-脱氧-alpha-D-吡喃半乳糖基氯化物 3,4,6-三乙酸酯 | 41355-44-6

• 物质功能分类: 医药中间体 - 杂环化合物 - 吡喃类化合物
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 2-(乙酰氨基)-2-脱氧-alpha-D-吡喃半乳糖基氯化物 3,4,6-三乙酸酯
• 中文别名: 2-(乙酰氨基)-2-脱氧-alpha-D-吡喃半乳糖基氯化物3,4,6-三乙酸酯
• 英文名称: 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-galactopyranosyl chloride
• 英文别名: 2-acetamido-3,4,6-tri-O-acetyl-1-chloro-1,2-dideoxy-α-D-galactopyranose；2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-a-D-galactopyranosyl chloride；[(2R,3R,4R,5R,6R)-5-acetamido-3,4-diacetyloxy-6-chlorooxan-2-yl]methyl acetate
• CAS: 41355-44-6
• 化学式: C₁₄H₂₀ClNO₈
• 分子量: 365.768
• InChiKey: NAYYKQAWUWXLPD-RGDJUOJXSA-N

物化性质

• 熔点：
  131-136 °C (decomp)
• 沸点：
  516.4±50.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  117
• 氢给体数：
  1
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存放在2-8℃环境下，应保持干燥并密封。

反应信息

• 作为反应物：
  描述：

  2-(乙酰氨基)-2-脱氧-alpha-D-吡喃半乳糖基氯化物 3,4,6-三乙酸酯 在 四(三苯基膦)钯 、 四丁基溴化铵 、 caesium carbonate 、 甲胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 N-((2S,3R,4R,5R,6R)-4,5-dihydroxy-2-((5'-hydroxy-2'-methoxy-[1,1'-biphenyl]-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide
  参考文献：
  名称：

  Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design

  摘要：

  The F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here, we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 by replacing the carboxylate with a sulfonamide as in 50. Other groups which can accept H-bonds were also tolerated. We pursued further modifications to the biphenyl aglycone resulting in significantly improved activity. Two of the most potent compounds, 86 (IC50 = 0.051 mu M) and 90 (IC50 = 0.034 mu M), exhibited excellent metabolic stability in mouse plasma and liver microsomes but showed only limited oral bioavailability (<1%) in rats. Compound 84 also showed a good pharmacokinetic (PK) profile in mice after IP dosing with compound exposure above the IC50 for 6 h. These new FmlH antagonists represent new antivirulence drugs for UTIs.

  DOI：

  10.1021/acs.jmedchem.8b01561
• 作为产物：
  描述：

  D-(+)-galactosamine hydrochloride 在 吡啶 、 盐酸 、 乙酰氯 作用下， 反应 33.0h， 生成 2-(乙酰氨基)-2-脱氧-alpha-D-吡喃半乳糖基氯化物 3,4,6-三乙酸酯
  参考文献：
  名称：

  合成的带有βGalNAc-Thr的MUC1糖肽作为Tn抗原异构体诱导产生针对肿瘤细胞的抗体。

  摘要：

  抗癌免疫原性：糖肽结合了αGalNAc-Thr（Tn）和βGalNAc-Thr残基作为Tn抗原异构体，被合成为MUC1肿瘤粘蛋白糖蛋白的模拟物。非天然的βGalNAc-糖肽-BSA具有改善的免疫原性，具有开发抗癌疫苗的潜力。

  DOI：

  10.1002/cbic.201600473

文献信息

• Gold Catalysis in Glycosylation Reactions
  作者：Horst Kunz、Sebastian Götze、Roland Fitzner

  DOI：10.1055/s-0029-1218356

  日期：2009.12

  Glycosylation of alcohols containing acid-sensitive groups, as tor example 1,2-5,6-di-O-isopropylidene-glucofuranose, Fmoc-threonine tert-butyl ester or famesol, is achieved using glycosyl trichloroacetimidates activated by gold(I) chloride (5―10 mol%). While glycosylation with 2-O-acyl protected glycosyl donors proceeds with 1,2-trans-selectivity, non-neighboring group active glycosyldonors give mixtures

  含有酸敏感基团的醇，例如 1,2-5,6-二-O-异亚丙基-呋喃糖、Fmoc-苏氨酸叔丁酯或法素醇的糖基化是使用由氯化金 (I) 活化的糖基三氯乙酰亚胺实现的(5-10 mol%)。虽然与 2-O-酰基保护的糖基供体的糖基化以 1,2-反式选择性进行，但非相邻基团活性糖基供体产生异头糖苷或 α-糖苷的混合物，这取决于它们的结构和糖基受体的反应性。
• Mechanism of Human Nucleocytoplasmic Hexosaminidase D
  作者：Matthew G. Alteen、Verena Oehler、Ivana Nemčovičová、Iain B. H. Wilson、David J. Vocadlo、Tracey M. Gloster

  DOI：10.1021/acs.biochem.5b01285

  日期：2016.5.17

  Mammalian β-hexosaminidases have been shown to play essential roles in cellular physiology and health. These enzymes are responsible for the cleavage of the monosaccharides N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) from cellular substrates. One of these β-hexosaminidases, hexosaminidase D (HexD), encoded by the HEXDC gene, has received little attention. No mechanistic studies have focused on the role of this unusual nucleocytoplasmically localized β-hexosaminidase, and its cellular function remains unknown. Using a series of kinetic and mechanistic investigations into HexD, we define the precise catalytic mechanism of this enzyme and establish the identities of key enzymic residues. The preparation of synthetic aryl N-acetylgalactosaminide substrates for HexD in combination with measurements of kinetic parameters for wild-type and mutant enzymes, linear free energy analyses of the enzyme-catalyzed hydrolysis of these substrates, evaluation of the reaction by nuclear magnetic resonance, and inhibition studies collectively reveal the detailed mechanism of action employed by HexD. HexD is a retaining glycosidase that operates using a substrate-assisted catalytic mechanism, has a preference for galactosaminide over glucosaminide substrates, and shows a pH optimum in its second-order rate constant at pH 6.5–7.0. The catalytically important residues are Asp148 and Glu149, with Glu149 serving as the general acid/base residue and Asp148 as the polarizing residue. HexD is inhibited by Gal-NAG-thiazoline (Ki = 420 nM). The fundamental insights gained from this study will aid in the development of potent and selective probes for HexD, which will serve as useful tools to improve our understanding of the physiological role played by this unusual enzyme.

  哺乳动物的β-己糖胺酶在细胞生理和健康中扮演着重要角色。这些酶负责从细胞底物中断裂单糖N-乙酰葡萄糖胺（GlcNAc）和N-乙酰半乳糖胺（GalNAc）。其中一种β-己糖胺酶，即己糖胺酶D（HexD），由HEXDC基因编码，一直以来受到的关注较少。目前没有机制研究专注于这种在细胞核和细胞质中定位的非典型β-己糖胺酶的作用，其细胞功能仍然未知。通过一系列对HexD的动力学和机制研究，我们确定了这种酶的确切催化机制，并确定了关键酶残基的身份。结合对野生型和突变型酶的动力学参数测定，对酶催化水解这些底物的线性自由能分析，通过核磁共振评估反应，以及抑制研究，共同揭示了HexD所采用的详细作用机制。HexD是一种保留型糖苷酶，采用底物辅助的催化机制，偏好半乳糖胺而非葡萄糖胺底物，并在pH 6.5-7.0的第二级速率常数中显示出最适pH。在催化中重要的残基是Asp148和Glu149，其中Glu149作为广义酸/碱残基，Asp148作为极化残基。HexD被Gal-NAG-噻唑烷抑制（Ki = 420 nM）。通过这项研究所获得的基本洞见将有助于开发强效且选择性的HexD探针，这将作为有用的工具来增进我们对这种非典型酶在生理学中作用的了解。
• Selenenylsulfide-Linked Homogeneous Glycopeptides and Glycoproteins: Synthesis of Human “Hepatic Se Metabolite A”
  作者：Omar Boutureira、Gonçalo J. L. Bernardes、Marta Fernández-González、Daniel C. Anthony、Benjamin G. Davis

  DOI：10.1002/anie.201106658

  日期：2012.2.6

  Introducing selenium: The synthesis and full characterization of human hepatic Se metabolite A has been accomplished by using a robust, efficient, and Cys‐specific selenenylation protocol (see scheme; NaPi=sodium phosphate). The selenenylsulfide linkage is sufficiently stable to allow quantification of Se‐containing glycoconjugates in biological fluids by using atomic detection methods.

  硒介绍：人肝硒代谢物 A 的合成和完整表征是通过使用稳健、高效和半胱氨酸特异性硒化方案完成的（参见方案；NaPi=磷酸钠）。硒基硫键足够稳定，可以使用原子检测方法对生物体液中的含硒糖缀合物进行定量。
• BIFUNCTIONAL COMPOUND WITH MONOSACCHARIDE AND N2S2 LIGAND, AND PREPARATION AND USE THEREOF
  申请人：LIU SHOW-WEN

  公开号：US20120009669A1

  公开（公告）日：2012-01-12

  A bifunctional compound with a monosaccharide and a N 2 S 2 ligand, and more particularly, a bifunctional compound with a N 2 S 2 ligand and aminohexylacetyl galactosamine (ah-GalNAc 4 ) is provided. A method for preparing the bifunctional compound with a monosaccharide and a N 2 S 2 ligand is also provided, including activating a carboxyl group in an organic ligand, reacting the activated carboxyl group with a galactopyranoside through amidation, and then hydrolyzing. The bifunctional compound of the present invention is widely useful in nuclear medicine for preparation of liver imaging agents for assisting in correct diagnosis of diseases.

  提供了一种具有单糖和N2S2配体的双功能化合物，更具体地说，提供了一种具有N2S2配体和氨基己酰半乳糖胺（ah-GalNAc4）的双功能化合物。还提供了一种制备具有单糖和N2S2配体的双功能化合物的方法，包括激活有机配体中的羧基，通过酰胺化将激活的羧基与半乳糖苷反应，然后水解。本发明的双功能化合物在核医学中广泛用于制备肝脏成像剂，以帮助正确诊断疾病。
• PRECURSOR USED FOR LABELING HEPATORCYTE RECEPTOR AND CONTAINING TRISACCHARIDE AND DIAMIDE DEMERCAPTIDE LIGAND, METHOD FOR PREPARING THE SAME, RADIOTRACER AND PHARMACEUTICAL COMPOSITION OF THE SAME
  申请人：LIU SHOW-WEN

  公开号：US20140031533A1

  公开（公告）日：2014-01-30

  A precursor used for labeling hepatocyte receptors and applied to radiotracers for imaging or pharmaceutical compositions for liver cancers is revealed. The precursor is a bifunctional compound. The bifunctional group includes a trisaccharide structure and a diamide dimercaptide (N 2 S 2 ) ligand. The trisaccharide has high affinity to asialoglycoprotein receptors (ASGPR) on surfaces of hepatocytes while N 2 S 2 ligand reacts with radioisotopes to form neutral complexes. Thus the precursor stays on surfaces of hepatocytes to provide radioisotope labeling or treatment effect of liver cancers.

  一种用于标记肝细胞受体并应用于用于肝癌成像或药物组合物的放射示踪剂的前体被揭示。该前体是一种双功能化合物。双功能基团包括三糖结构和二酰胺二巯基（N2S2）配体。三糖具有高亲和力，能与肝细胞表面的非糖蛋白受体（ASGPR）结合，而N2S2配体与放射性同位素反应形成中性络合物。因此，前体停留在肝细胞表面，提供放射同位素标记或治疗肝癌的效果。