壳聚糖基抗菌材料的制备研究新进展

壳聚糖及其衍生物的抗菌活性和优良加工性能,使其成为巨大潜力的抗菌材料,可用于食品保鲜、伤口敷料、纺织品功能化和组织工程等方面。本文综述了近年来壳聚糖基抗菌材料的制备研究新进展,并讨论了壳聚糖基材料的抗菌模型及影响抗菌活性的因素,希望对壳聚糖基抗菌材料的制备及抗菌活性的优化提供指导。     

糖基取代的胍类化合物合成研究

胍基化合物有较强的生理活性,如抗高血压、降血糖、抗病毒、治疗爱滋病和抗癌等性能[1].近年来,含糖基的胍越来越受到制药工业的关注[2,3],糖基碎片的引入提高了胍类化合物的活性.以糖基异硫氰酸酯和2-氨基-4-取代苯基噻唑为原料,得到硫脲,再与伯胺在氯化汞存在下发生反应,合成了一系列糖基胍类化合物.     

鼠李糖基转移酶研究进展

鼠李糖基化属于糖基化反应的一种,是化合物结构修饰及有机合成中广泛涉及到的一类反应.鼠李糖基转移酶是生物体中催化这一类反应的酶,能够将活性鼠李糖基从核苷糖转移到特定受体.这类酶广泛存在于自然界中,参与次生代谢产物的生成,并在生物体的结构组成及多种生理功能中发挥重要的作用.而且,得益于酶催化鼠李糖基化的特异性强、反应条件温和、环境友好等优点,其往往成为化学催化的有力补充,在有机化学合成及苷化修饰中发挥越来越重要的作用.对植物及微生物来源的鼠李糖基转移酶从酶催化功能、蛋白三维结构、鼠李糖基供体合成、酶催化底物杂泛性以及其在催化合成中的应用等方面进行了综述,并对其未来发展趋势进行了展望.     

N,N-二(2-氯乙基)果糖基磷酰胺酯的合成及其抗肿瘤活性研究

糖基磷酸酯类化合物,特别是葡萄糖基磷酸酯类化合物的合成及其生物活性的研究已有报道。1988年Hayachi等发现葡萄糖基磷酸酯衍生物具有抗肿瘤、抗病毒等生物活性,可用作医用药物。但果糖基磷酰胺酯及其衍生物的合成与抗肿瘤活性尚未见文献报道。为研究糖基磷酰胺酯的合成方法并筛选出有抗肿瘤活性的化合物,以期发现新型、高效、低毒、有应     

糖基异硫氰酸酯的合成及其应用

作为一类重要的有机合成中间体,糖基异硫氰酸酯广泛地应用于具有生理活性化合物的制备。本文对糖基异硫氰酸酯的结构、制备方法,以及作为中间体在糖基硫脲、糖基杂环、胍基糖苷、糖基缀合物等重要化合物的合成中的应用作了较详尽阐述。在对这些研究现状进行分析的基础上,对该研究领域下一步的发展方向提出了我们的观点。     

N-芳基(烷基)-N′-芳基(烷基)-N″-(葡萄糖基硫代亚脲基)膦酰三胺的合成

膦酰三胺类化合物具有优良的杀菌、抗病毒作用,其中部分还有抗肿瘤活性。脲和硫脲类化合物及其衍生物既具有优良的杀菌、除草等活性,又是一种重要的有机合成中间体。它的糖基衍生物是生物体内重要的代谢产物,具有维持代谢水平,提高机体耐受力等生理活性。糖基的多羟基特点,有利于增加这些化合物的水溶性,     

3-氨基脱氧糖的多样性合成及其糖苷键的构建

正Angew.Chem.Int.Ed.2017,56,5227~5231许多具有抗菌或抗肿瘤活性的天然产物和药物都包含有3-氨基脱氧糖这种糖基结构,不同的糖基结构对这些化合物的药理活性有着很大的影响.因此,对3-氨基糖糖基结构进行改变或者修饰为进一步的新药开发提供了一种有效途径.但是,有效获取各类3-氨基脱氧糖单糖及其衍生物面临着诸多困难.华中科技大学曾静教授和万谦教授团     

一种合成柔红霉素糖基类似物的新方法

与很多蒽环类抗生素一样,柔红霉素分子中含有3-氨基2,3,6-三脱氧己糖单元,糖基部分对药物分子的活性起着至关重要的作用.本文介绍了一种合成柔红霉素糖基类似物的新方法.     

一类新型大环内酯衍生物的合成及其生物活性研究

为了寻找高效、广谱的杀虫、杀菌剂,以去糖基或部分去糖基的多杀菌素为母体进行结构修饰,合成了8种大环内酯酰化衍生物,其结构经1H NMR,13C NMR和MS表征.对合成的化合物进行了生物活性测试.结果表明,这类化合物对鳞翅目、鞘翅目、双翅目、半翅目及线虫等害虫有较好的杀灭活性,其中化合物3e在100 mg/L浓度下对桃蚜的24 h杀灭率达到100%,化合物3f和3h在上药量为200μg时对假单胞菌有一定的抑制作用.     

壳聚糖及其衍生物抗菌机理研究进展

壳聚糖及其衍生物的抗菌活性和优良加工性能,使其成为具有巨大潜力的抗菌材料,可用于食品保鲜、伤口敷料和组织工程等方面。本文综述了近年来在壳聚糖基材料抗菌模型、影响抗菌活性因素及抗菌活性优化方案方面的研究进展,希望对壳聚糖衍生物抗菌材料的制备及优化提供参考。     

Identification of selective inhibitors for the glycosyltransferase MurG via high-throughput screening

Nucleotide-glycosyltransferases (NDP-Gtfs) play key roles in a wide range of biological processes. It is difficult to probe the roles of individual glycosyltransferases or their products because, with few exceptions, selective glycosyltransferase inhibitors do not exist. Here, we investigate a high-throughput approach to identify glycosyltransferase inhibitors based on a fluorescent donor displacement assay. We have applied the screen to E. coli MurG, an enzyme that is both a potential antibiotic target and a paradigm for a large family of glycosyltransferases. We show that the compounds identified in the donor-displacement screen of MurG are selective for MurG over other enzymes that use similar or identical substrates, including structurally related enzymes. The donor displacement assay described here should be adaptable to many other NDP-Gtfs and represents a new strategy to identify selective NDP-Gtf inhibitors.     

Utility of Bioluminescent Homogeneous Nucleotide Detection Assays in Measuring Activities of Nucleotide-Sugar Dependent Glycosyltransferases and Studying Their Inhibitors

Traditional glycosyltransferase (GT) activity assays are not easily configured for rapid detection nor for high throughput screening because they rely on radioactive product isolation, the use of heterogeneous immunoassays or mass spectrometry. In a typical glycosyltransferase biochemical reaction, two products are generated, a glycosylated product and a nucleotide released from the sugar donor substrate. Therefore, an assay that detects the nucleotide could be universal to monitor the activity of diverse glycosyltransferases in vitro. Here we describe three homogeneous and bioluminescent glycosyltransferase activity assays based on UDP, GDP, CMP, and UMP detection. Each of these assays are performed in a one-step detection that relies on converting the nucleotide product to ATP, then to bioluminescence using firefly luciferase. These assays are highly sensitive, robust and resistant to chemical interference. Various applications of these assays are presented, including studies on the specificity of sugar transfer by diverse GTs and the characterization of acceptor substrate-dependent and independent nucleotide-sugar hydrolysis. Furthermore, their utility in screening for specific GT inhibitors and the study of their mode of action are described. We believe that the broad utility of these nucleotide assays will enable the investigation of a large number of GTs and may have a significant impact on diverse areas of Glycobiology research.     

Surprising bacterial nucleotidyltransferase selectivity in the conversion of carbaglucose-1-phosphate

The drive to understand the molecular determinants of carbohydrate binding as well as the search for more chemically and biochemically stable sugar derivatives and carbohydrate-based therapeutics has led to the synthesis of a variety of analogues that replace the glycosidic oxygen with sulfur or carbon. In contrast, the effect of substitution of the ring oxygen on the conformations and enzymatic tolerance of sugars has been largely neglected, in part because of the difficulty in obtaining these analogues. Herein we report the first synthesis of the carbocyclic version of the most common naturally occurring sugar-1-phosphate, glucose-1-phosphate, and its evaluation with bacterial and eukaryotic sugar nucleotidyltransferases. In contrast to results with the eukaryotic enzyme, the carbaglucose-1-phosphate serves as a substrate for the bacterial enzyme to provide the carbocyclic uridinediphosphoglucose. This result demonstrates the first chemoenzymatic strategy to this class of glycosyltransferase inhibitors and stable activated sugar mimics for cocrystallization with glycosyltransferases and their glycosyl acceptors. This difference in turnover between enzymes also suggests the possibility of using sugar nucleotidyltransferases in vivo to convert prodrug forms of glycosyltransferase inhibitors. In addition, we report several microwave-assisted reactions, including a five minute Ferrier rearrangement with palladium, that accelerate the synthesis of carbocyclic sugars for further studies.     

A strategy for the solution-phase parallel synthesis of N-(pyrrolidinylmethyl)hydroxamic acids

Both five- and six-membered iminocyclitols have proven to be useful transition-state analogue inhibitors of glycosidases. They also mimic the transition-state sugar moiety of the nucleoside phosphate sugar in glycosyltransferase-catalyzed reactions. Described here is the development of a general strategy toward the parallel synthesis of a five-membered iminocyclitol linked to a hydroxamic acid group designed to mimic the transition state of GDP-fucose complexed with Mn(II) in fucosyltransferase reactions. The iminocyclitol 8 containing a protected hydroxylamine unit was prepared from D-mannitol. The hydroxamic acid moiety was introduced via the reaction of 8 with various acid chlorides. The strategy is generally applicable to the construction of libraries for identification of glycosyltransferase inhibitors.     

Design of Glycosyltransferase Inhibitors: Pyridine as a Pyrophosphate Surrogate

A series of ten glycosyltransferase inhibitors has been designed and synthesized by using pyridine as a pyrophosphate surrogate. The series was prepared by conjugation of carbohydrate, pyridine, and nucleoside building blocks by using a combination of glycosylation, the Staudinger–Vilarrasa amide‐bond formation, and azide–alkyne click chemistry. The compounds were evaluated as inhibitors of five metal‐dependent galactosyltransferases. Crystallographic analyses of three inhibitors complexed in the active site of one of the enzymes confirmed that the pyridine moiety chelates the Mn²⁺ ion causing a slight displacement (2 Å) from its original position. The carbohydrate head group occupies a different position than in the natural uridine diphosphate (UDP)–Gal substrate with little interaction with the enzyme.     

The first C-glycosidic analogue of a novel galactosyltransferase inhibitor

Structural analogues and mimics of the natural sugar-nucleotide UDP-galactose (UDP-Gal) are sought after as chemical tools for glycobiology and drug discovery. We have recently developed a novel class of galactosyltransferase (GalT) inhibitors derived from UDP-Gal, bearing an additional substituent at the 5-position of the uracil base. Herein we report the first C-glycosidic derivative of this new class of GalT inhibitors. We describe a practical convergent synthesis of the new UDP-C-Gal derivative, including a systematic study into the use of radical chemistry for the preparation of galactosyl ethylphosphonate, a key synthetic intermediate. The new inhibitor showed activity against a bacterial UDP-Gal 4'-epimerase at micromolar concentrations. This is the first example of a base-modified UDP-sugar as an inhibitor of a UDP-sugar-dependent enzyme which is not a glycosyltransferase, and these results may therefore have implications for the design of inhibitors of these enzymes in the future.     

Development of transition state analogue inhibitors for <Emphasis Type="Italic">N</Emphasis>-acetylglycosyltransferases bearing <Emphasis Type="SmallCaps">d</Emphasis>psico- or <Emphasis Type="SmallCaps">d</Emphasis>tagatofuranose scaffolds

New potential transition state analogue inhibitors for N-acetylglucosyltransferases (GnTs) were synthesised. These compounds based on psico- and tagatofuranose (structure) scaffold contained a 2-thiophenyl-1-O-diethylphosphate moiety mimicking the proposed model of the transition state of the enzymatic reaction catalysed by N-acetylglucosyltransferases. The synthesised compounds as well as their precursors were fully characterised by NMR, optical rotation and mass techniques. Anomeric configuration of tagatofuranose derivatives was confirmed by X-ray crystallography. Two types of potential human glycosyltransferase (GnTs) inhibitors representing donor UDP-GlcNAc, assigned for biological assays on human GnTs, were prepared.     

Design and Synthesis of Carbohydrate Mimetics: A New Strategy for Tackling the Problem of Carbohydrate-Mediated Biological Recognition

Carbohydrates have been known as poor candidates for drug development. Recent studies have, however, shown that structurally simplified small molecules as mimics of complex carbohydrates recognized by receptors can be developed as inhibitors of carbohydrate-mediated biological recognition. In addition, small molecules with higher affinity and specificity than the parent ligands can be developed by incorporating additional hydrophobic or charged groups in the carbohydrate mimetic which contains essential functional groups for receptor binding. Representative examples are illustrated in the studies of sialyl Lewis x - selectin interactions, glycosidase and glycosyltransferase reactions and aminoglycoside antibiotic - RNA interactions.