生物有机化学及合成化学界面之最新探索:生物系统中醣识别研究之化学—酶催化探讨(英文)

此报告叙述醣中介细胞粘附最近之研究工作,其中包括合成之新方法发展,细胞粘附过程中牵连之酶抑制及仿醣之设计及合成。     

生物医用高分子纤维材料

综述了医用的高分子纤维材料及其改性的方法。医用高分子纤维材料包括天然高分子及合成高分子两大类。其中包括不可降解的及可降解的高分子纤维材料。利用聚合物共混、交联、纤维表面改性,如等离子体处理、纤维表面化学反应及聚合物的表面接枝等物理化学方法可对医用纤维进行改性,改善纤维的力学性能、生物相容性,并使之具有细胞粘附性,利于组织的生长。     

聚合物材料表面纳米条纹对生物细胞生长的影响

20世纪 80年代后期 ,工程学科与生命学科的交叉融合产生了组织工程学 [1,2 ] ,细胞与生物材料之间的相互作用是组织工程学的一个主要领域 .细胞必须与材料发生适当的粘附 ,才能进行迁移、分化和增殖 ,细胞与材料粘附及随后的扩散能力的大小主要由材料表面的物理和化学性质所决定 [3,4 ] .目前 ,材料表面改性以提高细胞粘附力是组织工程学的一大难题 .聚苯乙烯 (PS)以其无毒、高透明度、低成本以及易加工等性能 ,被广泛应用于基础医学研究及临床医学实验 [5,6 ] .未改性 PS的生物相容性较差 ,只有表面改性后才能用于细胞培养 .目前文献报道…     

应用苯甲醇钠裂解氧三圜型内醚醣醚环的研究

应用苯甲醇钠可以裂解α-甲基2∶3-内醚-4∶6-苯亚甲基-D-同侧醣氧六圜配醣物的醚环,生成53%的α-甲基2-苯甲基-4∶6-苯亚甲基-D-2-异侧醣氧六圜配醣物及9%的α-甲基3-苯甲基-4∶6-苯亚甲基-D-葡萄糖氧六圜配醣物。此两化合物的结构,应用水解除去苯亚甲基及接触氢解除去苯甲基后,证明是已知的α-甲基 D-2-异侧醣氧六圜配醣物,及α-甲基 D-葡萄糖氧六圜配醣物;苯甲基在醣分子中的衔接位置,则应用高碘酸钠氧化测定。     

GRGDS修饰D,L-丙交酯-β-苹果酸共聚物的生物相容性研究

聚(D,L-丙交酯-β-苹果酸)(P-COOH)进行改性制得GRGDS修饰聚合物(P-GS5),利用红外光谱、元素分析和X射线光电子能谱确定了材料的结构和组成.通过内皮细胞粘附实验发现P-GS5可明显提高内皮细胞粘附(PDLLA,45%;P-GS5,109%),改善材料的细胞亲和性;同时血小板粘附实验结果也表明P-GS5可有效抑制血小板粘附(PDLLA,47%;P-GS5,18%),降低血栓形成的几率.     

仿贻贝粘附蛋白聚合物的研究及动态

贻贝粘附蛋白以其对不同基材表面及在水下都具备高强的粘附能力而闻名。根据仿生学原理,通过将贻贝粘附蛋白功能元即邻苯二酚基团与合成高分子相结合制备仿贻贝粘附蛋白聚合物,达到复制重现甚至超越天然贻贝粘附蛋白粘附效力的目的,是目前贻贝仿生领域研究热点之一。本文综述了近年来国内外仿贻贝粘附蛋白聚合物的研究进展。我们按照主链结构的种类进行了分类,对仿贻贝粘附蛋白聚合物材料的发展过程、材料的设计思路以及应用领域进行了系统的归纳总结。通过研究分子结构与仿生材料功能特性之间的相互关系,希望为以后设计合成新型的功能化的贻贝仿生材料提供有益的借鉴和参考。     

光响应智能生物粘附材料的设计与应用

智能生物粘附材料是一类通过生物粘附作用粘附于组织表面,且对外界刺激具有特定响应的新型粘合剂.因其止血快、生物相容性好、生物粘附性强且具有智能响应效果而在外科临床应用领域受到了极大的关注.其中,光响应生物粘附材料因具有无接触、时空调节、严格剪裁和远程控制等独特优势,被广泛用于伤口止血及组织修复等领域.除了广泛应用的紫外光,可见光和近红外光因其优异的组织穿透深度、高稳定性和低能量特性而在这类光响应生物粘附材料中受到广泛关注.本文总结了智能响应粘附材料的响应类型,重点介绍了近年来光响应生物粘附材料的研究进展,包括分类、性能及其在生物医学领域的具体应用等.     

光响应细胞粘附界面

光响应分子的响应过程可以通过简单调控光源波长、光强度以及曝光时间进行调节,近年来基于光响应分子构建的智能界面被越来越多地应用于调控细胞粘附行为。目前,用于构筑调控细胞粘附行为的光响应智能界面的功能分子主要有偶氮苯、螺吡喃以及它们的衍生物。基于这些光响应功能分子的光致异构化,光响应智能界面会发生物理化学性质转变,进而实现可控的细胞粘附和去粘附。设计光控细胞粘附界面为研究细胞粘附、迁移以及细胞诊断提供了一种新型便捷的策略。     

生物矿化合成纳米针状SiO2

利用少量有机大分子可控制大分子成核、生长,最后形成生物矿化纳米结构材料[1].这些合成的纳米结构材料有许多重要的性质,如流动性和运输行为、催化活性、分离效率、粘附特性、储存特性和从"智能"胶体中释放的动力学特性等[2].     

白三烯的化学

白三烯是最近发现的具有高度生理活性的化合物。本文主要综述白三烯在化学方面的研究状况,着重介绍白三烯及其阻断剂的化学合成。本文也介绍了有机合成方法学上的一些进展,如不对称合成和应用醣作为手性化合物的合成前体。     

Synthetic Studies on Sialoglycoconjugates 45: Synthesis of 1-Deoxynojirimycin-Containing Oligosaccharides Related to the Cancer-Associated Sialyl-Lewis a Antigen Recognized by Lec-Cams (Selectins)

Abstract

Sialyl-Lewis a (sLe^a), mainly expressed on cancer cells of the digestive organs,² has been known as an important cancer-associated carbohydrate antigen.³ Very recently, it has been demonstrated^4–9 that the (sLe^a) antigen is one of the possible ligands recognized by selectins, a family of lectin-type cell adhesion molecules (LEC-CAMS). These findings suggest that the (sLe^a) antigen may be involved in the process of hematogeneous metastasis of cancer cells. 1-Deoxynojirimycin (DNJ) and related compounds have been shown¹⁰ not only to be potent inhibitors of a-glycosidases and glycoprotein-processing enzymes, but also to be of potential clinical value as antidiabetic, antineoplastic and anti-HIV agents. In a preceding paper we reported the synthesis of DNJ-containing sialyl-Lewis x antigen which has been identified as a major carbohydrate ligand for leukocyte adhesion on vascular endothelium mediated by selectins. The present paper describes the first synthesis of l-deoxynojirimycin- containing cancer-associated (sLe^a) antigen and related compounds.     

Iterative synthesis of spacered glycodendrons as oligomannoside mimetics and evaluation of their antiadhesive properties

Dendrimer chemistry is an attractive concept for mimicry of the highly branched character of the bioactive carbohydrates found as part of a cell's sugar coat, called the glycocalyx. Glycodendrimers have thus been used to study biological processes occurring on cell surfaces, such as bacterial adhesion. This paper details a new approach in glycodendrimer synthesis, in which a 3,6-diallylated carbohydrate is utilised as core molecule, hydroboration-oxidation is the activating step, and glycosylation with branched and unbranched sugar trichloroacetimidates is used for dendritic growth. To obtain pure dendritic pseudo-tri- and -heptasaccharides in good yields, radical addition of mercaptoethanol to peripheral double bonds was also evaluated with great success. A collection of six new hyperbranched glycodendrons was tested for their potential as inhibitors of type 1 fimbriae-mediated bacterial adhesion in an ELISA and the results were interpreted with regard to sugar valency and spacer characteristics.     

Applications of controlled inversion strategies in carbohydrate synthesis

Inversion strategies via sulfonyl groups, oxidation/selective reduction, etc. have been wildly used in introducing functionalities like amino group, abundantly synthesizing rare sugars and constructing the β-configurations in glycosylation.     

Synthesis of Glycodendrimers with Antiviral and Antibacterial Activity

Glycodendrimers are an important class of synthetic macromolecules that can be used to mimic many structural and functional features of cell-surface glycoconjugates. Their carbohydrate moieties perform key important functions in bacterial and viral infections, often regulated by carbohydrate–protein interactions. Several studies have shown that the molecular structure, valency and spatial organisation of carbohydrate epitopes in glycoconjugates are key factors in the specificity and avidity of carbohydrate–protein interactions. Choosing the right glycodendrimers almost always helps to interfere with such interactions and blocks bacterial or viral adhesion and entry into host cells as an effective strategy to inhibit bacterial or viral infections. Herein, the state of the art in the design and synthesis of glycodendrimers employed for the development of anti-adhesion therapy against bacterial and viral infections is described.     

Enzymes in Organic Synthesis: Application to the Problems of Carbohydrate Recognition (Part 1)

Carbohydrates on cell surfaces are information molecules. Although only seven or eight monosaccharides are commonly used as building blocks in mammalian systems, the multifunctionality of these monomers can lead to the assembly of an immense variety of complex structures. Millions of different tetrasaccharide structures, for example, can be constructed from this small number of building blocks, if branching, the stereochemistry of glycosidic linkages, and the modification of hydroxyl and amino groups are taken into consideration. Oligosaccharides therefore represent an effective class of biomolecules that code for a vast amount of information required in various biological recognition processes, such as intercellular communication, signal transduction, cell adhesion, infection, cell differentiation, development and metastasis. The pace of development of pharmaceuticals based on carbohydrates has, however, been slower than that based on other classes of biomolecules. Part of the reason is the lack of technologies for the study of complex carbohydrates. There is no method to amplify oligosaccharides for sequence analysis. There is no machine available for automated synthesis of oligosaccharides. In addition, the possibly poor bioavailability and difficulties in the large-scale synthesis of carbohydrates have undoubtedly contributed to this slow pace. The enzymatic and chemoenzymatic methods, especially those based on aldolases and glycosyltransferases, described here appear to be useful for the synthesis of mono- and oligosaccaharides and related molecules. Further advances in glycobiology will probably lead to the development of new technologies for the study of carbohydrate recognition and for the synthesis of bioactive carbohydrates and mimetics to control the recognition processes.     

Clinical aspects of altered glycosylation of glycoproteins in cancer

Alteration of the expression of carbohydrate structures is frequently observed in tumor cells. This review summarizes the different changes of O- and N-linked glycoproteins observed in cancer cells, the impact of the tumor-related carbohydrate phenotypes on the clinical outcome of the cancer disease, and the various ways in which carbohydrate structures can interact with different carbohydrate-detecting adhesion molecules, selectins, and sialoadhesins. Various ways of inhibiting the formation of cell adhesion-engaged carbohydrates on the cell surface, or inhibiting the binding are discussed. Carbohydrate structures which are in clinical use as circulating tumor markers and the effect of genotypes on tumor marker concentrations are reviewed.     

与癌症相关的糖类抗原Globo-H六糖的全合成进展

Globo-H作为一种和乳腺癌、前列腺癌相关的复杂糖类抗原,其发现为糖类疫苗开发和癌症免疫治疗带来了机遇,但如何高效、高纯地获得合成糖类抗原,以供研究和临床应用,也向寡糖合成方法学提出了挑战.综述了1995年Danishefsky首次以糖烯组装策略全合成Globo-H以来的各种新方法,如:Schmidt的三氯乙酰亚胺酯法、Boons的双向糖苷化法、Wong的基于糖基给体活性差异的一锅煮策略、Seeberger的液相线性合成和固相自动组装法、Huang的多组份反复预活化一锅煮法和最新报道的酶法.就糖合成方法学而言,硫苷法依旧可称为"明星方法",糖烯、三氯乙酰亚胺酯和氟代糖也普遍采用,磷酸酯糖基给体在固相合成中的应用正显示出其新的活力.这些方法代表了当今糖化学的水平和发展趋势.     

Carbohydrate–Carbohydrate Recognition between LewisX Glycoconjugates

The strong dependence of the NOE on the molecular mobility rendered the weak bond of a homotypical carbohydrate–carbohydrate recognition detectable in a simplified model system. The membrane-bound Le^X trisaccharide 1 , which functions as a receptor, transiently binds the dissolved Le^X trisaccharide 2 , thus slowing down its rotational diffusion. This kind of molecular recognition plays an important part in cell adhesion.     

Divalent Sialylated Precision Glycooligomers Binding to Polyomaviruses and the Effect of Different Linkers

Divalent precision glycooligomers terminating in N‐acetylneuraminic acid (Neu5Ac) or 3′‐sialyllactose (3′‐SL) with varying linkers between scaffold and the glycan portions are synthesized via solid phase synthesis for co‐crystallization studies with the sialic acid‐binding major capsid protein VP1 of human Trichodysplasia spinulosa‐associated Polyomavirus. High‐resolution crystal structures of complexes demonstrate that the compounds bind to VP1 depending on the favorable combination of carbohydrate ligand and linker. It is found that artificial linkers can replace portions of natural carbohydrate linkers as long as they meet certain requirements such as size or flexibility to optimize contact area between ligand and receptor binding sites. The obtained results will influence the design of future high affinity ligands based on the structures presented here, and they can serve as a blueprint to develop multivalent glycooligomers as inhibitors of viral adhesion.     

Fluorescent Mimetics of CMP‐Neu5Ac Are Highly Potent,Cell‐Permeable Polarization Probes of Eukaryotic and Bacterial Sialyltransferases and Inhibit Cellular Sialylation

Oligosaccharides of the glycolipids and glycoproteins at the outer membranes of human cells carry terminal neuraminic acids, which are responsible for recognition events and adhesion of cells, bacteria, and virus particles. The synthesis of neuraminic acid containing glycosides is accomplished by intracellular sialyl transferases. Therefore, the chemical manipulation of cellular sialylation could be very important to interfere with cancer development, inflammations, and infections. The development and applications of the first nanomolar fluorescent inhibitors of sialyl transferases are described herein. The obtained carbohydrate‐nucleotide mimetics were found to bind all four commercially available and tested eukaryotic and bacterial sialyl transferases in a fluorescence polarization assay. Moreover, it was observed that the anionic mimetics intruded rapidly and efficiently into cells in vesicles and translocated to cellular organelles surrounding the nucleus of CHO cells. The new compounds inhibit cellular sialylation in two cell lines and open new perspectives for investigations of cellular sialylation.