Reviews in Molecular Biotechnology最新文献

Receptors for carbohydrates of the lectin type are multisubunit and multivalent proteins with many important biological functions. In order to put their unique biological activities into use in biotechnology and biomedicine, efficient carbohydrate ligands of the glycodendrimer type have been constructed. Although these compounds may be branched into the multiple generations, structures bearing four to 16 terminal carbohydrate substituents have proved to be efficient ligands in most lectin systems. These compounds are rapidly finding important practical applications as antitumor and antiinfective compounds.

Multivalent neoglycoconjugates with well-defined structures have considerable potential as inhibitors of cell surface protein–carbohydrate interactions and as tools for studying such recognition processes in vitro. In this review, we outline strategies and synthetic methods for making one such class of neoglycoconjugates based on dendrimers — the so-called glycodendrimers. Glycodendrimers can be classified as: (i) carbohydrate-coated; (ii) carbohydrate-centered; and (iii) fully carbohydrate-based. Approaches to their construction have included both the modification of commercially available dendrimers and de novo dendrimer synthesis. Examples from the authors’ and other laboratories are drawn upon to illustrate design considerations and the application of dendritic synthetic principles — including divergent and convergent syntheses — for making glycodendrimers. Key coupling reactions for the synthesis of glycodendrimers include: amide and thiourea formation; glycosylation; photoaddition to allyl ethers; and reductive amination. The advantages and disadvantages of using protected and unprotected saccharide building blocks and potential applications for glycodendrimers in both biotechnology and materials science are also discussed.

Dendrimers are well-defined hyperbranched macromolecules with characteristic globular structures for the larger systems. The recent impressive strides in synthetic procedures increased the accessibility of functionalized dendrimers at a practicable scale, resulting in a rapid development of dendrimer chemistry. Dendrimers have inspired many chemists to develop new materials and several applications have been explored, catalysis being one of them. The position of the catalytic site(s) as well as the spatial separation of the catalysts within the dendritic framework is of crucial importance. Dendrimers that are functionalized with transition metals in the core can potentially mimic properties of enzymes, their efficient natural counterparts, whereas the surface-functionalized systems have been proposed to fill the gap between homogeneous and heterogeneous catalysis. We prepared both core- and periphery-functionalized dendritic catalysts that are sufficiently large to enable separation by modern nanofiltration techniques. Here we review our recent findings using these promising novel transition metal-functionalized dendrimers as catalysts in several reactions. We will discuss some of the consequences of the architecturally different systems that have been studied and will elaborate on a novel non-covalent strategy of dendrimer functionalization.

Polyglycerol represents the first hyperbranched polymer that can be prepared in a controlled synthesis. It is characterized by the combination of a stable, biocompatible polyether scaffold, high-end group functionality and a compact, well-defined dendrimer-like architecture. These characteristics can be used to generate new materials properties and for biomedical applications to molecularly amplify or multiply effects or to create extremely high local concentrations of drugs, molecular labels, or probe moieties. Therefore, dendritic polyglycerols are expected to lead to new strategies for ‘molecular medicine’. In this brief summary, the current state of the art in polyglycerol research is given, focusing on applications in life sciences.

Peptide dendrimers are radial or wedge-like branched macromolecules consisting of a peptidyl branching core and/or covalently attached surface functional units. The multimeric nature of these constructs, the unambiguous composition and ease of production make this type of dendrimer well suited to various biotechnological and biochemical applications. Applications include use as biomedical diagnostic reagents, protein mimetics, anticancer and antiviral agents, vaccines and drug and gene delivery vehicles. This review focuses on the different types of peptide dendrimers currently in use and the synthetic methods commonly employed to generate peptide dendrimers ranging from stepwise solid-phase synthesis to chemoselective and orthogonal ligation.

The development of efficient methods to transfer genes into eukaryotic cells is important for molecular biotechnology. A number of different technologies to mediate gene transfer have been developed over the last 35 years, but most have drawbacks such as cytotoxicity, low efficiency and/or restricted applicability. Activated polyamidoamine (PAMAM)-dendrimers provide a new technology for gene transfer that offers significant advantages over classical methods. Reagents based on this technology provide high gene transfer efficiencies, minimal cytotoxicity, and can be used with a broad range of cell types. This technology could also be useful for in vivo gene transfer in gene therapy applications.

An overview is presented of the recent developments in the use of dendritic supports in organic synthesis. Examples are presented of the application of dendritic supports in both liquid- and solid-phase organic synthesis. In liquid-phase synthesis, soluble dendrimers are used as the substrate support, while in solid-phase synthesis, ‘dendronized’ insoluble resins are used for this purpose. Selected examples of the synthesis of compound libraries on dendritic supports via combinatorial techniques are discussed.

Glycodendrimers are relatively novel synthetic biomacromolecules that are made of biologically relevant carbohydrate ligands constructed at the periphery of a wide range of highly functionalized and repetitive scaffolds having varied molecular weights and structures. They were aimed to fill the gap between glycopolymers, having generally dispersed higher molecular weight, and small glycoclusters, in the study of multivalent carbohydrate protein interactions. In a way, glycodendrimers, with their spheroidal or dendritic (wedge) type structures, were initially designed as bioisosteres of cell surface multiantennary glycans. Taken as a curiosity and elegant molecules at their beginning, they are now considered as potent inhibitors of microbial adhesins. They have also been shown to play some roles in signal transduction and in receptor cross-linking. This brief report will describe advances that have been made toward the syntheses of a range of glycodendrimers bearing the immunodominant T-antigen disaccharide [β-d-Gal-(1-3)-α-d-GalNAc] found on malignant cells of carcinomas, particularly related to breast cancer. This antigen, usually cryptic on healthy tissues, is greatly increased on cancer cells as a result of aberrant glycosylation. It is considered to be an important cancer marker. The high incidence of these carcinomas to invade other tissues such as lymph nodes, lung, and liver by metastasis was one of the arguments raised to generate T-antigen dendrimers that might have the potential to block the receptor sites following surgery. The synthesis of the T-antigen disaccharide will be briefly described, followed by the elaboration of neoglycoproteins and glycopolymers used to raise monoclonal antibodies against the T-antigen and for screening purpose, respectively. Scaffolds made of poly(amidoamine) (PAMAM), poly(propylene imine), N,N′-bis(acrylamido)acetic acid, and finally hyperbranched l-lysine were used to construct relatively small glycodendrimers bearing T-antigen moieties. Few glycodendrimers were also linked to fluorescein and biotin probes to generate ligands that can be used to detect T-Ag receptor sites.