Synthesis of amphiphilic biodegradable glycocopolymers based on poly(ε‐caprolactone) by ring‐opening polymerization and click chemistry

Amphiphilic, biodegradable block glycopolymers based on poly(ε‐caprolactone) (PCL) with various pendent saccharides were synthesized by combination of ring‐opening polymerization (ROP) and “click” chemistry. PCL macroinitiators obtained by ROP of ε‐caprolactone were used to initiate the ROP of 2‐bromo‐ε‐caprolactone (BrCL) to get diblock copolymers, PCL‐b‐PBrCL. Reaction of the block copolymers with sodium azide converted the bromine groups in the PBrCL block to azide groups. In the final step, click chemistry of alkynyl saccharides with the pendent azide groups of PCL‐b‐PBrCL led to the formation of the amphiphilic block glycopolymers. These copolymers were characterized by ¹H NMR spectroscopy and gel permeation chromatography. The self‐assembly behavior of the amphiphilic block copolymers was investigated using transmission electron microscopy and atomic force microscope, spherical aggregates with saccharide groups on the surface were observed, and the aggregates could bind reversibly with Concanavalin A. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3583–3594, 2009     

Protecting‐group‐free synthesis of glycopolymers bearing thioglycosides via one‐pot monomer synthesis from free saccharides

Polyacrylamides having pendant thioglycosides were successfully synthesized from thioglycosidic monomers that were readily prepared by one‐pot method without any protection of the hydroxy groups on the starting free saccharides. The glycomonomers were synthesized by the direct synthesis of thioglycosides using 2‐chloro‐1,3‐dimethylimidazolinium chloride and 4‐aminobenzentiol, and the following acrylamidation. They were co‐polymerized with acrylamide into glycopolymers by reversible addition‐fragmentation chain transfer polymerization using a trithiocarbonate derivative as a chain transfer agent. The gold nanoparticles and gold‐coated quartz crystal microbalance sensor immobilized with the thiol‐terminated glycopolymers exhibited high affinity for the corresponding lectins due to multivalent interaction between saccharides and protein in aqueous solution. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3513–3520     

Preparation of glycopolymer‐substituted gold nanoparticles and their molecular recognition

Glycopolymer‐substituted gold nanoparticles were prepared via living radical polymerization with a reversible addition‐fragmentation chain transfer (RAFT) reagent. Polyacrylamide derivatives with α‐mannose (α‐Man) and N‐acetyl‐β‐glucosamine (β‐GlcNAc) were synthesized and hydrogenated to obtain thiol‐terminated polymer. The thiol‐terminated glycopolymers were mixed with gold nanoparticles to yield the polymer substituted gold nanoparticles with various diameters, which aggregated on addition of saccharide‐recognition proteins (lectins). The aggregation properties were analyzed using transmission electron microscopy and UV spectra. Molecular recognition was studied with E. coli, which induced aggregation of the nanoparticles at the cell periphery. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1412–1421, 2009     

Recent advances in the synthesis of well-defined glycopolymers

Glycopolymers are receiving increasing interest due to their application in areas, such as glycomics, medicine, biotechnology, sensors, and separation science. Consequently, new methods for their synthesis are constantly being developed, with an increasing emphasis on the preparation of well-defined polymers and on the production of complex macromolecular architectures such as stars. This review covers recent developments in the synthesis of glycopolymers, with a particular emphasis on (i) the use of controlled radical polymerization to prepare well-defined glycopolymers from unprotected monomers and (ii) postpolymerization modification strategies using reactive polymer precursors (including “click” reactions). Recent work on the production of glycosylated polypeptides, which are under investigation as mimics of naturally occurring glycoproteins, is also included. The authors offer some suggestions as to future developments and remaining challenges in this topical area of polymer chemistry. © 2007 Wiley Periodicals, Inc. J Polym Sci PartA: Polym Chem45: 2059–2072, 2007     

Synthesis of glycopeptides from glucosaminic acid

We report on the synthesis of polypeptides with saccharide side chains starting from d ‐glucosaminic acid. The hydroxyl groups were first protected by benzylation, followed by N‐carboxyanhydride formation, which was polymerized by ring opening to form a high molecular weight polyamide. De‐protection of the benzyl groups yields a polypeptide with fully de‐protected saccharide side chains. The resulting new non‐ionic, water soluble, and optically active polymers possessing the properties of both peptides and saccharides have potential use as scaffolds for tissue engineering and drug carriers. The method described here may be extended to any saccharide α‐amino acid. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 2657–2662     

Novel well‐defined glycopolymers synthesized via the reversible addition fragmentation chain transfer process in aqueous media

We describe here the direct synthesis of novel gluconamidoalkyl methacrylamides by reacting D ‐gluconolactone with aminoalkyl methacrylamides. The glycomonomers were then successfully polymerized via the reversible addition‐fragmentation chain transfer process (RAFT) using 4‐cyanopentanoic acid dithiobenzoate (CTP) as chain transfer agent and 4,4′‐azobis(4‐cyanovaleric acid) (ACVA) as the initiator in aqueous media. Well‐defined polymers were obtained as revealed by gel permeation chromatography. Diblock copolymers were then synthesized by the macro‐CTA approach. The cationic glycopolymers were subsequently used in the formation of nanostructures via the complexation with plasmid DNA. As noted by dynamic light scattering, monodisperse nanoparticles were obtained via the electrostatic interaction of the cationic glycopolymer with DNA. The sizes of the nanoparticles formed were found to be stable and independent of pH. In vitro cell viability studies of the glycopolymers were carried out using HELA cell lines. The RAFT synthesized glycopolymers and cationic glyco‐copolymers revealed to be nontoxic. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 614–627, 2009     

A detailed study on understanding glycopolymer library and Con A interactions

Synthetic glycopolymers are important natural oligosaccharides mimics for many biological applications. To develop glycopolymeric drugs and therapeutic agents, factors that control the receptor‐ligand interaction need to be investigated. A library of well‐defined glycopolymers has been prepared by the combination of copper mediated living radical polymerization and CuAAC click reaction via post‐functionalization of alkyne‐containing precursor polymers with different sugar azides. Employing Concanavalin A as the model receptor, we explored the influence of the nature and densities of different sugars residues (mannose, galactose, and glucose) on the stoichiometry of the cluster, the rate of the cluster formation, the inhibitory potency of the glycopolymers, and the stability of the turbidity through quantitative precipitation assays, turbidimetry assays, inhibitory potency assays, and reversal aggregation assays. The diversities of binding properties contributed by different clustering parameters will make it possible to define the structures of the multivalent ligands and densities of binding epitopes tailor‐made for specific functions in the lectin‐ligand interaction. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2588–2597     

One‐pot synthesis of hyperbranched glycopolymers by RAFT polymerization

Soluble hyperbranched glycopolymers were prepared by copolymerization of glycan monomers with reversible addition‐fragmentation chain transfer polymerization (RAFT) inimers in a simple one‐pot reaction. Two novel RAFT inimers, 2‐(methacryloyloxy)ethyl 4‐cyano‐4‐(phenylcarbonothioylthio)pentanoate (MAE‐CPP) and 2‐(3‐(benzylthiocarbonothioylthio)propanoyloxy)ethyl acrylate (BCP‐EA) were synthesized and used to prepare hyperbranched glycopolymers. Two types of galactose‐based saccharide monomers, 6‐O‐methacryloyl‐1,2:3,4‐di‐O‐isopropylidene‐D ‐galactopyranose (proGal‐M) and 6‐O‐(2′‐acrylamido‐2′‐methylpropanoate)‐1,2:3,4‐di‐O‐isopropylidene‐D ‐galactopyranose (proGal‐A), containing a methacrylate and an acrylamide group, respectively, were also synthesized and polymerized under the mediation of the MAE‐CPP and BCP‐EA inimers, respectively. In addition, hyperbranched poly(proGal‐M), linear poly(proGal‐A), and hyperbranched poly(proGal‐A) were generated and their polymerization kinetics were studied and compared. An unexpected difference was observed in the kinetics between the two monomers during polymerization: the relationship between polymerization rate and concentration of inimer was totally opposite in the two monomer–inimer systems. Branching analysis was conducted by using degree of branching (DB) as the measurement parameter. As expected, a higher DB occurred with increased inimer content. Furthermore, these polymers were readily deprotected by hydrolysis in trifluoroacetic acid solution resulting in water‐soluble polymers. The resulting branched glycopolymers have potential as biomimetics of polysaccharides. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis of poly(oxyethylene phosphoramidate)s and glycopolymers via Staudinger reaction: Multivalent binding studies with Concanavalin A

A new method for the preparation of poly(oxyethylene phosphoramidate)s and glycopolymers is developed via modification of poly(oxyethylene H‐phosphonate) which is a biodegradable, biocompatible and low toxic polymer. The phosphonate groups of the precursor are converted into tri‐coordinated phosphorus species yielding poly(oxyethylene trimethylsilyl phosphite). The latter is then reacted with different azides, including sugar azides, via Staudinger reaction to furnish the desired poly(oxyethylene phosphoramidate)s and such containing sugar moieties in the side chains attached to the P‐centers. 2002P NMR spectroscopy is applied as a powerful tool for determination of the conversion and structure of the reaction products. Studies on Concanavalin A binding to the obtained glycopolymers are performed using dynamic light scattering and analytical ultracentrifugation techniques. The viability of Human Embryonic Kidney 293 cell line is slightly affected when exposed to polyphosphoramidate glucoconjugate over a broad range of concentrations. The results obtained are encouraging for further investigations on the clustering and bio‐recognition properties of the synthesized glycopolymers. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 1730–1741     

含糖聚合物的酶促合成

介绍含糖聚合物的酶促催化合成研究进展，主要包括主链含糖聚糖酯，支链含糖聚合物，中心为糖的星形取合物，硅烷主链含糖聚合物等。主链含糖聚合物直接由酶促催化酯化或酯交换作用制得；支链含糖聚合物由酶促合成糖酯单体及单体的化学聚合两步制得。     

Synthesis and characterization of poly(vinyl amine)‐based amphiphilic comb‐like dextran glycopolymers by a two‐step method

Poly(vinyl amine) (PVAm)‐based amphiphilic glycopolymers were synthesized by a two‐step method, that is dextran molecules (Dex, M_w = 1500) were attached to the PVAm backbone by reacting amine groups with dextran lactone, and then, hexanoyl groups (Hex) were attached by reacting the PVAm free amine groups with N‐(hexanoyloxy)succinimide. By adjustment of the feed ratios of Dex/Hex, amphiphilic comb‐like glycopolymers with various hydrophilic and hydrophobic balances were prepared, and their structures were characterized by ¹H NMR. Surface activity of the amphiphilic glycopolymers at the air/water interface was demonstrated by reduction in water surface tension. Adsorption of the amphiphilic glycopolymers at the solid/water interface was examined on octadecyltrichlorosilane (OTS)‐coated coverslips by water contact angle measurements. The results show that the amphiphilic glycopolymers need about 20 mol % of dextran attachment to make an effective hydrophilic coating. In comparison with the one‐step reaction by addition of dextran lactone and alkyl succinimide simultaneously, the two‐step approach can attach Dex on PVAm as high as possible in the first step, and offers quantitative advantages in controlling the ratio of hydrophilic and hydrophobic chains along the PVAm backbone, resulting in increased water solubility for the final amphiphilic glycopolymers. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 192–199, 2006     

Glycopolymers resulting from ethylene–vinyl alcohol copolymers: Synthetic approach,characterization, and interactions with lectins

Ethylene–vinyl alcohol copolymers, EVOH, with two different vinyl alcohol compositions have been functionalized with carboxylic acid groups by reaction with phthalic anhydride. Later on, the coupling reaction of three aminosaccharides (D ‐(+)‐glucosamine, D ‐(+)‐galactosamine, and D ‐(+)‐mannosamine) to functionalized EVOH copolymers has been carried out in dimethyl sulfoxide at 70 °C to achieve water soluble glycopolymers. The structure of the resulting functionalized copolymers and the new glycopolymers was confirmed by ¹H and ¹³C NMR. Likewise, the thermal behavior of glycopolymers has been performed by differential scanning calorimetry and thermal gravimetric analysis. In addition, their affinity to lectins, specifically to Concanavalin A and Ricinus Communis Agglutinin, has been evaluated. © Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7238–7248, 2008     

1-(2-萘基)-3-甲基-5-吡唑啉酮衍生试剂的制备及其在高效液相色谱-质谱法测定糖类化合物中的应用

以1-(2-萘基)-3-甲基-5-吡唑啉酮(NMP)作为柱前衍生试剂,建立了简单、灵敏的糖类组分的反相高效液相色谱测定方法。NMP与糖在氨为催化剂的条件下,于70 ℃下反应可获得稳定的衍生产物。在Hypersil ODS 2反相色谱柱上,实现了8种单糖的基线分离。衍生物线性相关系数均大于0.9985,检出限为0.58～1.1 pmol。利用柱后在线串联质谱的电喷雾电离正离子模式监测,获得了各组分的质谱定性及裂解规律,特别是m/z 473的特征碎片离子可作为单糖NMP衍生物的判定依据。与1-苯基-3-甲基-5-吡唑啉酮(PMP)相比,NMP对糖的衍生化具有灵敏、简单、质谱裂解规律性强、重现性好等优点。该方法用于测定油菜花粉多糖中的单糖组成,结果令人满意。     

Prepolymerization and postpolymerization functionalization approaches to fluorescent conjugated carbazole‐based glycopolymers via “click chemistry”

Facile prepolymerization and postpolymerization functionalization approaches to prepare well‐defined fluorescent conjugated glycopolymers through Cu(I)‐catalyzed azide/alkyne “Click” ligation were explored. Two well‐defined carbazole‐based fluorescent conjugated glycopolymers were readily synthesized based on these strategies and characterized by ¹H NMR, ¹³C NMR, IR spectra, and UV‐vis spectra. The “Click” ligation offers a very effective conjugation method to covalently attach carbohydrate residues to fluorescent conjugated polymers. In addition, the studies of carbohydrate–lectin interactions were performed by titration of concanavalin A (Con A) to D ‐glucose‐bearing poly(anthracene‐alt‐carbazole) copolymer P‐2 resulting in significant fluorescence quenching of the polymer due to carbohydrate–lectin interactions. When peanut agglutinin (PNA) was added, no distinct change in the fluorescent properties of P‐2 was observed. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2948–2957, 2009     

Controlled block glycopolymers able to bind specific proteins

The syntheses of a variety of amphiphilic block glycopolymers based on 2‐{[(D ‐glucosamin‐2‐N‐yl)carbonyl]oxy}ethyl acrylate and n‐butyl acrylate or methyl methacrylate by single‐electron transfer‐living radical polymerization (SET‐LRP) are described. In a first step, the homopolymerization of unprotected acrylic glycomonomer to obtain well‐controlled glycopolymers is studied. Posterior and based on these studies, di‐ and triblock glycopolymers were synthesized via SET‐LRP of the glycomonomer from different hydrophobic blocks, varying the hydrophilic block lengths. All the copolymers are characterized by nuclear magnetic resonance spectroscopy and GPC. Moreover, their water solution behavior by dynamic light scattering and their capacity of interaction with Concanavalin A lectin by turbidimetry are analyzed. The effect on the block glycopolymers behavior of hydrophobic block nature and the length of glycopolymer segments is evaluated. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Aqueous synthesis of sialylglycopeptide-grafted glycopolymers with high affinity for the lectin and the influenza virus hemagglutinin

Glycopolymers with pendant complex-type sialyl N-glycans containing heptapeptides, that is, sialylglycopeptides (SGPs), were synthesized using a water soluble polymer backbone bearing N-hydroxysulfosuccinimidyl esters by post-polymerization modification in water. Although SGP has three amino groups on the peptide chain, the substitution reaction occurs preferentially at the N-terminus α-amino group in the lysine residue onto the polymer side chain because the reactivity of such α-amino group is higher than that of the ε-amino group in the lysine residue under mild acidic aqueous condition. The resulting SGP-grafted glycopolymers exhibited strong interaction with the lectin Sambucus sieboldiana agglutinin and the human influenza A virus hemagglutinin, with higher binding associate constant values than those of free saccharide according to quartz crystal microbalance analysis. © 2020 Wiley Periodicals, Inc. J. Polym. Sci. 2020 , 58, 548–556     

Porphyrin-bile acid conjugates: from saccharide recognition in the solution to the selective cancer cell fluorescence detection

This paper describes the preparation and use of conjugates of porphyrins and bile acids as ligands to bind to tumor expressed saccharides. Bile acid-porphyrin conjugates were tested for recognition of saccharides that are typically present on malignant tumor cells. Fluorescence microscopy, in vitro PDT cell killing, and PDT of subcutaneous 4T1 mouse tumors is reported. High selectivity for saccharide cancer markers and cancer cells was observed. This in vivo and in vitro study demonstrated high potential use for these compounds in targeted photodynamic therapy.     

Boronic acid based peptidic receptors for pattern-based saccharide sensing in neutral aqueous media, an application in real-life samples

The advent of the alternative sweeteners market has signaled a demand for chemosensors which target multiple saccharides and saccharide derivatives, in aqueous media at physiological pH. This demand has largely been unmet as existing molecular receptors for saccharides have generally not shown sufficient degrees of affinity and selectivity in aqueous media. A chemosensor array for saccharides and saccharide derivatives, fully operational in aqueous media at physiological pH, has been developed and is reported herein. Boronic acid based peptidic receptors, derived from a combinatorial library, served as the cross-reactive sensor elements in this array. The binding of saccharides to these receptors was assessed colorimetrically using an indicator uptake protocol in the taste-chip platform. The differential indicator uptake rates of these receptors in the presence of saccharides were exploited in order to identify patterns within the data set using linear discriminant analysis. This chemosensor array is capable of classifying disaccharides and monosaccharides as well as discriminating compounds within each saccharide group. Disaccharides have also been distinguished from closely related reduced-calorie counterparts. This linear discriminant analysis set was then employed as a training set for identifying a specific saccharide in a real-world beverage sample. The methodology developed here augurs well for use in other real-world samples involving saccharides as well as for sensing other desired analytes.     

Synthesis of well‐designed polymers carrying saccharide moieties via RAFT miniemulsion polymerization

Two hydrophobic vinyl saccharide monomers based on D ‐glucose and D ‐fructose were polymerized by employing the reversible addition‐fragmentation transfer (RAFT) miniemulsion polymerization technique to prepare well‐designed glycopolymers. Three dithiobenzoate‐RAFT agents [S?C(Ph)S? R], 1‐phenylethyl dithiobenzoate (PED), 2‐phenylprop‐2‐yl dithiobenzoate (PPD), and 2‐cyanoprop‐2‐yl dithiobenzoate (CPD), were used to control the growth of polymer chains. The best results were obtained in the presence of the PPD‐RAFT agent and the formed polymers have polydispersity index's (PDI) lower than 1.15. Under adequate miniemulsion polymerization conditions, a glycopolymer with PDI of 1.1 and molecular weight of 5 × 10⁴ g/mol has been successfully synthesized in a short reaction time of 100 min. Furthermore, some block copolymers containing saccharide segment with butyl or methyl methacrylate were prepared. Copyright © 2007 John Wiley & Sons, Ltd.     

Comparison of systematically functionalized heterogeneous and homogenous glycopolymers as toxin inhibitors

Multivalent glycosylated polymers and particles display enhanced binding affinity toward lectins compared to individual glycans. The design of glycopolymers with selectivity toward pathogen‐associated lectins (toxins) for sensing or in antiadhesion therapy is complicated due to lectins having promiscuous binding profiles and can be considered to be pattern recognition “readers,” with the capability to bind to several different glycans. Here, heterogeneous glycopolymers bearing variable densities of two different monosaccharides are synthesized by a three‐step postpolymerization modification approach, enabling systematic control over composition. It is found that heterogeneous polymers displayed increased inhibitory activity, compared to homogeneous polymers, against a RCA₁₂₀ and the cholera toxin. This demonstrates that embracing heterogeneity in glycomaterials could result in improved performance or emergent properties. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 40–47