Susan E. Matthews

A Pyrenyl-Appended Triazole-Based Calix[4]arene as a Fluorescent Sensor for Cd2+ and Zn2+

The synthesis and evaluation of a novel calix[4]arene-based fluorescent chemosensor 8 for the detection of Cd(2+) and Zn(2+) is described. The fluorescent spectra changes observed upon addition of various metal ions show that 8 is highly selective for Cd(2+) and Zn(2+) over other metal ions. Addition of Cd(2+) and Zn(2+) to the solution of 8 results in ratiometric measurement.

Calixarene-Based Anion Receptors

The selective complexation of anions by synthetic receptors offers a great challenge to the modern chemist. The last ten years have seen a great expansion in the design of synthetic anion receptors. In particular, this review has shown that calixarenes are excellent platforms for the incorporation of numerous ligands for co-operative binding of anions. Their unique topology offers not only the potential for designed cavities, through selective functionalisation, but also the fine tuning of binding due to the hydrophobic nature of the cavity. The development of calixarene based systems has enabled greater understanding of the complex interactions involved in binding, thus offering the prospect of a number of commercial applications as extractants and sensors.

Rational Design and Synthesis of Optimized Glycoclusters for Multivalent Lectin–Carbohydrate Interactions: Influence of the Linker Arm

The design of multivalent glycoclusters requires the conjugation of biologically relevant carbohydrate epitopes functionalized with linker arms to multivalent core scaffolds. The multigram-scale syntheses of three structurally modified triethyleneglycol analogues that incorporate amide moiety(ies) and/or a phenyl ring offer convenient access to a series of carbohydrate probes with different water solubilities and rigidities. Evaluation of flexibility and determination of preferred conformations were performed by conformational analysis. Conjugation of the azido-functionalized carbohydrates with tetra-propargylated core scaffolds afforded a library of 18 tetravalent glycoclusters, in high yields, by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The compounds were evaluated for their ability to bind to PA-IL (the LecA lectin from the opportunistic pathogen Pseudomonas aeruginosa). Biochemical evaluation through inhibition of hemagglutination assays (HIA), enzyme-linked lectin assays (ELLA), surface plasmon resonance (SPR), and isothermal titration microcalorimetry (ITC) revealed improved and unprecedented affinities for one of the monovalent probes (K(d)=5.8 μM) and also for a number of the tetravalent compounds that provide several new nanomolar ligands for this tetrameric lectin.

Cellular Uptake of a Fluorescent Calix[4]arene Derivative

A rapid synthetic route to a nontoxic fluorescently labeled water-soluble calixarene has been developed. Investigation of the cellular uptake of the labeled calixarene, via confocal microscopy, through coincubation with uptake inhibitors demonstrates that uptake is not through the common clathrin coated pits or caveolae (lipid raft) endocytic pathways and that the calixarene derivative localizes within the cytoplasm and does not enter the nucleus. The study demonstrates the power of fluorescent labeling for investigation of interactions between calixarenes and biological systems and the potential for calixarene based intracellular imaging agents.

Antiadhesive properties of glycoclusters against Pseudomonas aeruginosa lung infection

Pseudomonas aeruginosa lung infections are a major cause of death in cystic fibrosis and hospitalized patients. Treating these infections is becoming difficult due to the emergence of conventional antimicrobial multiresistance. While monosaccharides have proved beneficial against such bacterial lung infection, the design of several multivalent glycosylated macromolecules has been shown to be also beneficial on biofilm dispersion. In this study, calix[4]arene-based glycoclusters functionalized with galactosides or fucosides have been synthesized. The characterization of their inhibitory properties on Pseudomonas aeruginosa aggregation, biofilm formation, adhesion on epithelial cells, and destruction of alveolar tissues were performed. The antiadhesive properties of the designed glycoclusters were demonstrated through several in vitro bioassays. An in vivo mouse model of lung infection provided an almost complete protection against Pseudomonas aeruginosa with the designed glycoclusters.

Novel resorcin[4]arenes as potassium-selective ion-channel and transporter mimics.

A series of novel resorcin-[4]arenes with extended pi systems have been synthesised and developed as potassium-selective transporters. Resorcin[4]arenes that feature crown ether moieties function as efficient carriers of K+ across bulk liquid membranes showing enhanced selectivity over the other alkali metal ions relative to a model system (benzo[15]crown-5). Incorporation of functionalities suitable for pore formation, in addition to an extra annulus of aromatic residues, gives molecules which have remarkable ion-channel-mimicking behaviour in a biological lipid bilayer with outstanding K+/Na+ selectivity.

Macromolecular systems for chemotherapy and magnetic resonance imaging

Abstract The potential of macromolecular pro-drugs in drug delivery and diagnostic imaging lies in their ability to modify the pharmacokinetic distribution of low molecular weight drugs or diagnostic agents. At a simple level this may provide a means of sustaining release of drug from a soluble macromolecule which is retained in the circulation, perhaps avoiding distribution of active drug to a toxicity compartment in the process. There is greater potential in applications which make use of the intrinsic biodistribution of inert macromolecules, in relation to their hydrodynamic radius and net charge. Long circulating macromolecular systems may have advantages in magnetic resonance imaging of the blood circulation and diagnosis of damaged or inflamed tissues, which may take up the macromolecule to a greater extent than normal tissues. A related technology is developing based on the concept that circulating macromolecules accumulate passively in tumours, due to enhanced endothelial permeability and retention of the macromolecule due to poor lymphatic drainage. A secondary advantage potentially could be gained by targeting macromolecules to specific cells by receptor-mediated endocytosis, and designing systems which are degraded by lysosomal enzymes to release active drug in the target cell. The drawbacks of macromolecules are their limited penetration into tissues and the relatively slow rates of internalisation by endocytosis, which have discouraged drug delivery scientists in the recent past. Yet this field is still in its infancy. The tissue distribution of macromolecules with regard to polymer chemistry, molecular weight and charge are not yet fully understood, and advances in this field will depend on the synthesis of well-defined polymers, and careful characterisation of their properties. Here we review the rationale for the use of macromolecules in chemotherapy, the susceptibility of macromolecular pro-drugs to lysosomal degradation, developments in synthetic approaches within the field, and discuss how macromolecular pro-drug chemistry affects their biological properties. We pay particular attention to the rationale for their use in magnetic resonance imaging and the selection of MRI contrast agents for coupling to polymers.

Topological Effects and Binding Modes Operating with Multivalent Iminosugar-Based Glycoclusters and Mannosidases

Multivalent iminosugars have been recently explored for glycosidase inhibition. Affinity enhancements due to multivalency have been reported for specific targets, which are particularly appealing when a gain in enzyme selectivity is achieved but raise the question of the binding mode operating with this new class of inhibitors. Here we describe the development of a set of tetra- and octavalent iminosugar probes with specific topologies and an assessment of their binding affinities toward a panel of glycosidases including the Jack Bean α-mannosidase (JBαMan) and the biologically relevant class II α-mannosidases from Drosophila melanogaster belonging to glycohydrolase family 38, namely Golgi α-mannosidase ManIIb (GM) and lysosomal α-mannosidase LManII (LM). Very different inhibitory profiles were observed for compounds with identical valencies, indicating that the spatial distribution of the iminosugars is critical to fine-tune the enzymatic inhibitory activity. Compared to the monovalent reference, the best multivalent compound showed a dramatic 800-fold improvement in the inhibitory potency for JBαMan, which is outstanding for just a tetravalent ligand. The compound was also shown to increase both the inhibitory activity and the selectivity for GM over LM. This suggests that multivalency could be an alternative strategy in developing therapeutic GM inhibitors not affecting the lysosomal mannosidases. Dynamic light scattering experiments and atomic force microscopy performed with coincubated solutions of the compounds with JBαMan shed light on the multivalent binding mode. The multivalent compounds were shown to promote the formation of JBαMan aggregates with different sizes and shapes. The dimeric nature of the JBαMan allows such intermolecular cross-linking mechanisms to occur.

Conformationally Mobile Wide Rim Carbamoylmethylphosphine Oxide (CMPO)-Calixarenes.

Six new calix[4]arene derivatives 2a–f have been synthesised, bearing CMPO-like functions (-NH–C(O)–CH2–P(O)Ph2) at their wide rim. They differ by their alkoxy groups at the narrow rim, comprising all possible combinations of methoxy and syn-propoxy groups including the conformationally mobile tetramethyl ether 2e and the tetrapropyl ether 2f fixed in the cone conformation. Their extraction behaviour for thorium(IV) and several lanthanides(III) from 1M HNO3 to dichloromethane has been studied and compared also to non cyclic calixarene analogues 6a–e. Surprisingly the best extraction results were found for the 1,2-dimethoxy-3,4-dipropoxy derivative 2c among the calixarenes and for the tetramer 6d among the linear compounds. Extraction of americium(III) in comparison to curium(III) and various lanthanides(LaIII), Ce(III), Nd(III), Sm(III), Eu(III)) from 0.1– 3M HNO3 to NPHE (o-nitrophenyl hexyl ether) was most effective again for 2c. Among these cations, the highest distribution coefficients were found for Am(III) and the lowest for Ce(III) with a maximum generally in the range of 1–2M HNO3.

AFM investigation of Pseudomonas aeruginosa lectin LecA (PA-IL) filaments induced by multivalent glycoclusters

Atomic force microscopy reveals that Pseudomonas aeruginosa LecA (PA-IL) and a tetra-galactosylated 1,3-alternate calix[4]arene-based glycocluster self-assemble according to an aggregative chelate binding mode to create monodimensional filaments. Lectin oligomers are identified along the filaments and defects in chelate binding generate branches and bifurcations. A molecular model with alternate 90° orientation of LecA tetramers is proposed to describe the organisation of lectins and glycoclusters in the filaments.