Brendan L. Wilkinson

Synthesis of the bacteriocin glycopeptide sublancin 168 and S-glycosylated variants

The synthesis of sublancin 168, a unique S-glucosylated bacteriocin antibiotic, is described. The natural product and two S-glycosylated variants were successfully prepared via native chemical ligation followed by folding. The synthetic glycopeptides were shown to possess primarily an α-helical secondary structure by CD and NMR studies.

Reversible pH‐ and Photocontrollable Carbohydrate‐Based Surfactants

The parallel synthesis and properties of a library of photoswitchable surfactants comprising a hydrophobic butylazobenzene tail-group and a hydrophilic carbohydrate head-group, including the first surfactants to exhibit dual photo- and pH-responsive behavior, is reported. This new generation of surfactants shows varying micelle morphologies, photocontrollable surface tension, and pH-induced aggregation and adsorption.

Self-Assembly of Long-Chain Betaine Surfactants: Effect of Tailgroup Structure on Wormlike Micelle Formation

Long-chain amidopropyl betaines are known for their ability to self-assemble into viscoelastic wormlike micellar structures. Here, we explore the effect of tailgroup molecular architecture on this process, comparing five molecules, each with C18 chains but different levels of unsaturation and branching. The surfactants are synthesized from stearic, oleic, linoleic, linolenic, and isostearic acids. The self-assembly of these molecules in aqueous solutions is explored using small- and ultra-small-angle neutron scattering (SANS and USANS). It is seen that optimum wormlike micelle formation is achieved for the oleic-chained surfactant, and the alignment of self-assembled structures is further explored using rheo-SANS. The more highly unsaturated molecules form rodlike micelles, whereas the stearic-tailed molecule shows a pronounced Krafft point and the isostearic-chained surfactant is entirely water-insoluble. These results demonstrate the critical importance of tailgroup geometry on surfactant properties and self-assembly for this industrially important class of surfactants.

Synthesis of arabinose glycosyl sulfamides as potential inhibitors of mycobacterial cell wall biosynthesis

A series of arabinose glycosyl sulfamides with varying alkyl chain types and lengths were synthesised as mimics of decaprenolphosphoarabinose (DPA), and as potential inhibitors of mycobacterial cell wall biosynthesis. Unprecedented conversion of the desired furanose to the thermodynamically more stable pyranose form occurred during final de-protection. Biological testing against Mycobacterium smegmatis revealed low to moderate anti-mycobacterial activity with marked dependence on alkyl chain length, which in the case of mono-substituted sulfamides was maximal for a C-10 chain.

Synthesis and Properties of Photoswitchable Carbohydrate Fluorosurfactants

We describe the parallel synthesis, photocontrollable surface tension, and antibacterial performance of a new class of carbohydrate fluorosurfactant. Novel fluorosurfactants comprised a mono- or disaccharide head group linked to an azobenzene unit that was variably substituted with a trifluoromethyl group. Fluorosurfactants were rapidly assembled using the venerable CuI-catalysed azide–alkyne cycloaddition reaction and exhibited light-addressable surface activity, excellent water solubility, and selective antibacterial activity against Gram-positive Staphylococcus aureus. Notably, the physicochemical and biological activity of these novel materials was heavily dependent on the nature of the head group and the position of the trifluoromethyl substituent on the azobenzene ring. The UV-adapted cis-isomer of fluorosurfactants displayed good thermal stability at ambient temperature, with little reversion to the stable trans isomer after 16 h. These novel, light-responsive materials should find broad interest in a range of biomedical and technological fields, including drug and gene delivery, self-cleaning oleophobic surfaces, and antibacterial coatings for medical devices.

NMR characterization of cooperativity: fast ligand binding coupled to slow protein dimerization

We describe a general approach for analysis of 2D NMR spectra to evaluate the cooperativity of ligand binding and protein dimerization in coupled systems. The approach is applicable to systems in which NMR spectra display separate resonances for monomeric and dimeric species but each resonance shifts in response to ligand binding. Three experimental parameters (monomer chemical shift, dimer chemical shift and relative monomer–dimer peak intensity) are fitted globally, as a function of ligand concentration, to yield equilibrium constants for dimerization, monomer–ligand binding and dimer–ligand binding as well as the cooperativity between ligand binding and dimerization. We have applied the approach to characterise a system in which dimerization of the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is coupled to binding of peptides derived from the chemokine receptor CCR2. The global fitting approach allowed evaluation of cooperativity with higher precision than is possible by alternative methods.

1-(Acyloxy)benzotriazoles: Useful Reagents for the Regioselective Acylation of Diols

It is worth noting that HOBt and its monohydrate are now scheduled explosives and can no longer be shipped by sea or airfreight. Owing to this safety concern, great care must be exercised when handling anhydrous HOBt. To alleviate these concerns,HOBt can now be safely shipped andstored when wetted with up to 20wt-% of water. Such material can be used provided a suitable drying agent is employed,orwhenSchotten-Baumannconditionsareused. [3] Acylatingreagents1and 2 exist as a regioisomeric mixture of the O- and N-acylated forms in solution and in the solidstate. [2] Stablebenzotriazoleesters,including1-BBTZ1,havealsobeenshownto

Wormlike micelle formation of novel alkyl-tri(ethylene glycol)-glucoside carbohydrate surfactants: Structure–function relationships and rheology

Carbohydrates are appealing non-ionic surfactant head-groups as they are naturally abundant, generally biocompatible and biodegradable, and readily functionalized. Here, seven novel carbohydrate based surfactants (CBS) have been synthesized that contain a tri-ethylene glycol (TEG) linker between a glucose head-group and alkyl tail-group, with linear saturated (C8-18) and unsaturated (C18:1) alkyl chains. The aqueous adsorption and self-assembly of these surfactants was explored using tensiometry and small- and ultra-small-angle neutron scattering (SANS and USANS). With SANS we observed elongation from spherical to cylindrical micelles with increasing alkyl chain length. C16 and C18 chains exhibited pronounced Krafft points, yet formed worm-like micelles as single components upon heating to 43 and 48 °C respectively. The introduction of mono-unsaturation in the form of a C18:1 chain reduced the Krafft point and gave a surfactant that produced worm-like micelles in water without additives at room temperature. We also observed micellar elongation for C12 and C14 chains at 50 °C due to dehydration of the TEG linker. The room temperature worm-like micelles were further characterized using rheo-SANS and rheology, revealing the C18:1 surfactant to exhibit near ideal Maxwell behavior at low concentrations (2.9 wt.%). These results provide insight into structure-function relationships for CBS, and demonstrate a promising molecular candidate for the formation of viscoelastic worm-like micellar solutions.

1D Self-Assembly and Ice Recrystallization Inhibition Activity of Antifreeze Glycopeptide-Functionalized Perylene Bisimides

Antifreeze glycoproteins (AFGPs) are polymeric natural products that have drawn considerable interest in diverse research fields owing to their potent ice recrystallization inhibition (IRI) activity. Self-assembled materials have emerged as a promising class of biomimetic ice growth inhibitor, yet the development of AFGP-based supramolecular materials that emulate the aggregative behavior of AFGPs have not yet been reported. This work reports the first example of the 1D self-assembly and IRI activity of AFGP-functionalized perylene bisimides (AFGP-PBIs). Glycopeptide-functionalized PBIs underwent 1D self-assembly in water and showed modest IRI activity, which could be tuned through substitution of the PBI core. This work presents essential proof-of-principle for the development of novel IRIs as potential supramolecular cryoprotectants and glycoprotein mimics.

Photoswitchable Janus glycodendrimer micelles as multivalent inhibitors of LecA and LecB from Pseudomonas aeruginosa

The first example of the self-assembly and lectin binding properties of photoswitchable glycodendrimer micelles is reported. Light-addressable micelles were assembled from a library of 12 amphiphilic Janus glycodendrimers composed of variable carbohydrate head groups and hydrophobic tail groups linked to an azobenzene core. Spontaneous association in water gave cylindrical micelles with uniform size distribution as determined by dynamic light scattering (DLS) and small angle neutron scattering (SANS). Trans-cis photoisomerization of the azobenzene dendrimer core was used to probe the self-assembly behaviour and lectin binding properties of cylindrical micelles, revealing moderate-to-potent inhibition of lectins LecA and LecB from Pseudomonas aeruginosa.