Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through n-Alkyl Substitution.

Anion transport by synthetic carriers (anionophores) holds promise for medical applications, especially the treatment of cystic fibrosis. Among the factors which determine carrier activity, the size and disposition of alkyl groups is proving remarkably important. Herein we describe a series of dithioureidodecalin anionophores, in which alkyl substituents on one face are varied from C0 to C10 in two-carbon steps. Activities increase then decrease as the chain length grows, peaking quite sharply at C6 . Molecular dynamics simulations showed the transporter chloride complexes releasing chloride as they approach the membrane-aqueous interface. The free transporter then stays at the interface, adopting an orientation that depends on the alkyl substituent. If chloride release is prevented, the complex is positioned similarly. Longer chains tilt the binding site away from the interface, potentially freeing the transporter or complex to move through the membrane. However, chains which are too long can also slow transport by inhibiting movement, and especially reorientation, within the phospholipid bilayer.

Selective glucose sensing in complex media using a biomimetic receptor.

Glucose is a key biomedical analyte, especially relevant to the management of diabetes. Current methods for glucose determination rely on the enzyme glucose oxidase, requiring specialist instrumentation and suffering from redox-active interferents. In a new approach, a powerful and highly selective achiral glucose receptor is mixed with a sample, l-glucose is added, and the induced CD spectrum is measured. The CD signal results from competition between the enantiomers, and is used to determine the d-glucose content. The involvement of l-glucose doubles the signal range from the CD spectrometer and allows sensitivity to be adjusted over a wide dynamic range. It also negates medium effects, which must be equal for both enantiomers. The method has been demonstrated with human serum, pre-filtered to remove proteins, giving results which closely match the standard biochemical procedures, as well as a cell culture medium and a beer sample containing high (70 mM) and low (0.4 mM) glucose concentrations respectively.

A biomimetic receptor for glucose.

Specific molecular recognition is routine for biology, but has proved difficult to achieve in synthetic systems. Carbohydrate substrates are especially challenging, because of their diversity and similarity to water, the biological solvent. Here we report a synthetic receptor for glucose, which is biomimetic in both design and capabilities. The core structure is simple and symmetrical, yet provides a cavity which almost perfectly complements the all-equatorial ß-pyranoside substrate. The receptor's affinity for glucose, at Ka ~ 18,000 M-1, compares well with natural receptor systems. Selectivities also reach biological levels. Most other saccharides are bound approximately 100 times more weakly, while non-carbohydrate substrates are ignored. Glucose-binding molecules are required for initiatives in diabetes treatment, such as continuous glucose monitoring and glucose-responsive insulin. The performance and tunability of this system augur well for such applications.