Molecular Recognition of Disaccharides in Water: Preorganized Macrocyclic or Adaptive Acyclic?

When facing the dilemma of following a preorganized or adaptive design approach in conceiving the architecture of new biomimetic receptors for carbohydrates, shape-persistent macrocyclic structures were most often chosen to achieve effective recognition of neutral saccharides in water. In contrast, acyclic architectures have seldom been explored, even though potentially simpler and more easily accessible. In this work, comparison of the binding properties of two structurally related diaminocarbazolic receptors, featuring a macrocyclic and an acyclic tweezer-shaped architecture, highlighted the advantages provided by the acyclic receptor in terms of selectivity in the recognition of 1,4-disaccharides of biological interest. Selective recognition of GlcNAc2, the core fragment of N-glycans exposed on the surface of enveloped viruses, stands as an emblematic example. NMR spectroscopic data and molecular modeling calculations were used to ascertain the differences in binding mode and to shed light on the origin of recognition efficacy and selectivity.