Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups.

Synthetic carbohydrate receptors (SCRs) that bind cell-surface carbohydrates could be used for disease detection, drug-delivery, and therapeutics, or for the site-selective modification of complex carbohydrates but their potential has not been realized because of remaining challenges associated with binding affinity and substrate selectivity. We have reported recently a series of flexible SCRs based upon a biaryl core with four pendant heterocyclic groups that bind glycans selectively through noncovalent interactions. Here we continue to explore the role of heterocycles on substrate selectivity by expanding our library to include a series of indole and quinoline heterocycles that vary in their regiochemistry of attachment to the biaryl core. The binding of these SCRs to a series of biologically-relevant carbohydrates was studied by 1H NMR titrations in CD2Cl2 and density-functional theory calculations. We find SCR030, SCR034 and SCR037 are selective, SCR031, SCR032, and SCR039 are strong binders, and SCR033, SCR035, SCR036, and SCR038 are promiscuous and bind weakly. Computational analysis reveals the importance of C-H⋯π and H-bonding interactions in defining the binding properties of these new receptors. By combining these data with those obtained from our previous studies on this class of flexible SCRs, we develop a series of design rules that account for the binding of all SCRs of this class and anticipate the binding of future, not-yet imagined tetrapodal SCRs.