A Water Soluble Pd₂L₄ Cage for Selective Binding of Neu5Ac

Abstract

The sialic acid N‐acetylneuraminic acid (Neu5Ac) and its derivatives are involved in many biological processes including cell‐cell recognition and infection by influenza. Molecules that can recognize Neu5Ac might thus be exploited to intervene in or monitor such events. A key obstacle in this development is the sparse availability of easily prepared molecules that bind to this carbohydrate in its natural solvent; water. Here, we report that the carbohydrate binding pocket of an organic soluble [Pd2L4]4+ cage could be equipped with guanidinium‐terminating dendrons to give the water soluble [Pd2L4][NO3]16 cage 7. It was shown by means of NMR spectroscopy that 7 binds selectively to anionic monosaccharides and strongest to Neu5Ac with Ka=24 M−1. The cage had low to no affinity for the thirteen neutral saccharides studied. Aided by molecular modeling, the selectivity for anionic carbohydrates such as Neu5Ac could be rationalized by the presence of charge assisted hydrogen bonds and/or the presence of a salt bridge with a guanidinium solubilizing arm of 7. Establishing that a simple coordination cage such as 7 can already selectively bind to Neu5Ac in water paves the way to improve the stability, affinity and/or selectivity properties of M2L4 cages for carbohydrates and other small molecules.

Molecular Engineering of Carbohydrate Recognition

“…[56] Besides sucrose, two artificial sugar substitutes, sucralose chloride (Suc-Cl 24) and aspartame (Asp 25), could also be strongly bound by receptor 22. Mooibroek and colleagues introduced guanidiniums into palladium-ligand (Pd 2 L 4 ) cages to prepare water-soluble recep- [45][46][47][48][49][50][51][52][53] tors 26 for selective binding of N-acetylneuraminic acid (Neu5Ac) with selectivity > 8 for Neu5Ac compared to other sugars, [57] similar to the previous work by Schmuck. [58] The encapsulation of other components can also impact carbohydrate binding.…”

“…[75] In 2013, they further combined two pyrrolic tripodal moieties together to form a group of eight chiral ditopic receptors to recognize dimannosides. Among these, receptor (S)-55 showed the highest selectivity towards synthetic Oct(αMan)βMan ( 56) over octyl mannosides and Oct(αMan)αMan (57) in mixed CDCl 3 /DMF. [76]…”

“…In addition, similar cages were prepared as synthetic Ca 2+ ‐dependent lectin mimics, [101] octyl mannoside receptors, [102] and synthetic galectin mimics [103] . Introducing four pendant guanidium chains as solubilizing groups, a water‐soluble cage was developed that could selectively recognize anionic monosaccharide N‐Acetylneuraminic acid (NANA) with moderate binding affinity [57] . The selectivity was attributed to charge‐assisted hydrogen bonding and/or salt bridge formation between the NANA carboxylic acid moiety and guanidinium groups on the cage.…”

Towards Biomimetic Recognition of Glycans by Synthetic Receptors

“…The metal‐assembling strategy is indeed convenient to obtain polycyclic structures that generally requires long synthesis concerning macrocyclizations with low yields. Receptor 19 (Scheme 6) is a Pd 2 L 4 cage, where L is a dipyridyl ligand [92] . The guanidinium terminal functions of R groups are responsible of the water solubility and the receptor shown to recognize Neu5Ac in water with an affinity of K a =24.0 M −1 and good selectivity among other anionic monosaccharides such as glucuronic acid and galacturonic acid.…”

“…Receptor 19 (Scheme 6) is a Pd 2 L 4 cage, where L is a dipyridyl ligand. [92] The guanidinium terminal functions of R groups are responsible of the water solubility and the receptor shown to recognize Neu5Ac in water with an affinity of K a = 24.0 M À 1 and good selectivity among other anionic monosaccharides such as glucuronic acid and galacturonic acid.…”