Dendritic Galactosides Based on a β ‐Cyclodextrin Core for the Construction of Site‐Specific Molecular Delivery Systems: Synthesis and Molecular Recognition Studies

In order to evaluate the ability of multivalent glycosides based on a β ‐cyclodextrin core as site‐specific molecular carriers, a study on both the inclusion complexation behaviour and lectin binding affinity of branched and hyperbranched β ‐cyclodextrins is presented. A series of cluster galactosides constructed on β ‐cyclodextrin scaffolds containing seven 1‐thio‐ β ‐lactose or β ‐lactosylamine bound to the macrocyclic core through different spacer arms were synthesised. In addition, the first synthesis of three first‐order dendrimers based on a β ‐cyclodextrin core containing fourteen 1‐thio‐ β ‐ D ‐galactose, 1‐thio‐ β ‐lactose and 1‐thio‐ β ‐melibiose residues was performed. Calorimetric titrations performed at 25 °C in buffered aqueous solution (pH 7.4) gave the affinity constants and the thermodynamic parameters for the complex formation of these β ‐cyclodextrin derivatives with guests sodium 8‐anilino‐1‐naphthalenesulfonate (ANS) and 2‐naphthalenesulfonate, and lectin from peanut ( Arachis hypogaea ) (PNA). The persubstitution of the primary face of the β ‐cyclodextrin with saccharides led to a slight increase of the binding constant values for the inclusion complexation with ANS relative to the native β ‐cyclodextrin. However, the increase of the steric congestion due to the presence of the saccharide residues on the narrow rim of the β ‐cyclodextrin may cause a decrease of the binding ability as shown for sodium 2‐naphthalenesulfonate. The spacer arms are not passive elements and influence the host binding ability according to their chemical nature. PNA forms soluble cross‐linked complexes with cluster galactosides and lactosides scaffolded on β ‐cyclodextrin but not with cluster galactopyranosylamines or melibiose. Both, perbranched and hyperbranched β ‐cyclodextrins, form stronger complexes with PNA than the monomeric analogues. However, the use of hyperbranched CDs does not contribute to the improvement of the complex stability relative to heptakis‐glycocyclodextrin derivatives. Finally, a titration experiment with PNA and a complex formed by a heptakis lactose β ‐cyclodextrin derivative with sodium 2‐naphthalenesulfonate showed the formation of a soluble cross‐linked complex with stronger affinity constant and higher stoichiometry than those observed for the complex formation of PNA with the same heptakis‐lactose β ‐cyclodextrin derivative, suggesting the formation of a three component complex.