Dendritic galactosides based on a beta-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 beta-cyclodextrin core as site-specific molecular carriers, a study on both the inclusion complexation behaviour and lectin binding affinity of branched and hyperbranched beta-cyclodextrins is presented. A series of cluster galactosides constructed on beta-cyclodextrin scaffolds containing seven 1-thio-beta-lactose or beta-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 beta-cyclodextrin core containing fourteen 1-thio-beta-D-galactose, 1-thio-beta-lactose and 1-thio-beta-melibiose residues was performed. Calorimetric titrations performed at 25 degrees C in buffered aqueous solution (pH 7.4) gave the affinity constants and the thermodynamic parameters for the complex formation of these beta-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 beta-cyclodextrin with saccharides led to a slight increase of the binding constant values for the inclusion complexation with ANS relative to the native beta-cyclodextrin. However, the increase of the steric congestion due to the presence of the saccharide residues on the narrow rim of the beta-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 beta-cyclodextrin but not with cluster galactopyranosylamines or melibiose. Both, perbranched and hyperbranched beta-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 beta-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 beta-cyclodextrin derivative, suggesting the formation of a three component complex.
Vargas-Berenguel
Antonio
A
Area de Química Orgánica Universidad de Almería, 04120 Almería, Spain. avargas@ual.es
Ortega-Caballero
Fernando
F
Santoyo-González
Francisco
F
García-López
Juan J
JJ
Giménez-Martínez
Juan J
JJ
García-Fuentes
Luis
L
Ortiz-Salmerón
Emilia
E
D000817:Anilino Naphthalenesulfonates / Q000378:metabolism; D010367:Arachis / Q000737:chemistry; D001665:Binding Sites; D002151:Calorimetry; D003505:Cyclodextrins / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005697:Galactosides / Q000138:chemical synthesis* / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D009282:Naphthalenesulfonates / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013816:Thermodynamics; D017186:Titrimetry; D047392:beta-Cyclodextrins
D000817:Anilino Naphthalenesulfonates; D003505:Cyclodextrins; D005697:Galactosides; D037102:Lectins; D009282:Naphthalenesulfonates; D047392:beta-Cyclodextrins; C027132:1-anilino-8-naphthalenesulfonate; C031215:betadex