Aminocyclodextrins as polytopic receptors for biologically relevant molecule

Aminocyclodextrins (ACDs), cyclodextrins which are (per) derivatized with amino pendant groups, are attractive compounds to model and affect biological processes. ACDs contain at least two structural domains: a cationic annulus and hydrophobic cyclodextrin cavity provide sites for electrostatic and hydrophobic interactions, respectively. Strength of binding to putative substrates can be controlled with the functionalization of ACDs with different amino pendant groups on the primary face and derivatization of the secondary face of the ACDs.;ACDs have been found to affect neurite growth in vitro. These compounds are peptidomimetic in that they mimic the basement membrane template poly-D-lysine (PDL) in providing sites of interactions with glycosaminoglycan (GAG) sulfates. GAG sulfates are polyanionic sugars of the neuronal environment composed of repeating disaccharide units which are variably N- and O-sulfonated. In order to model the interactions of heterogeneous GAG sulfates with ACD receptors, smaller model systems were examined so that the electrostatic and hydrophobic contributions to binding could be delineated.;Accordingly, small aryl sulfonate, phosphonate and phosphate-containing substrates were chosen to bind to ACDs and the strength and nature of binding was deduced from UV-Vis and 31P NMR spectroscopy. The hydrophobic interaction between such guests and an ACD contributed 0.5--1 kcal/mol to the free energy of binding; the strength of electrostatic interactions was found to depend on the charge of both substrate and ACD receptor at physiological pH. ACDs act as nucleotide receptors. Furthermore, the binding of 5 '-AMP, 5'-ADP, and 5'-ATP to ACDs is more complex than has been portrayed in the literature. Both the enthalpy and entropy of 5'AMP-alphaACD complexation were found to be favourable, suggesting that the entropy gain resulting from desolvation of host and guest contributed to the driving force of complexation. A barrier to 5'-AMPalphaACD complex dissociation of ≥17 kcal/mol was calculated.;While the electrostatic interactions at the primary face contribute to the free energy of binding between ACDs and anionic GAG sulfates, nucleotides, and small aryl anions, it is the secondary face of ACDs that most strongly influences the selectivity of binding.