REDOX-DEPENDENT BINDING ABILITY OF A FLAVIN CYCLOPHANE IN AQUEOUS-SOLUTION - HYDROPHOBIC STACKING VERSUS CAVITY-INCLUSION COMPLEXATION

A novel water-soluble fiavinophane (1) and a nonmacrocyclic isoalloxazine comparison compound 3 were prepared. The host-guest binding interactions and the self-association of these flavin derivatives were investigated in an aqueous borate buffer at pH 10 in concentration ranges below 5 × 10-3 mol L-1. The two oxidized derivatives 1a and 3a undergo a very similar, strong self-association, and the experimental data are best explained by the formation of dimers, stabilized by hydrophobic π-π stacking interactions. The free energies for the formation of these dimers are between 3 and 4 kcal mol-1. A significant self-associationis not observed with the reduced forms 1b and 3b. The two oxidized flavin derivatives 1a and 3a show very similar capabilities in host-guest binding. They both form hydrophobic π-π stacking complexes with naphthalene derivatives that are stabilized by free energies of formation of 3-4 kcal mol-1. The experimental data indicate that the fiavinophane 1a does not bind substrates in its cavity because external π-π stacking between guest and isoalloxazine moiety occurs preferentially. Whereas no significant complexation ability is observed for the dihydroisoalloxazine 3b, the reduced fiavinophane 1b forms cavity-inclusion complexes with naphthalene derivatives. These cavity-inclusion complexes are of similar stability to the external π-π stackingcomplexes formed by the oxidized host. The results of the association and binding studies with the oxidized 1a and 3a lead to the conclusion that π-π stacking interactions play a considerable rolein the binding of aromatic substrates in proximity to the isoalloxazine unit of FAD or FMN at flavoenzyme active sites. © 1990, American Chemical Society. All rights reserved.