Pure and Applied Chemistry

Abstract: The tetramethylene-bridged molecular tweezers bearing lithium methanephosphonate or dilithium phosphate substituents in the central benzene or naphthalene spacer-unit and the dimethylene-bridged clips containing naphthalene or anthracene sidewalls substituted by lithium methanephosphonate, dilithium phosphate, or sodium sulfate groups in the central benzene spacer-unit are water-soluble. The molecular clips having planar naphthalene sidewalls bind flat aromatic guest molecules preferentially, for example, the nicotinamide ring and/or the adenine-unit in the nucleotides NAD(P)⁺, NMN, or AMP, whereas the benzene-spaced molecular tweezers with their bent sidewalls form stable host–guest complexes with the aliphatic side chains of basic amino acids such as lysine and argenine. The phosphonate-substituted tweezer and the clips having an extended central naphthalene spacer-unit or extended anthracene and benzo[k]fluoranthene sidewalls, respectively, form highly stable self-assembled dimers in aqueous solution, evidently due to non-classical hydrophobic interactions. The phosphate-substituted molecular clip containing naphthalene sidewalls inhibits the enzymatic, ADH-catalyzed ethanol oxidation by binding the cofactor NAD⁺ in a competitive reaction. Surprisingly, tweezer-bearing phosphate substituents in the central benzene spacer-unit are more efficient inhibitors for the ethanol oxidation than the correspondingly substituted naphthalene clip, even though the tweezer does not bind the cofactor NAD⁺ within the limits of detection. The phosphate-substituted naphthalene clip is, however, a highly efficient inhibitor of the enzymatic oxidation of glucose-6-phosphate (G6P) with NADP⁺ catalyzed by glucose-6-phosphate dehydrogenase (G6PD), whereas the phosphonate-substituted clip only functions as an inhibitor by forming a complex with the cofactor. Detailed kinetic, thermodynamic, and computational modeling studies provide insight into the mechanism of these novel enzyme inhibition reactions.