Aromatic interactions by molecular tweezers and clips in chemical and biological systems.
Noncovalent interactions involving aromatic rings, such as π-stacking and CH-π, occur throughout a range of fundamental processes including self-assembly and (bio)catalysis. Molecular clips and tweezers possess a central parallel or torus-shaped cavity with a surrounding belt of convergent aromatic rings; hence these structures exploit multiple aromatic interactions in a positively cooperative manner. Both clips and tweezers demonstrate selective binding of cationic or neutral guests that bear acceptor groups. The electrostatic surface potentials (ESP) explain this unexpected behavior: calculated ESPs were highly negative inside the tweezer or clip cavity, providing complementary profiles to the positive ESP plots of their preferred guest molecules. This Account presents more complex systems that use aromatic clips and tweezers to alter the reactivities of included guest species, to distinguish between guest enantiomers, and to interfere with biological processes such as enzymatic activity and protein aggregation. Napthalene tweezers show potential applications in organocatalysis. When pyridinium moieties are bound within the spacious cavity of naphthyl-spaced tweezers, the resulting complex significantly influences the first step of single-electron reductions of (bi)pyridinium salts. In addition, the environment within the tweezer cavity strongly accelerates the Menshutkin reaction (the alkylation of pyridine derivatives). Introduction of phosphonate, phosphate, or sulfate anions into the central aromatic bridge renders clips and tweezers water-soluble. Larger systems form extremely tight intertwined dimers that rely on the nonclassical hydrophobic effect for their stability. Smaller clips and tweezers with a simple benzene bridge remain monomeric in buffered aqueous solution and display a complementary binding profile. While the clips with parallel sidewalls prefer flat aromatic cations such as pyridinium salts, the torus-shaped tweezers bind to basic amino acids lysine and arginine via a threading process. These mutually exclusive binding modes make water-soluble clips and tweezers valuable tools for probing critical biological interactions with positively charged amino acid side chains and cofactors. Molecular clips and tweezers can be employed for the complete inhibition of dehydrogenases. The clip extracts NAD(+) from its Rossman fold, while the tweezer complexes access strategic lysine residues around the active site. Our new enzyme inhibitors recognize the protein surface and thus offer additional targets for medicinal chemistry. Finally, the ability of molecular tweezers to cap critical lysine residues can be used to interfere with the pathology of protein misfolding diseases such as Alzheimer's disease, because many of them involve noncovalent interactions with these critical residues during their early stages. When the key protein produces a β-sheet-rich nucleus, this structure undergoes spontaneous polymerization into highly toxic oligomers, ultimately leading to mature fibrils. The benzene-spaced phosphate tweezer forms a specific complex with lysine residues 16 and 28 in Aβ42 and thus prevents the formation of misfolded oligomers rich in β-sheets. This entirely new process-specific mechanism that prevents pathologic protein aggregation also operates in many other related amyloidogenic proteins.
Institute of Organic Chemistry, University of Duisburg-Essen, 45117 Essen, Germany. frank.klaerner@uni-due.de
Frank-Gerrit
FG
Klärner
Thomas
T
Schrader
D001554:Benzene / Q000737:chemistry; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*
D006841:Hydrocarbons, Aromatic; D011506:Proteins; D001554:Benzene