Heteroleptic Coordination Environments in Metal-Mediated DNA G-Quadruplexes

The presence of metal centers with often highly conserved coordination environments is crucial for roughly half of all proteins, having structural, regulatory, or enzymatic function. To understand and mimic the function of metallo-enzymes, bioinorganic chemists pursue the challenge of synthesizing model compounds with well-defined, often heteroleptic metal sites. Recently, we reported the design of tailored homoleptic coordination environments for various transition metal cations based on unimolecular DNA G-quadruplex structures, templating the regioselective positioning of imidazole ligandosides L(I). Here, we expand this modular system to more complex, heteroleptic coordination environments by combining L(I) with a new benzoate ligandoside L(B) within the same oligonucleotide. The modifications still allow the correct folding of parallel tetramolecular and antiparallel unimolecular G-quadruplexes. Interestingly, the incorporation of L(B) results in strong destabilization expressed in lower thermal denaturation temperatures T(m). While no transition metal cations could be bound by G-quadruplexes containing only L(B), heteroleptic derivatives containing both L(I) and L(B) were found to complex Cu(II), Ni(II), and Zn(II). Especially in case of Cu(II) we found strong stabilizations of up to ΔT(m) = +34°C. The here shown system represents an important step toward the design of more complex coordination environments inside DNA scaffolds, promising to culminate in the preparation of functional metallo-DNAzymes.