The development of synthetic agents able to hydrolytically cleave DNA with high efficiency and selectivity is a fascinating challenge that will show the way to obtaining artificial nucleases able to compete with the natural enzymes. This Feature Article highlights the progress reported toward the realization of synthetic nucleases with particular attention to the strategies that can be pursued to improve efficiency and sequence selectivity.

The development of synthetic agents able to hydrolytically cleave DNA with high efficiency and selectivity is still a fascinating challenge. Over the years, many examples have been reported reproducing part of the behaviour of the corresponding natural enzymes. Eventually, even the possibility to apply such systems to the manipulation of DNA of higher organisms has been demonstrated. However, efficiency of enzymes is still unrivalled. This feature article discusses the progress reported toward the realization of synthetic nucleases with particular attention to the comprehension of the reaction mechanisms and to the strategies that need to be addressed to obtain more efficient systems.

The development of synthetic agents able to hydrolytically cleave phosphate diester bonds with high efficiency is a fascinating challenge, which will ultimately open the way to artificial nucleases able to compete with the natural enzymes. This Perspective highlights the progress reported in the realization of hydrolytic catalysts based on the Zn 2+ ion, a metal ion which, due to its peculiar properties, is a very promising candidate. The review critically examines the reactivity of such catalysts toward model substrates and nucleic acids, paying particular attention to the strategies that can be pursued to improve efficiency and sequence selectivity.

The catalytic effects of the Zn(II) complexes of a series of poliaminic ligands in the hydrolysis of the activated phosphodiesters bis-p-nitrophenyl phosphate (BNP) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) have been investigated. The reactions show first-order rate dependency on both substrate and metal ion complex and a pH dependence which is diagnostic of the acid dissociation of the reactive species. The mechanism of the metal catalyzed transesterification of HPNP has been assessed by solvent isotopic kinetic effect studies and involves the intramolecular nucleophilic attack of the substrate alcoholic group, activated by metal ion coordination. The intrinsic reactivity of the different complexes is controlled by the nature and structure of the ligand: complexes of tridentate ligands, particularly if characterized by a facial coordination mode, are more reactive than those of tetradentate ligands which can hardly allow binding sites for the substrate. In the case of tridentate ligands that form complexes with a facial coordination mode, a linear Brønsted correlation between the reaction rate (log k) and the pK(a) of the active nucleophile is obtained. The beta(nuc) values are 0.75 for the HPNP transesterification and 0.20 for the BNP hydrolysis. These values are indicated as the result of the combination of two opposite Lewis acid effects of the Zn(II) ion: the activation of the substrate and the efficiency of the metal coordinated nucleophile. The latter factor apparently prevails in determining the intrinsic reactivity of the Zn(II) complexes.

Self-assembling and self-organizing methodologies are powerful tools for the "bottom-up" approach for the realization of complex structure with functional properties. Recently, this concept has been extended to the design of fluorescent chemosensors providing new exciting potentialities for the development of innovative sensing systems. This Concept Article deals mainly with this new approach and discusses its evolution, applications, and limitations.