Macrocyclic Metal Complexes for Metalloenzyme Mimicry and Sensor Development

Abstract

Examples of proteins that incorporate one or more metal ions within their structure are found within a broad range of classes, including oxidases, oxidoreductases, reductases, proteases, proton transport proteins, electron transfer/transport proteins, storage proteins, lyases, rusticyanins, metallochaperones, sporulation proteins, hydrolases, endopeptidases, luminescent proteins, iron transport proteins, oxygen storage/transport proteins, calcium binding proteins, and monooxygenases. The metal coordination environment therein is often generated from residues inherent to the protein, small exogenous molecules (e.g., aqua ligands) and/or macrocyclic porphyrin units found, for example, in hemoglobin, myoglobin, cytochrome C, cytochrome C oxidase, and vitamin B12. Thus, there continues to be considerable interest in employing macrocyclic metal complexes to construct low-molecular weight models for metallobiosites that mirror essential features of the coordination environment of a bound metal ion without inclusion of the surrounding protein framework. Herein, we review and appraise our research exploring the application of the metal complexes formed by two macrocyclic ligands, 1,4,7-triazacyclononane (tacn) and 1,4,7,10-tetraazacyclododecane (cyclen), and their derivatives in biological inorganic chemistry. Taking advantage of the kinetic inertness and thermodynamic stability of their metal complexes, these macrocyclic scaffolds have been employed in the development of models that aid the understanding of metal ion-binding natural systems, and complexes with potential applications in biomolecule sensing, diagnosis, and therapy. In particular, the focus has been on "coordinatively unsaturated" metal complexes that incorporate a kinetically inert and stable metal-ligand moiety, but which also contain one or more weakly bound ligands, allowing for the reversible binding of guest molecules via the formation and dissociation of coordinate bonds. With regards to mimicking metallobiosites, examples are presented from our work on tacn-based complexes developed as simplified structural models for multimetallic enzyme sites. In particular, structural comparisons are made between multinuclear copper(II) complexes formed by such ligands and multicopper enzymes featuring type-2 and type-3 copper centers, such as ascorbate oxidase (AO) and laccase (Lc). Likewise, with the aid of relevant examples, we highlight the importance of cooperativity between either multiple metal centers or a metal center and a proximal auxiliary unit appended to the macrocyclic ligand in achieving efficient phosphate ester cleavage. Finally, the critical importance of the Zn(II)-imido and Zn(II)-phosphate interactions in Zn-cyclen-based systems for delivering highly sensitive electrochemical and fluorescent chemosensors is also showcased. The Account additionally highlights some of the factors that limit the performance of these synthetic nucleases and the practical application of the biosensors, and then identifies some avenues for the development of more...

An Off–On–Off Fluorescent Sensor for pH Windows Based on the 13aneN4–Zn2+ System

“…and Supplementary Information, Figure SI1). Derivatives of tetraaza macrocycles are typically based on the 14aneN4 (cyclam) and 12aneN4 (cylen) frameworks, in which easy access to derivatization occurs at the secondary amino groups . However, this often depresses the coordinating ability of the tetraaza ring.…”

Internal Hydrogen Bond Influences the Formation of [2+2] Schiff Base Macrocycle: Open‐Chain Vs. Hemiaminal and Macrocycle Forms

“…[1][2][3][4][5][6][7][8] Indeed, they are capable of binding selectively metal cations or/and organic guests molecules, so many macrocycles have been synthesized as ligands to form metal complexes imitating the role of natural transporters. [1][2][3][4][5][6][7][8] Indeed, they are capable of binding selectively metal cations or/and organic guests molecules, so many macrocycles have been synthesized as ligands to form metal complexes imitating the role of natural transporters.…”

Harnessing the Coordination Chemistry of 1,4,7‐Triazacyclononane for Biomimicry and Radiopharmaceutical Applications

“…Critical for these applications is to exploit the basic principles of coordination chemistry, including Pearson's “hard and soft acids and bases” (HSAB) theory, coordination geometry preferences, and the thermodynamic stability and kinetic inertness of metal complexes . 1,4,7‐Triazacyclononane ([9]aneN 3 or TACN, Scheme ) derivatives represent particularly attractive candidates in this regard because, compared to other tri‐ or tetradentate chelating ligands, their metal complexes can have much larger stability constants . Synthetic elaboration of TACN with a range of pendant groups has proven successful for controlling the coordination sphere and its ability to form complexes with metals, as well as for introducing imaging and sensing capabilities .…”

“…1,4,7‐Triazacyclononane ([9]aneN 3 or TACN, Scheme ) derivatives represent particularly attractive candidates in this regard because, compared to other tri‐ or tetradentate chelating ligands, their metal complexes can have much larger stability constants . Synthetic elaboration of TACN with a range of pendant groups has proven successful for controlling the coordination sphere and its ability to form complexes with metals, as well as for introducing imaging and sensing capabilities . Research has generated structural and functional models for active sites of a number of metalloenzymes, which have contributed deeply to our understanding of various aspects of these natural systems.…”

“…Synthetic elaboration of TACN with a range of pendant groups has proven successful for controlling the coordination sphere and its ability to form complexes with metals, as well as for introducing imaging and sensing capabilities . Research has generated structural and functional models for active sites of a number of metalloenzymes, which have contributed deeply to our understanding of various aspects of these natural systems. Similarly, a number of symmetrical and unsymmetrical TACN derivatives integrated with chemically accessible side‐arms have been generated for various medicinal chemistry applications .…”