Applications of scorpionate ligands in enzyme modeling and biological studies

Forty-three years ago Swiatoslaw Trofimenko in a truthfully seminal paper introduced the “Boron-Pyrazole Chemistry”. It is likely that even Trofimenko could not have foreseen the true immensity of the field that was to spring from his pioneering discovery of the poly(pyrazolyl)borates or “scorpionates” ligands. In fact, tris(pyrazolyl)borates are a very useful class of monoanionic, nitrogen-based, auxiliary ligands in coordination, organometallic and bioinorganic chemistry. They readily coordinate, usually as face-capping tridentate ligands, to a wide variety of metal ions affording stable metal complexes. Furthermore, it is possible to modify the steric and electronic properties of these ligands quite easily by varying the number and nature of substituents on the pyrazolyl rings and on the boron atom, thereby providing a convenient avenue to finetune the properties at the tris(pyrazolyl)borate ligand bound metal center. Actually, more than 3000 papers have appeared in the intervening years concerned with the coordination chemistry of this versatile class of ligands. In surveying this literature notes a recurrent feature is the acknowledgement to Jerry Trofimenko for generously providing samples of his ligands to help others initiate work. This generosity has no doubt played a role in the wider embrace of these ligands and stands as an example to enforce the name of Trofimenko’s ligands. Scorpionates have been extensively used in biomimetic chemistry as spectator ligands, which modulate the electronic and steric properties of the metal ion and of the co-ligands or actor ligands, but are not directly involved in the metal-based reactivity. A common approach for obtaining synthetic analogues of the type [{XYZ}M-L] (e.g., L = OH, H2O, Cys, etc.) involves the application of tridentate ligands which incorporate the requisite X, Y, and Z donor groups to mimic the protein residues that bind metals at the active site. In particular, tripodal ligands in which the X, Y, and Z groups are attached to a common tetrahedral (or trigonal pyramidal) center have proven to be of particular benefit for several reasons: a) tripodal ligands enforce the “facial” binding that is required to create a tetrahedral metal center; b) tripodal ligands typically possess only a single relevant binding conformation; c) as a consequence of the directional nature of tripodal ligands, it is possible to incorporate substituents that directly influence the steric environment about the metal center; d) the substituents on these ligands can be readily modified to provide a means to influence both the size of the coordination pocket and the electronic properties of the metal center. One of the most versatile tripodal ligand typology that can be utilized for biomimetic purposes is represented by the scorpionates. The pyrazole rings of these ligands can in fact be considered as good models of the histidine residues of proteins, and their spatial disposition provide the steric arrangements found in many active sites. In addition, from a synthetic point of view, the steric and electronic properties of these ligands can be easily modulated by placing opportune substituents in close proximity of the N donor atoms. In recent years complexes of scorpionate ligands were successfully used to mimic the activity of enzymes containing various metals such as vanadium, manganese, iron, cobalt, nickel, copper, zinc, molybdenum and tungsten. With this ever-growing wealth of scorpionate-supported coordination and bioinorganic chemistry, this issue would provide a valuable resource for chemists and biologist, clarifying the properties of metal complexes with scorpionate ligands with biological activity or used as models for active sites of enzymes and proteins. The structural and functional characteristics of copper complexes with scorpionate ligands used as synthetic analogues for the binding sites of copper proteins are the subject of the first review. The specific Cu-binding sites examined are: the T3 binuclear and the T2 mononuclear sites of dioxygen-binding proteins, the T1 sites of electron-transfer in blue copper proteins, and the T2 site of nitrite reductase. The second review presents an overview of the active site structure for manganese redox proteins and their model compounds, including the study of manganese(II/III) complexes with pyrazoles and poly(pyrazolyl)borates and the investigation of the biological activity of some Mn-complexes. The third review focuses on the biological uses of methimazole based soft scorpionates and their potential for further study. At the centre of this report is the importance of the sulfur donor set. It becomes evident that the success of this system in modelling bioinorganic motifs stems from a number features of the ligand: the charge does not reside solely on the sulphur atoms, the ligand is not subject to facile oxidation to disulfide and finally it has the ability alter its denticity. In the fourth review some aspects of mononuclear zinc and iron enzymes inhibitor studies with zinc scorpionate ligands have been summarized. In particular this review focus on pharmacological relevant zinc and their scorpionate models, further discussing the chances to extend such biomimetic studies to iron enzymes and scorpionate complexes thereof. The structural and functional properties of group 6 metal complexes with scorpionate ligands, used as synthetic analogues for the binding sites of the molybdenum and tungsten enzymes, are the subject of the last review, together with an introductive overview on the bioinorganic application of scorpionate metal complexes. This issue “Applications of Scorpionate Ligands in Enzyme Modeling and Biological Studies” has analyzed the chemical diversity exhibited by some metal complexes of scorpionate ligands and the overall progress on synthetic analogues of enzyme centers, focusing primarily on systems in which coordination spheres contain poly(pyrazolyl)borate ligands.