Current Bioactive Compounds - Volume 5, Issue 4, 2009

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 with 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 tune 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, 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 analogs 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, and 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 appropriate 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 analogs 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 modeling bioinorganic motifs stems from several properties 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 to alter its denticity. The fourth review summarizes some aspects of mononuclear zinc and iron enzymes inhibitor studies with zinc scorpionate ligands. In particular, this review focuses 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 analogs 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” analyzes the chemical diversity exhibited by some metal complexes of scorpionate ligands and the overall progress on synthetic analogs of enzyme centers, focusing primarily on systems in which coordination spheres contain poly(pyrazolyl)borate ligands.

The bioinorganic relevance of copper is made evident by its involvement in many crucial biological functions, which include: (1) dioxygen activation (copper oxidases and oxygenases) and transport (hemocyanin), (2) electron transfer (cupredoxins), and (3) nitrite reduction to nitric oxide (copper nitrite reductases). As metalloprotein chemistry is governed by the environment close to the metal center(s), a fertile field of investigation is concerned with the preparation of low molecular weight complexes that mimic the structural or functional features of protein active sites. Trofimenko's scorpionate ligands 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 (“actor ligands”), but are not directly involved in the metal-based reactivity. The structural and functional properties of copper complexes with scorpionate ligands used as synthetic analogs for the binding sites of copper proteins are the subject of the present review. The specific Cu-binding sites examined are: the T3 binuclear and the T2 mononuclear sites of dioxygen-binding proteins, the T1 sites of electrontransfer in blue copper proteins, and the T2 site of nitrite reductase.

Interest in the biomimetic properties of soft scorpionates based on methimazole commenced shortly after the reported synthesis of the hydrotris(methimazolyl)borate anion (TmMe) in 1996. These ligands are thione based and are thus not subject to facile oxidation and disulfide formation (c.f. thiolates). This allows these species to participate in an extensive coordination chemistry with a wide variety of metals. This review focuses on the chemistry of the RTmR and RBmR ligands with special reference to their use in biomimetic chemistry (alcohol dehydrogenase, Ada repair proteins, 5- aminolevulinate dehydratase, sulfite oxidase, hydrogenase, MerB) and their emerging use as radiopharmaceuticals (rhenium, technetium).

The review starts with a brief summary on pharmaceutical relevant mononuclear zinc and non heme iron enzymes, with a main focus on zincins such as the angiotensin converting enzyme (ACE). Different approaches to classify such enzymes will be discussed. Especially, the main features of the metal binding motifs are highlighted. Recent advances in coordination chemistry with the purpose to mimic these features by small molecule ligands and metal complexes thereof are referred. The review then focuses on current developments in inhibitor studies based on such structural models. Exemplary, tripodal model complexes for matrix metalloproteinases (MMPs) are summarised, which have been successfully applied in identifying new inhibitors e.g. for zincins. Several recently developed inhibitors as well as their coordination modes towards zinc will be reflected. The report will further focus on the quest for new zinc binding groups (ZBGs) in respect of zincin inhibitors. Such novel and up to now rather uncommon ZBGs might have a huge impact on new lead structures in pharmaceutical research. It will be discussed how the model complexes are currently improved by mimicking also the hydrogen bridges in the enzymes active site. Finally, in some sort of perspective, a similar approach for mononuclear non heme iron oxygenases will be discussed.

This review presents an overview of the active site structure for manganese redox proteins and their model compounds. This includes manganese (II/III) complexes with pyrazoles, pyrazolylborates and biological activity of some complexes. The active site structure of native protein, synthesis, crystal structure and catalytic activity of these complexes are reviewed. The plan of the review is: 1. Introduction 2. Synthetic and structural aspect 3. Reactivity aspect 4. Conclusion

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 present review. The group 6 elements molybdenum and tungsten are the only second and third row transition metals essential to all forms of life on Earth. Molybdenum is found at the active sites of nitrogenase and all of the more than 50 known Mo-molybdopterin (Mo- MPT) enzymes that play vital roles in plant, animal, and human health, the carbon, sulfur, and nitrogen cycles, biofeedback systems, and the control of global climate; tungsten is also associated with MPTbased ligands in all its known biological manifestations. Chemical approaches to molybdenum enzyme sites have been directed toward mimicking a portion of the structural center in order to ascertain the role of that particular feature of the center on the chemical reactivity and the spectroscopic properties of the center. Here we attempt to analyze the overall progress on synthetic analogues of these enzyme centers and dissect the contributions of systems in which coordination spheres contain poly(pyrazolyl)borate ligands, focusing primarily on research that has appeared since the structures of the active sites of representative enzymes have become known.