Current Medicinal Chemistry (v.17, #31)

Medicinal Inorganic Chemistry is an area of growing interest. Metal compounds have demonstrated their participation in biological processes and their significance in both therapeutic and diagnostic medicine. Bioactivity of many organic drugs is dependent on the presence of metal ions in the biological media. Moreover, coordination of pharmacologically interesting metal ions to suitable ligands constitutes a tool to modulate biological properties of these ions. In addition, the coordination of organic drugs to metal ions commonly improves the original activity, leading in many cases to synergistic or additive effects, or at least to improvement of bioavailability. Consequently, the development of novel metal-based drugs is a current area of research and development in Medicinal Chemistry. In addition, Medicinal Inorganic Chemistry is also involved in the development of noninvasive means of assessing physiology and morphology of tissues and organs, leading to useful information for the diagnosis of disease and the follow-up of its evolution. Besides, Inorganic Chemistry knowledge can be used to treat metal ion overload diseases through the development of suitable metal ion chelating agents or to supplement elements that playing an essential role in living organisms show anomalous deficient levels generating disease. Current research and perspectives on many of these aspects will be included in different contributions of this thematic issue.

Copper Compounds in Cancer Chemotherapy by L. Ruiz-Azuara, M. E. Bravo-Gomez (3606-3615).
Transitional metals have a large variety of coordination numbers and geometries, accessible redox states in physiological conditions and a wide range of thermodynamic and reactivity properties which can be successfully tuned by selection of suitable ligands. These characteristics can be used to develop new drugs with numerous advantages over the organic based drugs. Historically, research in this field has focus on platinum and DNA targeting; however, anticancer drug research may be expanded to include alternative metal compounds with different mode of action resulting in markedly different cytotoxic response profiles. Copper complexes with selected ligands are being extensively studied as agents for the treatment of cancer. Current research on copper compounds as antitumoral compounds is being reviewed in this chapter particularly focused on the family of copper Casiopeinas.

Medicinal Inorganic Chemistry offers the high diversity of metal coordination chemistry for the development of bioactive compounds for therapeutic or diagnostic medicinal purposes. The design of novel metal-based antitumor agents occupies a privileged position in this discovery process. On the other hand, the research on metal-based radiopharmaceuticals for therapy and imaging is a subarea of high priority and development. This review describes therapeutic applications of metal compounds directed towards hypoxic tissues. Strategies in the search for new bioreductive metal-based prodrugs will be discussed. In addition, approaches for the imaging of hypoxic tissues by using metal radionuclides will be exemplified.

Potential Use of Vanadium Compounds in Therapeutics by D. A. Barrio, S. B. Etcheverry (3632-3642).
Vanadium is a trace element present in practically all cells in plants and animals. While the essentiality of vanadium for human beings remains to be well established, vanadium has become an increasingly important environmental metal. Vanadium compounds exert a variety of biological activities and responses. At pharmacological doses, vanadium compounds display relevant biological actions such as insulin and growth factor mimetic or enhancing effects, as well as osteogenic and cardioprotective activity. On the other hand, depending on the nature of compounds and their concentrations, toxicological actions and adverse side effects may also be shown. Nevertheless, the toxic effects may be useful to develop new antitumoral drugs. In this review, the authors summarize current knowledge and new advances on in vitro and in vivo effects of inorganic and organically-chelated vanadium compounds. The effects of vanadium derivatives on some cellular signaling pathways related to different diseases are compiled. In particular, the pathways relevant to the insulin mimetic, osteogenic, cadioprotective and antitumoral actions of vanadium compounds have been comprehensively reviewed. The knowledge of these intracellular signaling pathways may facilitate the rational design of new vanadium compounds with promising therapeutic applications as well as the understanding of secondary side effects derived from the use of vanadium as a therapeutic agent.

Tailoring NO Donors Metallopharmaceuticals: Ruthenium Nitrosyl Ammines and Aliphatic Tetraazamacrocycles by E. Tfouni, F G. Doro, L. E. Figueiredo, J. C.M. Pereira, G. Metzke, D. W. Franco (3643-3657).
The discovery of the involvement of nitric oxide (NO) in several physiological and pathophysiological processes launched a spectacular increase in studies in areas such as chemistry, biochemistry, and pharmacology. As a consequence, the development of NO donors or scavengers for regulation of its concentration and bioavailability in vivo is required. In this sense, ruthenium nitrosyl ammines and aliphatic tetraazamacrocyles have attracted a lot of attention due to their unique chemical properties. These complexes are water soluble and stable in solution, not to mention that they can deliver NO when photochemically or chemically activated by the reduction of the coordinated nitrosonium (NO+). The tuning of the energies of the charge transfer bands, the redox potential, and the specific rate constants of NO liberation, in both solution and matrices, is desirable for the achievement of selective NO delivery to biological targets, hence making the ruthenium ammines and aliphatic tetraazamacrocyles a quite versatile platform for biological application purposes. These ruthenium nitrosyls have shown to be active in firing neurons in mouse hippocampus, performing redox reactions in mitochondria, acting in blood pressure control, exhibiting cytotoxic activities against trypanosomatids (T.cruzi and L.major) and tumor cells. This tailoring approach is explored here, being heavily supported by the accumulated knowledge on the chemistry and photochemistry of ruthenium complexes, which allows NO donors/scavengers systems to be custom made designed.

Chelation therapy occupies a central place in modern medicine and pharmacology, because continuous studies with laboratory animals and extensive clinical experience demonstrate that acute or chronic intoxications with a variety of metals can be considerable improved by administration of a suitable chelating agent. In this review the chemical characteristics, properties and uses of the most common chelating agents as well as those of some new and very promising agents of this type, are discussed. In the second part of the review the biological and biochemical impact of these agents, as well as their use for the treatment of some selected diseases and disorders, are also analyzed and discussed in detail.

Radiometals have become increasingly important because of their use both for diagnostic molecular imaging and therapy in Nuclear Medicine. The focus is on the study of biochemical processes at cellular and sub-cellular level in order to detect metabolic abnormalities associated with various diseases. For that purpose, molecules that selectively accumulate in the organ or tissue of interest by a specific mechanism such as receptor binding or interaction with biomolecules are labeled with 99mTc, 68Ga, 153Sm, 186/188Re, 177Lu, among others and used as radiopharmaceuticals. However, considerable effort is necessary to combine these radionuclides with biomolecules relevant to different pathological conditions. Intensive research on the coordination chemistry of these metals has led to novel labeling methods that yield stable compounds which retained the original biological activity of the ligand. Chemical aspects and clinical applications will be reviewed in this paper.

Advances in Metal-Based Probes for MR Molecular Imaging Applications by E. Terreno, W. Dastru, D. Delli Castelli, E. Gianolio, S. Geninatti Crich, D. Longo, S. Aime (3684-3700).
The role of MRI in the armory of diagnostic modalities for the medicine of the forthcoming years largely depends on how chemistry will provide advanced tools to meet the medical needs. This review aims at outlining the most innovative approaches that have been undertaken in the recent history of MRI contrast agents for tackling the challenges of sensitivity and specificity required by the new generation of contrast agents that should allow the visualization of pathological processes occurring on cellular and molecular scale (the so-called Molecular Imaging). Most of the classes of MRI agents clinically approved or currently under investigation in a preclinical phase exploit peculiar magnetic properties of metals. The conventional agents acting as T1 or T2/T2* relaxation enhancers are primarily based on the paramagnetic or the superparamagnetic properties of Gd(III)-, Mn(II)- and iron oxides systems. Recently, there has been a renewed interest towards paramagnetic lanthanide complexes with an anisotropic electronic configuration thanks to their ability to induce strong effect on the resonance frequency of the spins dipolarly coupled with them. Such systems, formerly mainly used as shift reagents, have now attracted much attention in the emerging field of Chemical Exchange Saturation Transfer (CEST) MRI agents.

Low molecular weight and high molecular weight metal ion binders present in blood plasma are shortly described. The binding of vanadium and ruthenium complexes by these components has received much attention, namely their interactions with human serum albumin and transferrin, and these studies are critically reviewed. The influence of the protein binding on the bioavailability of the prospective drugs, namely on the transport by blood plasma and uptake by cells is also discussed. It is concluded that vanadium compounds are mainly transported in blood by transferrin, but that no study has properly addressed the influence of albumin and transferrin in the vanadium uptake by cells. Ruthenium complexes bind strongly to HSA, most likely at the level of His residues, leading to the formation of stable adducts. If the kinetics of binding to this protein is fast enough, probably they are mainly transported by this serum protein. Nevertheless, at least for a few RuIII-complexes, hTf seems to play an active role in the uptake of ruthenium, while HSA may provide selectivity and higher activity for the compounds due to an enhanced permeability effect.

Recent Insights on the Medicinal Chemistry of Metal-Based Compounds: Hints for the Successful Drug Design by M. Z. Hernandes, F. S. Pontes, L. C.D. Coelho, D. R.M. Moreira, V. R.A. Pereira, A. C.L. Leite (3739-3750).
Although more complex than usually described, the anticancer action mechanism of cisplatin is based on binding to DNA. Following this line of reasoning, most the metal-based compounds discovered soon after cisplatin were designed to acting as DNA-binding agents and their pharmacological properties were thought to be correlated with this mechanism. Apart from the DNA structure, a significant number of proteins and biochemical pathways have been described as drug targets for metal-based compounds. This paper is therefore aimed at discussing the most recent findings on the medicinal chemistry of metal-based drugs. It starts illustrating the design concept behind the bioinorganic chemistry of anticancer complexes. Anticancer metallic compounds that inhibit the protein kinases are concisely discussed as a case study. The accuracy and limitations of molecular docking programs currently available to predict the binding mode of metallic complexes in molecular targets are further discussed. Finally, the advantages and disadvantages of different in vitro screenings are briefly commented.

Matrix Metalloproteinases by O. Zitka, J. Kukacka, S. Krizkov, D. Huska, V. Adam, M. Masarik, R. Prusa, R. Kizek (3751-3768).
Matrix metalloproteinases (MMPs), also known as matrixins, belong to a group of zinc-dependent proteins, which are thought to play a central role in the breakdown of extracellular matrix. Collagen, elastin, gelatin and casein are major components cleaved by MMPs. The breakdown of these components is essential for many physiological processes such as embryonic development, morphogenesis, reproduction, and tissue resorption and remodelling. MMPs also participate in pathological processes such as arthritis, cancer, cardiovascular and neurological diseases. This review summarizes current knowledge regarding these proteins, their participation in physiological and pathophysiological roles, their involvement in activation and inhibition, and their interactions with other metal-binding proteins including metallothioneins.