Metal ions in life sciences最新文献

Metal ions are indispensable for living organisms. However, the roles of metal ions in humans is complex, and remains poorly understood. Imbalances in metal ion levels, due to genetic or environmental sources, are associated with a number of significant health issues. However, in clinical medicine, the role of metal ions and metal-based drugs is notable in three major areas: as metal-related diseases; as metal-based medicines (including drugs, imaging agents, and metal chelators); and as agents of metal-based toxicity.

After 40 years of significant work, it was generally accepted that chromium in its trivalent valence state, Cr(III), is an essential micronutrient for humans. This view began to be challenged around the turn of the millennium. Some investigators argue that its effects on glucose and lipid metabolism reflect a pharmacological rather than a nutritional mode of action while yet others express concern about the toxicity and safety of supplemental chromium. Understanding the conjectures requires a reflection on the different definitions of "essential" and a perspective on the development of the field, which in itself is a remarkable snippet of science history and education. At the center of the discussion is our failure to have established a molecular structure and a specific site of action of a biological chromium complex. Instead, many different types of Cr(III) complexes, in particular chromium picolinate, but also those with nicotinate, propionate, histidinate, chloride, and other ligands, all with different chemical properties and biological activities, are being used in laboratory investigations and supplementation. Without knowledge of the metabolic transformations and the specific chemical properties that biological ligands impart on chromium, many of these investigations, in particular those ex vivo, have limited value for understanding chromium's biological function. Whether a chromium deficiency exists in humans and who is affected is poorly defined. There is evidence for the efficacy of chromium supplements in improving conditions in metabolic syndrome and in some diabetes Type 2 patients, but there are no effects on body composition in healthy individuals. Chromium is present in human tissues and in our food and Cr(III) compounds are given in (total) parenteral nutrition, taken as a supplement by athletes and bodybuilders, are ingredients of vitamin pills consumed by the general population, and are employed in animal nutrition. Another contentious issue is whether Cr(III) complexes are safe, as chromium in its hexavalent state, Cr(VI) (chromate), is genotoxic and a group I carcinogen for humans with sufficient evidence for inhalation and lung cancer. For the benefit of human health, there is a continuing need for a balanced view and informed and robust experiments to determine the specific biological molecules that are involved in the metabolism of Cr(III), the activity of biological Cr(III) complexes at specific sites of action, and the amount of supplemental Cr(III) that potentially causes long-term toxicity.

Physiological metabolism of cyanide takes place by a single major pathway that forms non-toxic thiocyanate that is subsequently excreted. Rhodanese is the primary enzyme to execute metabolism of cyanide with minor pathways from other sulfurtransferases in vivo. The rhodanese enzyme depends on sulfur donor availability to metabolize cyanide and poisoning occurs at elevated cyanide concentrations in vivo. Cyanide interacts with over 40 metalloenzymes, but its lethal action is non-competitive inhibition of cytochrome c oxidase, halting cellular respiration and causing hypoxic anoxia. Only a handful of antidotes for treatment of cyanide poisoning are known; they are primarily inorganic compounds and metal complexes which are intended to intercept cyanide before it inhibits cellular respiration. The inorganic compounds manipulate hemoglobin, forming methemoglobin, or supply sulfur for the rhodanese enzyme. The metal complexes intercept the cyanide and bind it before reaching its target. Cobalt complexes of corrins and vitamin B12 derivatives are the state-of-the-art agents, while the longest employed complex, Co2EDTA, is designed to deliver "free" cobalt for binding of cyanide. Compounds that are in development are discussed from the point of how they are designed to intercept cyanide. The challenge of reversing the cyanide inhibition of cytochrome c oxidase is based on the catalytic active site structure and reactivity. General information about history and occurrence of poisoning and clinical symptoms is discussed and the challenges related to analytical methods available to analyze blood cyanide levels and to confirm the presence of cyanide poisoning.

Our understanding of the broad principles of cellular and systemic iron homeostasis in man are well established with the exception of the brain. Most of the proteins involved in mammalian iron metabolism are present in the brain, although their distribution and precise roles in iron uptake, intracellular metabolism and export are still uncertain, as is the way in which systemic iron is transferred across the blood-brain barrier. We briefly review current concepts concerning the uptake and distribution of iron in the brain, before turning to the ways in which brain iron homeostasis might be regulated. The distribution of iron between different brain regions is then discussed as is the increase in brain iron with normal aging, and the different forms in which iron is present. The increased levels of iron found in specific brain regions and their potential contribution to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease and other polyglutamine expansion diseases, amyotrophic lateral sclerosis, Friedreich's ataxia, as well as a number of neurodegenerative diseases with iron accumulation, are discussed. The interactions between neuroinflammation and iron are presented, and the chapter concludes with a review of current clinical studies and discussion of the potential and efficacy of iron chelation therapy in the treatment of neurodegenerative diseases.

Metal compounds seem to be a promising approach in the search of new therapeutic solutions for neglected tropical diseases. In this chapter, efforts in the design of prospective metal-based drugs for the treatment of Chagas disease, human African trypanosomiasis, and leishmaniasis are discussed. Careful selection of the metal center (including organometallic cores) and the types and number of coordinated ligands is essential for controlling the reactivity of the complexes and hence, tuning their biological properties. In a target-based approach, some targets that have been validated for organic antiparasitic compounds are expected to remain targets for metal complexes of these compounds. In addition, specific targets for metal compounds, like parasitic enzymes or DNA, would also be included for these metal complexes leading to potential additive or even synergistic effects between organic ligand and metal ion. However, even though a good number of prospective antiparasitic metal-based drugs have been developed, further systematic efforts are needed for these metal compounds to accomplish the regulatory guidelines that let them reach the different stages of clinical trials.

Vanadium has been known for centuries to have beneficial effects on health and has the potential to be used as an alternative to other diabetic and anticancer medicines. The beneficial effects of vanadium salts or organic compounds have been explored in vitro, ex vivo, and in vivo in animal and human studies. A consensus among researchers is that increased bioavailability of these compounds could markedly increase the efficacy of this class of compounds. In addition, because many commercially available vanadium derivatives are being used by body builders to enhance performance, more understanding of their mode of action is desirable. Future studies of various vanadium compounds need to evaluate their biodistribution, biotransformation, and the effects of food and formulation on the bioavailability of the compounds. To date, most studies in humans have employed vanadium salts, mainly vanadyl sulfate, and dose-limiting side effects were reported at therapeutic doses. One organic vanadium compound, bis(ethylmaltolato)oxovanadium(IV), had improved efficacy compared to the vanadyl sulfate and was selected for Phase 1 and 2 clinical trials. Future studies should be conducted as randomized, placebo controlled trials lasting several months, with monitoring of both fasting blood glucose and hemoglobin A1c. Now, the most promising potential uses of vanadium compounds are as nutritional supplements to control glucose levels and perhaps, as an anticancer agent potentiated by immunotherapy.

Anticancer platinum-based drugs are widely used in the treatment of a variety of tumorigenic diseases. They have been identified to target DNA and thereby induce apoptosis in cancer cells. Their reactivity to biomolecules other than DNA has often been associated with side effects that many cancer patients experience during chemotherapy. The development of metal compounds that target proteins rather than DNA has the potential to overcome or at least reduce the disadvantages of commonly used chemotherapeutics. Many exciting new metal complexes with novel modes of action have been reported and their anticancer activity was linked to selective protein interaction that may lead to improved accumulation in the tumor, higher selectivity and/or enhanced antiproliferative efficacy. The development of new lead structures requires bioanalytical methods to confirm the hypothesized modes of action or identify new, previously unexplored biological targets and pathways. We have selected original developments for review in this chapter and highlighted compounds on track toward clinical application.

There has been much recent interest in the development of therapeutic transition metal-based complexes in part fueled by the clinical success of the platinum(II) anticancer drug, cisplatin. Yet known platinum drugs are limited by their high toxicity, severe side-effects, and incidences of drug resistance. Organometallic ruthenium-arene complexes have risen to prominence as a pharmacophore due to the success of other ruthenium drug candidates in clinical trials. In this chapter, we highlight higher order multinuclear ruthenium-arene complexes and their respective investigations as chemotherapeutic agents. We discuss their unique structural properties and the associated biochemical evaluation in the context of anticancer drug design. We also review the structural considerations for the design of these scaffolds and new therapeutic applications that are uncovered for this class of complexes.

The most effective class of anticancer drugs in clinical use are the platins which act by binding to duplex B-DNA. Yet duplex DNA is not DNA in its active form, and many other structures are formed in cells; for example, Y-shaped fork structures are involved in DNA replication and transcription and 4-way junctions with DNA repair. In this chapter we explore how large, cationic metallo-supramolecular structures can be used to bind to these less common, yet active, nucleic acid structures.

Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials.