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Metal Ions in Life Sciences

Silvia Ziliotto, Olivia Ogle, Kathryn M Taylor
Zinc is an important element that is gaining momentum as a potential target for cancer therapy. In recent years zinc has been accepted as a second messenger that is now recognized to be able to activate many signalling pathways within a few minutes of an extracellular stimulus by release of zinc(II) from intracellular stores. One of the major effects of this store release of zinc is to inhibit a multitude of tyrosine phosphatases which will prevent the inactivation of tyrosine kinases and hence, encourage further activation of tyrosine kinasedependent signalling pathways...
February 5, 2018: Metal Ions in Life Sciences
Delphine Denoyer, Sharnel A S Clatworthy, Michael A Cater
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...
February 5, 2018: Metal Ions in Life Sciences
Frank Thévenod
Iron (Fe) is an essential metal, vital for biological functions, including electron transport, DNA synthesis, detoxification, and erythropoiesis that all contribute to metabolism, cell growth, and proliferation. Interactions between Fe and O2 can result in the generation of reactive oxygen species (ROS), which is based on the ability of Fe to redox cycle. Excess Fe may cause oxidative damage with ensuing cell death, but DNA damage may also lead to permanent mutations. Hence Fe is carcinogenic and may initiate tumor formation and growth, and also nurture the tumor microenvironment and metastasis...
February 5, 2018: Metal Ions in Life Sciences
Ulrich Schatzschneider
As the carrier of the inheritable information in cells, DNA has been the target of metal complexes for over 40 years. In this chapter, the focus will be on non-covalent recognition of the highly structured DNA surface by substitutionally inert metal complexes capable of either sliding in between the normal base pairs as metallointercalators or flipping out thermodynamically destabilized mispaired nucleobases as metalloinsertors. While most of the compounds discussed are based on ruthenium(II) and rhodium(III) due to their stable octahedral coordination environment and low-spin 4d6 electronic configuration, most recent developments of alternative metal complexes, based on both transition metals and main group elements, will also be highlighted...
February 5, 2018: Metal Ions in Life Sciences
Matthew P Sullivan, Hannah U Holtkamp, Christian G Hartinger
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...
February 5, 2018: Metal Ions in Life Sciences
Ramon Vilar
Guanine-rich sequences of DNA can readily fold into tetra-stranded helical assemblies known as G-quadruplexes (G4s). It has been proposed that these structures play important biological roles in transcription, translation, replication, and telomere maintenance. Therefore, over the past 20 years they have been investigated as potential drug targets for small molecules including metal complexes. This chapter provides an overview of the different classes of metal complexes as G4-binders and discusses the application of these species as optical probes for G-quadruplexes as well as metallo-drugs...
February 5, 2018: Metal Ions in Life Sciences
Lucia Cardo, Michael J Hannon
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.
February 5, 2018: Metal Ions in Life Sciences
Christopher R Chitambar
Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials...
February 5, 2018: Metal Ions in Life Sciences
Debbie C Crans, Lining Yang, Allison Haase, Xiaogai Yang
Vanadium compounds have been known to have beneficial therapeutic properties since the turn of the century, but it was not until 1965 when it was discovered that those effects could be extended to treating cancer. Some vanadium compounds can combat common markers of cancer, which include metabolic processes that are important to initiating and developing the phenotypes of cancer. It is appropriate to consider vanadium as a treatment option due to the similarities in some of the metabolic pathways utilized by both diabetes and cancer and therefore is among the few drugs that are effective against more than one disease...
February 5, 2018: Metal Ions in Life Sciences
Edit Y Tshuva, Maya Miller
Titanium(IV) coordination complexes represent attractive alternatives to platinumbased anticancer drugs. The advantage of the titanium metal lies in its low toxicity, and the hydrolysis of titanium(IV) coordination complexes in biological water-based environment to the safe and inert titanium dioxide is an enormous benefit. On the other hand, the rapid hydrolysis of titanium(IV) complexes in biological environment and their rich aquatic chemistry hampered the exploration and the development of effective compounds...
February 5, 2018: Metal Ions in Life Sciences
Angela Casini, Raymond Wai-Yin Sun, Ingo Ott
Since ancient times gold and its complexes have been used as therapeutics against different diseases. In modern medicine gold drugs have been applied for the treatment of rheumatoid arthritis, however, recently other medical applications have come into the focus of inorganic medicinal chemistry. This chapter provides a non-comprehensive overview of key developments in the field of gold anticancer drugs. Exciting findings on gold(I) and gold(III) complexes as antitumor agents are summarized together with a discussion of relevant aspects of their modes of action...
February 5, 2018: Metal Ions in Life Sciences
Maria V Babak, Wee Han Ang
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...
February 5, 2018: Metal Ions in Life Sciences
Enzo Alessio, Luigi Messori
The general interest in anticancer metal-based drugs and some encouraging pharmacological results obtained at the beginning of the investigations on innovative Ru-based drugs triggered a lot of attention on NAMI-A and KP1019, the two Ru(III) coordination compounds that are the subject of this review. This great attention led to a considerable amount of scientific results and, more importantly, to their eventual admission into clinical trials. Both complexes share a relatively low systemic toxicity that allows reaching rather high dosages, comparable to those of carboplatin...
February 5, 2018: Metal Ions in Life Sciences
Nicholas P Farrell, Anil K Gorle, Erica J Peterson, Susan J Berners-Price
Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate molecules that bind to a wide variety of proteins and exercise important physiological and pathological processes. This chapter focuses on the concept of metalloglycomics and reviews the structure and conformation of GAGs and the role of various metal ions during the interaction of GAGs with their biological partners such as proteins and enzymes. The use of metal complexes in heparin analysis is discussed. Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumor-related events including angiogenesis, cell invasion, metastasis, and inflammation...
February 5, 2018: Metal Ions in Life Sciences
V Venkatesh, Peter J Sadler
This chapter is an overview of recent progress in the design of Pt(IV) prodrugs. These kinetically-inert octahedral prodrugs can be reduced in cancer cells to active squareplanar Pt(II) complexes, for example by intracellular reducing agents such as glutathione or by photoexcitation. The additional axial ligands in Pt(IV) complexes which are released on reduction, allow bioactive molecules to be delivered which can act synergistically with Pt(II) in killing cancer cells, or act as targeting vectors, allow attachment to polymer and nanoparticle delivery systems, or labelling with fluorescent probes...
February 5, 2018: Metal Ions in Life Sciences
Viktor Brabec, Jana Kasparkova, Vijay Menon, Nicholas P Farrell
Polynuclear platinum complexes (PPCs) represent a discrete structural class of DNA-binding agents with excellent antitumor properties. The use of at least two platinum coordinating units automatically means that multifunctional DNA binding modes are possible. The structural variability inherent in a polynuclear platinum structure can be harnessed to produce discrete modes of DNA binding, with conformational changes distinct from and indeed inaccessible to, the mononuclear agents such as cisplatin. Since our original contributions in this field a wide variety of dinuclear complexes especially have been prepared, their DNA binding studied, and potential relevance to cytotoxicity examined...
February 5, 2018: Metal Ions in Life Sciences
Imogen A Riddell
Following the serendipitous discovery of the anticancer activity of cisplatin over 50 years ago, a deep understanding of the chemical and biochemical transformations giving rise to its medicinal properties has developed allowing for improved treatment regimens and rational design of second and third generation drugs. This chapter begins with a brief historical review detailing initial results that led to the worldwide clinical approval of cisplatin and development of the field of metal anticancer agents. Later sections summarize our understanding of key mechanistic features including drug uptake, formation of covalent adducts with DNA, recognition and repair of Pt-DNA adducts, and the DNA damage response, with respect to cisplatin and oxaliplatin...
February 5, 2018: Metal Ions in Life Sciences
Samuel Caito, Ana Carolina B Almeida Lopes, Monica M B Paoliello, Michael Aschner
The toxicity of lead has been appreciated for centuries. Lead is a commonly used metal in industrialized nations, which results in the release of lead into the environment. Governmental agencies regulate the amount of lead permissible for workers to be exposed to; however, unregulated environmental lead exposure is a high concern. While essential metals have physiologic roles, there are no health benefits from lead intake. In this chapter, we discuss sources of lead exposure, the absorption, distribution, and elimination of lead from the human body, and molecular mechanisms of lead-induced toxicity...
April 10, 2017: Metal Ions in Life Sciences
Hendrik Küpper
This review looks critically at the relevance of lead (Pb2+) toxicity and proposed mechanisms of Pb2+ -induced stress in algae and higher plants. As a basis, the current main sources of Pb2+ contamination in the environment are presented, which include agriculture, industry, and road traffic. Further, bioavailability of lead is discussed as a basis for evaluating the environmental relevance of the many studies on lead toxicity that have been published in the past decades. These studies suggest three main mechanisms of toxicity of Pb2+: inhibition of photosynthesis, oxidative stress, and "genotoxicity" including DNA damage and defects in mitosis...
April 10, 2017: Metal Ions in Life Sciences
Montserrat Filella, Josep Bonet
The use of alkyl lead derivatives as antiknock agents in gasoline can be considered as one of the main pollution disasters of the 20th century because of both the global character of the pollution emitted and the seriousness of the impact on human health. Alkyl lead derivatives in themselves cannot be considered to be persistent pollutants because they readily degrade either before being released from the tailpipes or soon afterwards in the atmosphere. However, the inorganic lead they produced has been deposited in soils all over the planet, largely, but not exclusively in urban areas and along motorways, since the direct emission of lead into the atmosphere favored its dispersal over great distances: The signal of the massive use of alkyl lead derivatives has been found all over the world, including in remote sites such as polar areas...
April 10, 2017: Metal Ions in Life Sciences
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