Current Topics in Medicinal Chemistry - Volume 11, Issue 5, 2011

Complexes of essential metal ions (e.g., iron, copper, zinc) as well as exogenous metal ones (platinum, ruthenium, gold) have found many pharmacological applications. The best and most well known example is the cancer chemotherapeutic cisplatin, cis-[Pt(NH3)2Cl2], that has made a significant impact in the treatment of a number of tumors e.g. small cell lung cancer, ovarian carcinoma etc. In this volume of Current Topics in Medicinal Chemistry, we have brought together experts in many fields to cover a broad spectrum of topics examining the use of metals and their complexes for a variety of chemotherapeutic applications. These subjects include novel cancer chemotherapeutics, radiopharmaceuticals, anti-diabetic agents and anti-inflammatory drugs. In addition, chelators that bind intracellular metals can be used to treat a variety of diseases, including iron- or copper-overload disorders and also potentially some neuro-degenerative diseases. In each case, characterising the reactivity of the complexed metal formed within the cell is essential to understanding its function. The first review in this issue is a product of our own research focus and examines the design and use of novel iron chelators for the treatment of cancer. While many chemotherapeutics have been designed to target other essential nutrients e.g. folate, very little attention has been invested to specifically interfere with the metabolism of iron which is necessary for DNA synthesis and a plethora of other functions. Recent work has clearly demonstrated that novel thiosemicarbazone ligands are effective at inhibiting tumour growth and are well tolerated, demonstrating the great potential of this strategy. Donnelly and Ma then present a review assessing the use of peptide targeted 64Cu-labelled diagnostic agents for positron emission tomography imaging of cancer cells. The authors describe that the bio-distribution of such radiotracers are influenced by the design of the construct, namely the chelate group, linker and targeting peptide. Recent advances in the field of peptide targeted 64Cu-labelled radiopharmaceuticals are discussed and examples are reviewed as case studies in the optimisation of radiotracer design. Transition metal based anti-cancer drugs are next discussed in a thorough analysis on the subject by Janice Aldrich-Wright and colleagues. Since the discovery of the anti-cancer properties of cisplatin, a vast family of platinum compounds have emerged. Their modes of action vary with structure and reactivity of the complex; some coordinating to DNA, while others act as intercalators that disturb DNA replication etc. This review also covers a wide variety of other transition metal complexes that have shown promise, including ruthenium, palladium, gold and titanium (which like platinum, are exogenous metals). Complexes of copper, vanadium and cobalt are also included in the review which illustrates that the diversity of approaches taken in the treatment of cancer reflects the different characteristics of these metals. The role of metals in disease is not confined to cancer. Jones and Badrick provide an interesting assessment of the potential use of chelation in halting the progression of neuro-degenerative disorders such as Alzheimer's disease, Parkinson's disease and Creutzfeldt-Jakob disease. The disruption of copper, zinc and iron homeostasis in the brain is linked with these medical conditions. For example, there is some evidence in Alzheimer's disease that copper is re-distributed to become associated with β-amyloid plaques. Chelators and copper complexes offer a potential strategy to restore the proper balance of copper metabolism and hopefully prevent the pathology. In a review written by Peter Lay et al., the authors point out that most metal-based pharmaceuticals are pro-drugs and their chemical structures, properties and bio-distribution may change markedly upon administration. By utilising examples from their own laboratory, these authors describe the use of X-ray absorption spectroscopy and X-ray microprobe techniques to provide information on the bio-transformation and bio-distribution of metal-containing drugs. Applications of these techniques to anti-cancer, anti-diabetic and anti-inflammatory drugs are discussed. These relatively new techniques are, for the first time, providing insight into issues such as toxicity and efficacy through accurate mapping of the cellular distribution of the metal or metalloid. Stephen Ralph reviews a novel and highly interesting application of metal complexes in the battle against cancer cell proliferation. Telomeres are single-stranded DNA at the ends of chromosomes and are continually degraded with each cell division until the amount lost reaches a critical value, triggering apoptosis. Cancer cells may avoid programmed cell death by replenishment of their telomeric DNA through elevated telomerase activity (a DNA polymerase). Telomeres are also known to assemble into structures known as DNA quadruplexes, and in this form, telomerase activity is inhibited, rendering the cancer cell vulnerable to apoptosis. The review explores metal complexes that interact with telomeric DNA and which induces the formation of quadruplex DNA as a novel approach to inhibiting cancer cell proliferation. Finally, Bernhardt and co-workers examine the topic of iron chelation. This review covers the first and most intensively used iron chelator in the clinic, the bacterial siderophore, desferrioxamine, to the recently developed and synthetic, orally-active iron chelator, Exjade®. From analysis of this spectrum of ligands, it is clear that many approaches have been investigated in the quest for small molecules that are capable of reversing potentially fatal iron overload disorders in humans. Recent developments in the chemistry and biology of potential new iron overload drugs are reviewed, examining both synthetic compounds and natural products capable of chelating and mobilising excess intracellular iron. We trust that this issue of Current Topics in Medicinal Chemistry provides an illuminating overview of some interesting facets currently being explored in the implementation of metals in the development of novel and effective chemotherapeutics.

Cancer is one of the leading causes of death worldwide and there is an increasing need for novel anti-tumor therapeutics with greater selectivity and potency. A new strategy in the treatment of cancer has focused on targeting an essential cell metabolite, iron (Fe). Iron is vital for cell growth and metabolism, forming a crucial component of the active site of ribonucleotide reductase (RR), the rate-limiting enzyme in DNA synthesis. Cancer cells in particular require large amounts of Fe to proliferate, making them more susceptible to the Fe deficiency caused by Fe chelators. Beginning with primordial siderophores, Fe chelators have since evolved to a new generation of potent and efficient anti-cancer agents. Recently, investigations have led to the generation of novel di-2-pyridylketone thiosemicarbazone (DpT) and 2- benzoylpyridine thiosemicarbazone (BpT) ligands that demonstrate marked and selective anti-tumor activity both in vitro and in vivo against a wide spectrum of tumors. The mechanism of action of these novel ligands includes alterations in the expression of key regulatory molecules as well as the generation of redox active Fe complexes. Interestingly, nonsynthetic Fe chelators including silybin and curcumin, both of which are derived from plants, also have a high potential in the treatment of cancer. This review explores the development of novel Fe chelators for the treatment of cancer and their mechanisms of action.

Peptide targeted 64Cu-labelled diagnostic agents for positron emission tomography are viable candidates for molecular imaging of cancer. In a clinical setting, optimal image quality relies on selective tumor uptake of the 64Culabelled radiotracer. The three components of the radiotracer construct - the chelate group, linker and targeting peptide - all influence the biodistribution of the 64Cu-labelled radiotracer in vivo. Low or moderate Cu complex stability in vivo results in transmetallation of 64Cu to endogenous proteins, giving rise to high background activity. The length and the nature of the linker group affect the affinity of the 64Cu-labelled radiotracer for the target receptor. Variations in the peptide sequence can impact on the metabolic stability and therefore the bioavailability and tumor retention of the 64Cu-labelled radiotracer in vivo. Lastly, the hydrophilicity of the construct can influence radiotracer metabolism and clearance pathways. Recent advances in the field of peptide targeted 64Cu-labelled radiopharmaceuticals involve GRPR-targeted and αvβ3 integrin receptor-targeted constructs. These constructs are based on the bombesin peptide sequence and the RGD recognition motif respectively. These examples are reviewed as case studies in the optimisation of 64Cu radiotracer design.

With an ageing baby-boomer population in the Western World, cancer is becoming a significant cause of death. The prevalence of cancer and all associated costs, both in human and financial terms, drives the search for new therapeutic drugs and treatments. Platinum anticancer agents, such as cisplatin have been highly successful but there are several disadvantages associated with their use. What is needed are new compounds with different mechanisms of action and resistance profiles. What needs to be recognised is that there are many other metals in the periodic table with therapeutic potential. Here we have highlighted metal complexes with activity and illustrate the different approaches to the design of anticancer complexes.

Metal ions, particularly copper, zinc and iron, are implicated in several amyloidogenic neurodegenerative disorders. In the brain, as elsewhere in the body, metal ion excess or deficiency can potentially inhibit protein function, interfere with correct protein folding or, in the case of iron or copper, promote oxidative stress. The involvement of metal ions in neurodegenerative disorders has made them an emerging target for therapeutic interventions. One approach has been to chelate and sequester the ions and thus limit their potential to interfere with protein folding or render them unable to undergo redox processes. Newer approaches suggest that redistributing metal ions has therapeutic benefits, and recent studies indicate that alleviating cellular copper deficiency may be a plausible way to limit neurodegeneration. In this review we discuss the role of metals in amyloidogenic, neurodegenerative disorders and highlight some mechanisms and compounds used in various therapeutic approaches.

Most metal-based drugs are pro-drugs; therefore, it is essential that methods are developed to follow their speciation in biological fluids, cells and tissues. This will lead to both a better understanding of the factors that affect their efficacies and toxicities and, consequently, to the design of new and superior drugs. The use of X-ray absorption spectroscopy on bulk samples, and X-ray microprobe techniques on cells and tissues, provides unprecedented information on the biotransformations and biodistributions of metal-containing drugs that is required for a better understanding of their pharmacology. Here the methodologies that have been used on a range of metal- or metalloid-containing drugs and dietary supplements are reviewed, with an emphasis on research conducted within our group. In particular, applications of these techniques to anti-cancer, anti-diabetic, and anti-inflammatory drugs are discussed.

Compounds that can bind to and stabilize quadruplex DNA structures in telomeres, or induce formation of such structures from ssDNA, represent an attractive general approach to the treatment of cancer. Until recently most effort in this area has been directed towards the synthesis of organic compounds for this purpose. More recently there has been growing recognition that metal complexes offer a number of potential advantages for the preparation of lead complexes that bind with high affinity and selectivity for quadruplex DNA. This review seeks to discuss the work that has been reported in this area to date. While most early studies focused on metal complexes of porphyrin ligands, during the past 4 years there has been a dramatic increase in the number of papers in the literature examining the potential of mononuclear complexes of a variety of other ligands, particularly Schiff base ligands and those based on phenanthroline, as quadruplex DNA binders and telomerase inhibitors. In addition, there has been growing interest in exploiting supramolecular chemistry to prepare novel multinuclear complexes that bind to this new drug target.

An evaluation of existing and proposed Fe chelators, both synthetic and natural products, for the treatment of Fe-overload disease must address a number of issues. There are fundamental parameters that determine the efficacy of a drug: absorption, distribution, metabolism, clearance and toxicity. However, the administration of chelators for Fe overload aims to generate Fe complexes in vivo that are able to be excreted. Hence, the chemical and pharmacological properties of the complexes formed are as equally important as the chelators themselves. The redox properties of the Fe complexes formed are particularly relevant to their toxicity. If both FeII and FeIII oxidation states of the complexes are biologically accessible, then there is potential for the catalytic production of deleterious free radicals by Fenton-type chemistry. In addition, since the burden of Fe overload disease falls predominantly on some of the poorest economies, the cost of a drug must be considered, as well as the mode of delivery. There are also possible issues with the use of naturally occurring ligands, which may form Fe complexes capable of being utilised by opportunistic bacteria. This review will concentrate on recent developments in our chemical understanding of existing chelators approved or proposed for use and will also consider some of the candidates from natural sources that have been recently proposed.