Current Medicinal Chemistry - Volume 25, Issue 1, 2018

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

Background: The understanding of the bioinorganic and coordination chemistry of metalloproteins containing unusual poly-Xaa sequences, in which a single amino acid is repeated consecutively, is crucial for describing their metal binding-structure-function relationship, and therefore also crucial for understanding their medicinal potential. To the best of our knowledge, this is the first systematic review on metal complexes with polyXaa sequences. Methods: We performed a thorough search of high quality peer reviewed literature on poly-Xaa type of sequences in proteins, focusing on their biological importance and on their interactions with metal ions. Results: 228 papers were included in the review. More than 70% of them discussed the role of metal complexes with the studied types of sequences. In this work, we showed numerous medically important and chemically fascinating examples of possible ‘poly-Xaa' metal binding sequences. Conclusion: Poly-Xaa sequences, in which a single amino acid is repeated consecutively, are often not only tempting binding sites for metal ions, but very often, together with the bound metal, serve as structure determinants for entire proteins. This, in turn, can have consequences for the whole organism. Such sequences in bacterial metal chaperones can be a possible target for novel, antimicrobial therapeutics.

Depleted uranium (DU) is generally considered an emerging pollutant, first extensively introduced into environment in the early nineties in Iraq, during the military operation called “Desert Storm”. DU has been hypothesized to represent a hazardous element both for soldiers exposed as well as for the inhabitants of the polluted areas in the war zones. In this review, the possible consequences on human health of DU released in the environment are critically analyzed. In the first part, the chemical properties of DU and the principal civil and military uses are summarized. A concise analysis of the mechanisms underlying absorption, blood transport, tissue distribution and excretion of DU in the human body is the subject of the second part of this article. The following sections deal with pathological condition putatively associated with overexposure to DU. Developmental and birth defects, the Persian Gulf syndrome, and kidney diseases that have been associated to DU are the arguments treated in the third section. Finally, data regarding DU exposure and cancer insurgence will be critically analyzed, including leukemia/lymphoma, lung cancer, uterine cervix cancer, breast cancer, bladder cancer and testicular cancer. The aim of the authors is to give a contribution to the debate on DU and its effects on human health and disease.

Tungsten or wolfram was regarded for many years as an enemy within the tin smelting and mining industry, because it conferred impurity or dirtiness in tin mining. However, later it was considered an amazing metal for its strength and flexibility, together with its diamond like hardness and its melting point which is the highest of any metal. It was first believed to be relatively inert and an only slightly toxic metal. Since early 2000, the risk exerted by tungsten alloys, its dusts and particulates to induce cancer and several other adverse effects in animals as well as humans has been highlighted from in vitro and in vivo experiments. Thus, it becomes necessary to take a careful look at all the most recent data reported in the scientific literature, covering the years 2001-2016. In fact, the findings indicate that much more attention should be devoted to thoroughly investigate the toxic effects of tungsten and the involved mechanisms of tungsten metal or tungsten metal ions.

Background: Research into gold-based drugs for a range of human diseases has seen a revival in recent years. This article reviews the most important applications of gold products in different fields of human pathology. Au(I) and Au(III) compounds have been re-introduced in clinical practice for targeting the cellular components involved in the onset and progression of viral and parasitic diseases, rheumatoid arthritis and cancer. Results: After some brief historical notes, this article takes into account the applications of gold compounds against Mycobacterium tuberculosis, and also in tuberculosis and in rheumatoid arthritis treatment. The use of gold containing drugs in the cure of cancer are then considered, with special emphasis to the use of nanoparticles and to the photo-thermal cancer therapy. The use of colloidal gold in diagnostics, introduced in the last decade is widely discussed. As a last point a survey on the adverse effects and on the toxicity of the various gold derivatives in use in medicine is presented. Conclusion: In this review, we described the surprisingly broad spectrum of possible uses of gold in diagnostics and in therapeutic approaches to multiple human diseases, ranging from degenerative to infectious diseases, and to cancer. In particular, gold nanoparticles appear as attractive elements in modern clinical medicine, combining high therapeutic properties, high selectivity in targeting cancer cells and low toxicity.

Background: Iron is an essential micronutrient for bacteria, fungi, and humans; as such, each has evolved specialized iron uptake systems to acquire iron from the extracellular environment. Objective: To describe complex ‘tug of war’ for iron that has evolved between human hosts and pathogenic microorganisms in the battle for this vital nutrient. Methods: A review of current literature was performed, to assess current approaches and controversies in iron therapy and chelation in humans. Results: In humans, sequestration (hiding) of iron from invading pathogens is often successful; however, many pathogens have evolved mechanisms to circumvent this approach. Conclusion: Clinically, controversy continues whether iron overload or administration of iron results in an increased risk of infection. The administration of iron chelating agents and siderophore- conjugate drugs to infected hosts seems a biologically plausible approach as adjunctive therapy in the treatment of infections caused by pathogens dependent on host iron supply (e.g. tuberculosis, malaria, and many bacterial and fungal pathogens); however, thus far, studies in humans have proved unsuccessful.

Hydroxypyridinones (HPs) are a family of N-heterocyclic metal chelators, which have been an attractive target in the development of a variety of new pharmaceutical drugs, due to their high metal chelating efficacy/specificity and easy derivatization to tune the desired biological properties. In fact, along the last decades, hydroxypyridinone derivatives, but mostly 3-hydroxy-4-pyridinone (3,4-HP), have been intensively used in drug design, following either a multitarget approach, in which one chelating unity is extrafunctionalized (hybridized) to enable the interaction with other important specific biological sites, or a polydenticity approach, in which more than one chelating moiety is conveniently attached to one scaffold, to increase the metal chelating efficacy. This review represents an update of the most recent publications (2014-2016) in mono-HP hybrids, namely as potential anti-Alzheimer's drugs, inhibitors of metalloenzymes and anti-microbials, and also polychelating compounds (poly- HP), in view of potential application, such as anti-microbial/biostatic agents, luminescent biosensors or diagnostic agents.

Background: Lanthanum (La) is considered to be a non-essential element. La has been used for several decades in China to improve yield in plant production and has also been shown to have significant performance enhancing effects in feeding trials on animal husbandry. The estimated dietary intake of La in humans is below 150 μg, which is lower than 10% of the estimated limit of safe and acceptable daily intake. Methods: The present review is based on literature search in available databases. Results: Upon ingestion of La as carbonate, the lanthanum ion (La3+) is released in the stomach and traps dietary phosphate as insoluble lanthanum phosphate complexes in the gut, thereby inhibiting phosphate absorption. Lanthanum carbonate as a drug to lower serum phosphate in endstage kidney failure was approved for human use by the US FDA in 2004 and by the EU in 2006. When used to treat patients with advanced renal insufficiency, lanthanum carbonate is administered orally at a dose of maximally 3000 mg per day. The uptake of lanthanum ions from the gut to the circulation is negligible. And few systemic side effects have been recorded upon the use of lanthanum carbonate as a phosphate binding drug, although gastrointestinal discomfort with pain, vomiting and diarrhea may occur. Lanthanum carbonate has the potential to chelate to drugs with anionic groups and therapeutic co-administration with lanthanum carbonate may reduce the bioavailibility of drugs like tetracyclines, quinolones and levothyroxine. Conclusion: The findings in this review confirm that lanthanum carbonate is a clinically useful phosphate binding drug with few side effects in advanced renal failure.