Current Medicinal Chemistry - Volume 16, Issue 5, 2009

The classical square planar transition metal complex cis-diamminodichlorido platinum(II) (cisplatin) ranks among the most successful and widely applied antitumor drugs for the treatment of a number of cancers. However, the risk of unforeseen resistance formation and the appearance of severe side effects in cancer patients constitutes a considerable need for the development of novel platinum based antitumor compounds. Since the introduction of cisplatin into the clinic, a few similar compounds, like cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin), were developed, which can partly overcome the problems. The ubiquitously occurring small zinc and copper binding proteins metallothioneins (MTs) constitute the most potent cytosolic sink for platinum drugs. It appeared that, besides the formation of the very strong platinum(II)-sulfur bond involving the twenty cysteine residues of MT, the incorporation of platinum(II) into the MT structure contributes effectively to the scavenging of the drug. However, recently it became evident that the extent, to which MT sequesters platinum drugs, depends not only on the type of cancer, but also on the interaction of MT with the ligand sphere of the platinum center. For example, in contrast to cis-platinum(II) compounds, trans-platinum(II) compounds retain their N-donor ligands upon reaction with MT. From these studies, guidelines may be derived for the development of N-donor carrier ligands leading to novel platinum(II) drugs. This review describes the role of metallothioneins for the platinum(II) drug sequestration in vivo. Furthermore, it summarizes the recent developments toward the understanding of the reaction between platinum(II) and MT thiols and the structural aspects of the platinum(II) incorporation into the MT domains, and comments about future perspectives are given.

Microcin J25 (MccJ25) is a plasmid-encoded peptide of 21 L-amino acids (G1-G-A-G-H5-V-P-E-Y-F10-V-GI- G-T15-P-I-S-F-Y20-G), excreted to the medium by an Escherichia coli strain. MccJ25 is active on Gram-negative bacteria related to the producer strain, including some pathogenic strains. The four-plasmid genes mcjABCD, are involved in MccJ25 production: mcjA encodes a 58-residue precursor, mcjB and mcjC codify two processing enzymes required for the in vivo synthesis of the mature peptide and mcjD encodes the immunity protein (McjD), a member of the super family of ABC transporters. Immunity is mediated by active efflux of the peptide, keeping its intracellular concentration below a critical level. YojI, a chromosomal protein with ATP-binding-cassette-type exporter homology, is also able to export MccJ25. The E. coli outer membrane protein, TolC, is necessary for MccJ25 secretion mediated by either McjD or YojI. The uptake of MccJ25 is dependent on the outer-membrane receptor FhuA and the four inner-membrane proteins TonB, ExbD, ExbB and SbmA. At least two mechanisms described the action of MccJ25 on the target cells: (1) inhibition of the RNA-polymerase (RNAP) activity by obstructing the secondary channel, and consequently, preventing the access of the substrates to its active sites; and (2) operating on the cell membrane, MccJ25 disrupts the electric potential inhibiting the oxygen consumption in Salmonella enterica. MccJ25 also inhibits oxygen consumption and the respiratory chain enzymes in E. coli throughout the increasing of ROS concentration. Nevertheless the exact mechanism of this phenomenon must be elucidated. The MccJ25 exhibits a prolonged antimicrobial activity in a mouse infection model, suggesting a noteworthy potential for therapeutic uses.

Human urotensin II (U-II), the most potent vasoconstrictor undecapeptide identified to date, and its receptor (UT) are involved in the pathogenesis of systemic and pulmonary hypertension. Here, we review recent advances in our understanding of the pathophysiology of U-II with particular reference to its role in atherosclerotic cardiovascular diseases. Single-nucleotide polymorphisms of U-II gene (S89N) are associated with onset of essential hypertension, type II diabetes mellitus, and insulin resistance in the Asian population. Plasma U-II levels are elevated in patients with vascular endothelial dysfunction-related diseases such as essential hypertension, diabetes mellitus, atherosclerosis, ischemic heart disease, and heart failure. Chronic infusion of U-II enhances atherosclerotic lesions in the aorta in apolipoprotein Eknockout mice. In human atherosclerotic plaques from the aorta and coronary and carotid arteries, U-II is expressed at high levels in endothelial cells (ECs) and lymphocytes, whereas UT is expressed at high levels in vascular smooth muscle cells (VSMCs), ECs, monocytes, and macrophages. U-II stimulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in human ECs as chemoattractant for monocytes, and accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages. U-II produces reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate oxidase activation in human VSMCs, and stimulates VSMC proliferation with synergistic effects when combined with ROS, oxidized LDL, and serotonin. Clinical studies demonstrated increased plasma U-II levels in accordance with the severity of carotid atherosclerosis in patients with essential hypertension and that of coronary artery lesions in patients with ischemic heart disease. Here, we summarize the key roles of U-II in progression of hypertension and atherosclerotic cardiovascular diseases.

Objectives: Beta-lactam antibiotics represent the most commonly prescribed antibacterial agents. Since many bacteria have developed resistance to older agents, new beta-lactams have been introduced constantly. In the late 1970s, a new class of exceptionally broad-spectrum beta-lactams, the carbapenems, was identified. The carbapenems, such as the most popular imipenem and meropenem, have the widest spectra of antibacterial activity of all the beta-lactams and provide excellent coverage of many gram-negative and gram-positive aerobic and anaerobic bacteria. Despite the wide antibacterial spectrum, the carbapenems globally lack activity against Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA) and Stenotrophomonas maltophilia. Methods: We reviewed the principal characteristics of the novel carbapenems and their clinical implications. Results and conclusions: We included in our review: ertapenem, biapenem, panipenem, doripenem, tebipenem pivoxil and tomopenem.

Imbalances of iron homeostasis cause frequent clinical syndromes. Iron deficiency affects almost 25% of the global population and approximately one billion people suffer from iron deficiency anaemia. Moreover, the anaemia of chronic disease, which develops primarily in subjects suffering from malignancies, infections and autoimmune disorders is pivotally caused by an iron-limited erythropoiesis, which arises from iron retention within cells of the reticulo endothelial system. In contrast, one of the most frequent inherited disorders in people of Northern-Western European origin is hereditary hemochromatosis (HH). HH leads to progressive iron overload in parenchymal organs with subsequent organ failure. In addition, secondary iron overload develops in patients receiving repetitive blood transfusion for the treatment of genetic hemoglobinopathies or for the correction of anaemia in cancer or myelodysplastic syndromes. Due to the discovery of new genes, our knowledge on the regulation of iron homeostasis has dramatically expanded which offers avenues for new treatment options. This is of importance, since some of these clinical syndromes (e.g. anaemia of chronic disease or secondary iron overload) are not sufficiently treatable with current medications (e.g. iron chelators, iron, erythropoietin) in many patients. In addition, some patients with iron deficiency face side effects from iron therapy or refuse phlebotomy for treatment of HH. Thus, new treatment strategies for iron metabolism disorders or improvement of existing concepts are necessary. This review discusses established, approaching and future putative treatment strategies and concepts for combating iron metabolism disorders.

The current adenosine diphosphate inhibitors, ticlopidine and clopidogrel, are thienopyridine compounds that inhibit adenosine diphosphate mediated platelet aggregation. They interfere with platelet activation by selectively and irreversibly blocking P2Y12 sub-unit of the adenosine diphosphate receptor on the surface of platelets. This provides an antiplatelet effect that is additive to the inhibition of the thromboxane A2 pathway by aspirin. Dual antiplatlet therapy is extensively used in cardiovascular medicine. Randomized controlled trials have substantiated the fact that thrombotic complications after percutaneous coronary intervention procedures can be decreased by using dual antiplatelet therapy. However, there is a concern of bleeding due to enhanced and irreversible platelet inhibition in patients who will require any operation including coronary artery bypass grafting while on adenosine diphosphate inhibitors. This applies to a large population of patients requiring either coronary artery bypass grafting after angiographic definition of their coronary anatomy, or patients requiring semi-elective or urgent operation while under dual antiplatlet therapy. This concern is more present in era of drug-eluting stents, where long-term use of dual antiplatelet therapy is encouraged, and the incidence of late thrombosis after late cessation of adenosine diphosphate inhibitors is increasingly surfacing in the literature. The goal this review is to provide the medical chemistry of most commonly used adenosine diphosphate inhibitors, examine the literature on the effect of adenosine diphosphate inhibitors in hemorrhagic-related complications after surgical intervention, and provide the ramifications and alternatives in modern clinical practice.

Leishmaniasis is a disease that ranges in severity from skin lesions to serious disfigurement and fatal systemic infection. WHO estimates that the disease results in 2 million new cases a year, threatens 350 million people in 88 countries and that there are 12 million people currently infected worldwide. Current treatment is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost, toxicity, difficult route of administration and lack of efficacy in endemic areas. Pentavalent antimonials have been the mainstay of antileishmanial therapy for over 70 years with second line drugs, Amphotericin B and Pentamidine, used in case of antimonial failure. Since the introduction of miltefosine at the beginning of this century, no new antileishmanial compounds have been approved for human treatment. Leishmaniasis is considered one of a few parasitic diseases likely to be controllable by vaccination. However, to date no such vaccine is available despite substantial efforts by many laboratories. The development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. This review outlines the current status of vaccine development and looks at the currently available chemotherapy as well as examples of drugs in development and different approaches to antileishmanial drug discovery and identification of novel antiparasitic compounds.

Neurodegenerative disorders are often characterized by the aggregation and accumulation of misfolded proteins (e.g. Alzheimer's disease, Parkinson’s disease, Amyotrophic lateral sclerosis). Aggregated proteins are very toxic to cells in culture and both in vitro and in vivo there is overwhelming evidence that these aberrant proteins are key players in neurodegeneration. Protein quality control is a cellular defense mechanism against misfolded proteins that prevents aggregate formation under physiological conditions. The presence of accumulated aggregates of misfolded proteins in many neurodegenerative disorders, suggests that protein quality control failed to restore homeostasis in these pathological conditions. In fact, evidence from observations in cellular disease models, mouse models, as well as from post mortem patient material indicates activation of the quality control machinery in response to the pathological process. In addition, interference with protein quality control by genetic or chemical manipulation often results in aggregate formation and neurodegeneration. This stresses the importance of proper quality control in neurodegenerative disorders and indicates that it may provide a target for therapeutic intervention. In this review we will focus on the protein quality control systems in the endoplasmic reticulum (ER) and address the involvement of ER quality control in neurodegenerative disease as well as its potential as therapeutic target.

Contrast-enhanced ultrasound has shown convincing results for monitoring vessel morphology, surrogate markers of vascularization and changes in molecular marker expression in oncological and cardiovascular diseases. Ultrasound contrast agents have the ability to increase the backscattering signal intensity of an ultrasound pulse. An interesting class of ultrasound contrast agents are gas filled microbubbles, which can be synthesized by external bubble encapsulation using sugar matrices or microspheres consisting of lipids or polymers with or without surfactant and by selecting gases with low blood solubility and diffusion coefficient such as perfluorocarbons or sulphur hexafluoride. Ultrasound contrast agents can be classified according to the rigidity of their shell. Soft-shell microbubbles are coated with a thin monolayer of surfactant molecules such as palmitic acid or phospholipids and are very sensitive to pressure changes. Hard-shell microbubbles have a rigid shell made of polymers such as polycyanoacrylate, which dramatically increases their stability. Depending on the acoustic properties of the microbubbles and on the purpose of the examination either destructive or non destructive methods are preferred for their detection. Microbubbles can be detected by destructive and non-destructive methods. Both soft- and hard-shell microbubbles coated with target-specific molecules can also be used for molecular imaging. Using target-specific approaches, the expression of several angiogenic markers such as VEGFR2, αvβ3 Integrins, ICAM, and E-selectin has been investigated in neoplastic and vascular diseases. This article summarizes the synthesis and properties of contrast agents as well as the indications, limitations and future potential of contrast-enhanced functional and molecular ultrasound.