Current Medicinal Chemistry - Volume 16, Issue 35, 2009

The immune system balances effector responses with tolerance, to protect the host from pathogens while minimizing local damage to tissue. An altered control of immune homeostasis can lead to loss of tolerance to self antigens in autoimmunity, or promote unwanted tolerance to tumor growth. This review focuses on the dual activity of CD4+ regulatory T cells (Tregs) in autoimmunity and cancer. Tregs play a key role in the mechanisms of immune tolerance and actively suppress pro-inflammatory responses, thus providing a beneficial action in autoimmunity and detrimental effects in cancer.

Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half live, change the biodistribution and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Duplex and multiplex drugs consist of distinct active drugs with different mechanisms of action, which are linked to each other with either a lipid or a phosphodiester. Enzymatic cleavage of such a prodrug inside the cell releases the drug or the phosphorylated form of the drug. Antitumor activity of cytotoxic drugs can also be enhanced by the use of nanoparticles as carriers. Nanoparticles have the advantage of high stability, high carrier capacity, incorporation of hydrophobic and hydrophilic compounds and variable routes of administration. Encapsulating drugs in liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. Nanoparticles and liposomes can be used to target drugs either actively or passively to the tumor. In this review we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy) nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems. We expect that combining different strategies could further increase the efficacy of these compounds.

Neopterin is produced by human and primate monocyte/macrophages upon activation by pro-inflammatory stimuli like Th1-type cytokine interferon-γ. Neopterin has pro-oxidative properties, which have been demonstrated in vitro in physicochemical and cell culture studies and also in in vivo experiments, e.g. the Langendorff perfusion model of rat hearts. In the past several years, the measurement of neopterin concentrations in body fluids including serum, urine and cerebrospinal fluid has revealed a potential role of this molecule in the prediction of long-term prognosis in both patients with cancer and those with systemic infections such as HIV-1 infection. Moreover, elevated neopterin concentrations have been reported in patients with coronary disease compared to controls and in recent years it has become apparent that increased neopterin concentrations are an independent marker for cardiovascular disease and a predictor of future cardiovascular events in patients with coronary artery disease. Current data suggest that the diagnostic performance of neopterin testing is comparable to that of well established biomarkers such as C-reactive protein and cholesterol plasma levels. The present article reviews the role of neopterin in the pathogenesis of cardiovascular disease and as a marker of coronary artery disease progression.

Chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions forms an integral part of the development of cardiovascular diseases (CVD), and in particular atherosclerosis. These ROS are released from different sources, such as xanthine oxidase, lipoxygenase, nicotinamide adenine dinucleotide phosphate oxidase, the uncoupling of nitric oxide synthase and, in particular, mitochondria. Endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not clear, oxidative stress seems to play an important role. In general, ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects of excessive ROS production. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. This review considers the process of atherosclerosis from a mitochondrial perspective, and assesses strategies for the targeted delivery of antioxidants to mitochondria that are currently under development. We will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as atherosclerosis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for atherosclerosis.

Coordinated and constructive physical activity is correlated with the maintenance of cognitive function in humans. Voluntary running also enhances neuroplasticity in adult and aging rodents, but the molecular pathways underlying these effects are still being elucidated. Considering the multifactorial nature of the biochemical links between physical activity and neurophysiology, it is likely that there are many pharmacological mechanisms by which the beneficial actions of exercise can be effectively reproduced using chemical agents. Most studies to date have focused on brain-derived neurotrophic factor (BDNF) as a signaling target for the enhancement of neuronal function by exercise. The goal of the current review is to move beyond BDNF by exploring the diversity of molecular pathways regulated by physical activity in a variety of situations. We will discuss the availability and mechanism of action for several diverse physical activity pharmacomimetics. As physical activity enhances both neuroplasticity and cognition, understanding the molecular targets for these effects may lead to the development of potent new therapeutic interventions for age-related neurodegenerative conditions such as Alzheimer's disease.

During the transduction of extracellular signals within the cell, the stimulation of specific G protein-coupled receptors (GPCRs) can modulate adenylyl or guanylyl cyclase, phospholipase C activity and ion channels, which regulate second-messengers. These, in turn, trigger several biochemical cascades, including Ca2+ release, activation of protein kinases and gene expression. Significant changes of monoamine GPCR activity may occur in patients suffering from mood disorders and the majority of antidepressants exert part of their effects through GPCR-mediated systems. The main signal transduction pathways activated by metabotropic receptors in the brain and their possible involvement in the pathophysiology of mood disorders will be reviewed herein with a special focus on the horizons opened by this approach in terms of innovative therapeutic strategies.

Endothelial cells (ECs) play a pivotal role in physiological and altered tissue neovascularization. They face multiple morphological, biochemical and functional changes during the different phases of angiogenesis, under the regulation of a great number of proangiogenic and antiangiogenic signals, including soluble and insoluble factors, cell-cell and cell-matrix interactions. ECs mutual contacts (and also interactions with other cell types, such as pericytes and smooth vascular muscle cells), motility, proliferation, apoptosis and differentiation are all calcium-dependent events finely tuned in space and time. Most of the angiogenic-related peptidic factors (VEGF, bFGF and others) promote an increase of cytosolic free calcium concentration in ECs, giving rise to calcium-activated intracellular cascades engaged in the different steps of the angiogenic process. A better knowledge of such signals could allow to set new diagnostic and therapeutical approaches aimed to interfere with altered neovascularization, particularly during cancer progression. This review reports the state of the art about endothelial angiogenic-related calcium signaling and discusses the most attractive perspectives for the future.

For the development of new antiepileptics the kainate receptors, GluR6 and GluR5, are important targets. Based on the anticonvulsant effects of chinazolines and thieno[2,3-d]pyrimidines that are known from the literature, thieno[2,3-d][1.3]oxazines were synthesized and studied for their inhibitory properties at GluR6 and GluR5 receptors. The strongest inhibitor activity was observed with 5-methyl-6-phenyl-thieno[2,3-d][1.3]oxazines with C1 or C3-substituents in position 2 (3b-f). The 2-trihalide-methyl-substituted compounds 3c and 3d were the most active inhibitors at the GluR5- receptor (IC50=23.4 μmol, 16 μl). The 2-isopropyl-substituted compound 3f displayed the strongest activity at the GluR6- receptor (IC50=8.7 μmol). A number of thieno[2,3-d][1.3]thiazines and thieno[2,3-d]pyrimidines that were synthesized from the thieno[2,3][1.3]oxazines did not show any activity.

Superparamagnetic iron oxide nanoparticles can be used for numerous applications such as MRI contrast enhancement, hyperthermia, detoxification of biological fluids, drug delivery, or cell separation. In this work, we will summarize the chemical routes for synthesis of iron oxide nanoparticles, the fluid stabilization, and the surface modification of superparamagnetic iron oxide nanoparticles. Some examples of the numerous applications of these particles in the biomedical field mainly as MRI negative contrast agents for tissue-specific imaging, cellular labeling, and molecular imaging will be given. Larger particles or particles displaying a non-neutral surface (thanks to their coating or to a cell transfection agent with which they are mixed) are very useful tools, although the cells to be labeled have no professional phagocytic function. Labeled cells can then be transplanted and monitored by MRI in a broad spectrum of applications. Direct in vivo magnetic labeling of cells is mainly performed by intravenous injection of long-circulating iron oxide-based MRI contrast agents, which can extravasate and/or undergo a cellular uptake in an amount sufficient to allow an MRI visualization of areas of interest such as inflamed regions or tumors. Particles with long circulation times, or able to induce a strong negative effect individually have been also modified by conjugation to a ligand, so that their cellular uptake, or at least their binding to the cell surface, could occur through a specific ligand-receptor interaction, in vivo as well as in vitro. Thus, experimentally as well as in a few trials on humans, iron oxide particles currently find promising applications.

Several hundreds of studies published the last decade have reported that α-lipoic acid (LA) possesses the potential to intervene in various therapeutically interesting pathways. However, it should be noted that LA reportedly exerts most of its effects at high micromolar concentrations; that amides of LA exhibit higher biological activity than the parent compound; and that molecular combinations (hybrids) obtained by coupling LA with an amino-substituted bioactive moiety, possess multifunctional activity. The design and synthesis of hybrid molecules encompassing two pharmacophores in one molecular scaffold is a well established approach to the synthesis of more potent drugs with dual activity. Using this approach, various research groups have recently designed and synthesized LA containing hybrid compounds with antioxidant activity hyphenated with a wide variety of other activities such as neuroprotective, cardioprotective, anti-inflammatory, antidiabetic and anticancer activity as well as enzyme inhibition. Moreover, LA represents an ideal chemical entity for the development of biologically interesting functionalized nanoparticles. Many recent publications describe the use of LA: i) as component of nanospheres and nanoprodrugs, ii) as a linker for the attachment of lipids, carbohydrates, proteins and oligonucleotides on gold nanoparticles to form Self Assembled Monolayers (SAMs) and iii) as surface ligand for cap exchange reactions to prepare water-soluble semiconducting nanocrystal Quantum Dots (QDs). This review is focused on the growing field of the design and synthesis of LA conjugates, for the development of novel molecules with a dual mode of action and the construction of nanosized antioxidants, Self Assembled Monolayers and Quantum Dots.

T lymphocytes bearing the γδ T cell receptor are known to play an important role in the first-line defense against viral, bacterial and fungal pathogens. Two main subsets of γδ T cells are known, showing distinct functional behavior: Vδ2 T lymphocytes, circulating in the peripheral blood, are involved in the response to mycobacterial infections and certain viruses, including coxsackie virus B3 and herpes simplex virus type 2. Vδ1 T cells are resident in the mucosalassociated lymphoid tissue and are reported to participate in the immunity against Listeria monocytogenes and cytomegalovirus. Vδ2 T lymphocytes recognize non-peptidic phosphorylated metabolites of isoprenoid biosynthesis, expressed by mycobacteria, while Vδ1 T cells mainly interact with MHC-related antigens (MIC-A and MIC-B) and with receptors, called UL-16 binding proteins, for the UL-16 protein produced by cytomegalovirus-infected cells. Both Vδ1 and Vδ2 T cells can produce interferon-γ in response to MIC-A+ cells or non-peptide antigens, respectively. Moreover, production of TNF-α by human Vγ9/Vδ2 T cells has been demonstrated in response to bacterial products and non-peptidic molecules. Recently, it has been reported that γδ T lymphocytes can produce IL-17 during Escherichia coli or Mycobacterium tuberculosis infections in mice. This is of interest as IL-17 is emerging as a cytokine crucial in the control of intracellular pathogens and fungi. In this review, we will discuss the possible role of IL-17 producing γδ T cells in the regulation of acute and chronic inflammation, focusing on the different responses of the two subsets to mycobacterial, viral or fungal antigens.

Glycosaminoglycans (GAGs), such as heparin and heparan sulphate, are a class of linear, anionic polysaccharides that constitute the carbohydrate component of proteoglycans. The structure of GAG complexes with proteins can reveal details of their mechanisms of action in living systems and help to design new pharmaceuticals. Molecular modelling together with nuclear magnetic resonance (NMR) and other spectroscopic techniques such as circular dichroism (CD) provide indispensable information on structure and dynamics of GAGs and their complexes. The present review focuses on applications of high-resolution NMR, CD and molecular modelling to the analysis of GAGs. The most advanced theoretical methods used at present in GAG research, density functional theory methods (DFT), are also discussed.