Current Medicinal Chemistry - Volume 14, Issue 9, 2007

We succeeded in purifying a major glycolipids fraction (i.e., Fraction-II) in the class of monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG) from spinach using hydrophobic column chromatography. Fraction-II inhibited the activities of replicative DNA polymerases (pols) such as α, δ and η, and mitochondrial pol g with IC50 values of 43 - 79 μg/ml, but had no influence on the activity of repair-related pols β and lλ. MGDG, DGDG, SQDG were purified from Fraction-II of spinach using silica gel column chromatography, and SQDG was the strongest inhibitor of mammalian pols in the three glycolipids. Therefore, SQDG and its related compounds were chemically synthesized, and the sulfate group and fatty acid moiety of the compound were suggested to be important for pol inhibition. These glycolipids showed no effect even on the activities of plant pols, prokaryotic pols and other DNA metabolic enzymes such as T4 polynucleotide kinase, T7 RNA polymerase and deoxyribonuclease I. Fraction-II also inhibited the proliferation of human cervix carcinoma (HeLa) cells with LD50 values of 57 μg/ml, and could halt the cell cycle at the G1-phase, and subsequently induced severe apoptosis. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, Fraction-II was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that tumor necrosis with hemorrhage was significantly enhanced with Fraction-II in vivo. The spinach Fraction-II containing SQDG might be a potent anti-tumor compound, and may be a healthy food substance with antitumor activity.

Many tumor-associated mutations result in the abnormal regulation of protein kinases involved in the progression throughout the cell division cycle. The cyclin-dependent kinase (CDK) family has received special attention due to their function as sensors of the mitogenic signals and their central role in cell proliferation. These kinases are frequently upregulated in human cancer most frequently due to overexpression of their cyclin partners or inactivation of the CDK inhibitors. A plethora of small-molecule CDK inhibitors have been characterized in the last years and some of them are currently under clinical development. Other serine-threonine protein kinases such as the Aurora proteins (mostly Aurora A and B) or Polo-like kinases (PLK1) are receiving increased attention as putative cancer targets. Other less studied mitotic kinases such TTK (MPS1), BUB and NEK proteins might also be relevant candidates as new targets of interest in cancer therapy since they play relevant roles on mitotic progression and the spindle checkpoint. Although targeting cell cycle kinases is an efficient procedure to arrest cell proliferation, the best strategy to potently and specifically inhibit tumor cell proliferation is not obvious yet. Thus, some cell cycle kinases may be of interest as targets to abrogate checkpoints and favor apoptotic cell death in tumor cells. New biochemical and genetic studies are required to clarify the use of these kinases as targets in new opportunities to improve cancer therapy.

The theoretical use of mass spectrometric profiling of low-molecular-weight volatile compounds, as one possible method to non-invasively and rapidly diagnose a variety of diseases, such as cancer, infection, and metabolic disorders has greatly raised the profile of this technique over the last ten years. Despite a number of promising results, this technique has not been introduced into common clinical practice yet. The use of mass spectrometric profiling of exhaled air is particularly hampered by various technical problems and basic methodological issues which have only been partially overcome. However, breath analysis aside, recently published studies reveal completely new ideas and concepts on how to establish fast and reliable diagnosis by using this valuable tool. These studies focussed on the headspace screening of various bodily fluids and sample fluids obtained during diagnostic procedures, as well as microbial cell cultures and demonstrated the vast diagnostic potential of this technique in a wide variety of settings, predominantly in vitro. It is the aim of the present review to discuss the most commonly detected low-molecular-weight volatile compounds and to summarize the current potential applications, latest developments and future perspectives of this promising diagnostic approach.

The photodynamic process induces cell damage and death by the combined effect of a photosensitizer (PS), visible light, and molecular oxygen, which generate singlet oxygen (1O2) and other reactive oxygen species that are responsible for cytotoxicity. The most important application of this process with increasing biomedical interest is the photodynamic therapy (PDT) of cancer. In addition to hematoporphyrin-based drugs, 2nd generation PSs with better photochemical properties are now studied using cell cultures, experimental tumors and clinical trials. Porphycene is a structural isomer of porphyrin and constitutes an interesting new class of PS. Porphycene derivatives show higher absorption than porphyrins in the red spectral region (lλ > 600 nm, η > 50000 M-1·cm-1) owing to the lower molecular symmetry. Photophysical and photobiological properties of porphycenes make them excellent candidates as PSs, showing fast uptake and diverse subcellular localizations (mainly membranous organelles). Several tetraalkylporphycenes and the tetraphenyl derivative (TPPo) induce photodamage and cell death in vitro. Photodynamic treatments of cultured tumor cells with TPPo and its palladium(II) complex induce cytoskeletal changes, mitotic blockage, and dose-dependent apoptotic or necrotic cell death. Some pharmacokinetic and phototherapeutic studies on experimental tumors after intravenous or topical application of lipophilic alkylsubstituted porphycene derivatives are known. Taking into account all these features, porphycene PSs should be very useful for PDT of cancer and other biomedical applications.

Leukoaraiosis (LA), one of the most frequent causes of cognitive disturbances, is presumed to involve vascular demyelinization and cerebral small-vessel diseases. Although it has been suggested that the development of LA is associated with cerebral circulatory disturbances, the pathomechanism of this circulatory problem is not completely understood. Extensive debate is continuing as regards the detailed features of the circulatory disturbances in LA. An endothelial dysfunction may lead to breakdown of the blood-brain barrier, thereby resulting in chronic toxic edema in the perivascular areas. This can then cause the slow development of LA. Endothelial dysfunctions may also give rise to molecular events involving a shift in the O2 and CO2 trafficking system in the red blood cells, which will result in special complex microcirculation disturbances in the white matter of the brain; these molecular phenomena may therefore account for chronic slight hypoxia leading to the development of LA. This article discusses these hypothetical alternative molecular events behind LA. The review also illustrates how medicinal chemistry can offer new insight into a common, but still mysterious cerebral phenotype.

Chronic Obstructive Pulmonary Disease is characterized by an abnormal inflammatory response of the lungs to noxious particles and gases, caused primarily by cigarette smoking. Although COPD affects the lung, it also produces significant systemic consequences. Inflammation, proteases-antiproteases imbalance, oxidative stress, tissue damage and tissue repair, apoptosis and several genes seem to be involved in the pathogenesis of the disease. The cellular and molecular events underlying COPD pathogenesis are driven by multifunctional molecules including enzymes, cytokines, chemokines, growth factors, lipid mediators and their respective receptors. A large number of biomarkers evaluated in COPD, showed a high degree of redundancy. Nevertheless, current understanding of the pathobiology of COPD suggests a number of biomarkers as potential candidates. The development of relevant markers of lung damage, pulmonary inflammation, and systemic disease will be essential to our further understanding of the natural history of COPD and the discovery of new, effective treatments for its progression This review summarizes recent findings, on potential pulmonary biomarkers in the induced sputum, the exhaled air condensate, the peripheral blood, the urine, the bronchoalveolar lavage fluid, and in selective cases, in bronchial biopsies.

Severe and difficult-to-treat asthma patients have impaired health status and account for over half of the cost of the disease and probably all of its mortality. Guideline-based treatment for these refractory asthma patients includes high doses of inhaled steroids and long acting beta2-agonists (LABA) as well as additional medication such as theophylline, oral steroids and leukotriene-antagonists. However, management regimens are rarely successful in these patients, the treating physicians are often at a loss and there are still many areas of uncertainty regarding steroid-responsiveness, safety issues and maximal dosing of inhaled corticosteroids (ICS) and bronchodilators and possible differences between ICS preparations. Furthermore, there are many other classes of medication that have been or are currently tested in severe asthma: Anti - Immunoglobulin E (IgE) seems to have a good clinical effect while results on anti - Interleukin 5 (IL-5) are less promising and anti - tumor necrosis factor alpha (TNFα) treatment is currently being tested in controlled studies. Other steroid sparing drugs (cyclosporine, tacrolimus, methotrexate, gold) have been used but results are unsatisfactory and side-effects are notable so steroids remain the cornerstone of severe asthma treatment. The addition of macrolides is beneficial in many cases and this is in step with the evidence of chronic chlamydia infection in severe asthma. Although there are case reports supporting the use of Immunoglobulin G (IgG), there are no controlled studies supporting this type of treatment. In this report, the authors review the various issues of guideline based therapy but also new approaches that include anti-IgE antibodies, anti-cytokines (anti-IL-5, anti-IL9, anti-TNF).