Current Medicinal Chemistry - Volume 14, Issue 7, 2007

Molecular therapies target key functional molecules in order to halter viable operation of cancer cells. Receptor tyrosine kinases (RTKs) constitute attractive targets, as quite often their abnormal signaling has been associated with tumor development and growth. Overexpression of growth factor receptors, including IGF, EGF, TGF-α, SCF and PDGF receptors, has been associated with poor prognosis in breast cancer. Therefore, a number of RTKs are already targets for novel designed drugs, which involve tyrosine kinase inhibitors and monoclonal antibodies. Despite the fact that c-Kit and PDGF-R have been effective targets in a number of cancers, the experimental results in breast have not yet clarified their importance. The expression and function of c-Kit in breast cancer is a quite controversial subject. Several studies propose that the loss of c-Kit expression has been associated with tumor progress, whereas other reports indicate not only its expression but also the implication of c-Kit in breast cancer. On the other hand, the expression of PDGF-R in breast cancer is not in question. A number of inhibitors against tyrosine kinases are currently in trials as to demonstrate their importance in breast cancer treatment. Imatinib (STI571), which is a selective tyrosine kinase inhibitor and particularly of c-Kit and PDGF-R, exhibited encouraging results in respect to its inhibitory effect in cell growth and invasion potential in a panel of human breast cancer cell lines. In this review, the importance of RTKs in human cancer and of c-Kit and PDGF-R as molecular targets in breast cancer treatment, in the view of their expression profiles and the in vitro effects of STI571 is discussed.

Ageing is an aggravating factor leading to alterations in the biotransformation of drugs, and therefore their therapeutic efficacy and safety. In this review we discuss the influence of ageing on drug metabolizing enzymes in male Wistar rats. We report that drug metabolizing enzymes can be affected by ageing either by post-translational modifications or by transcriptional modifications. The post-translational modifications could be due to an increase of oxidative stress during ageing. Although it is now well established that transcriptional modifications are due to a change in the GH secretion profile in senescent rats, the intracellular mechanisms underlying these modifications are still unclear. In addition to the strong decrease in the activity of the main CYPs of male rats, we discuss the potential consequences on human drug metabolism in the elderly.

Malaria is one of the most severe tropical parasitic disease causing 1-3 million deaths annually. In the last 25 years very few new antimalarial molecules have been developed and only a limited number of them are currently in various stages of clinical development. The presently available antimalarial drugs include artemisinin analogs, quinoline derivatives and antifolates. This review summarizes recent advances in antimalarial drug development and world patents published between 2000-2006 claiming new synthetic antimalarial compounds and their activities. The most over-represented classes of compounds in malaria patent literature in order of frequency are artemisinin analogs, quinoline derivatives, DOXP reductoisomerase inhibitors, antifolates and febrifugine analogues. Many of these patents describe the novelty and potential of these synthetic derivatives with an attempt to identify the next generation antimalarials that may have potential commercial advantages.

There is an urgent clinical need to research novel methods of fertility control that are also protective against sexually transmitted diseases (STDs) such as the human immunodeficiency virus (HIV) or Chlamydia. The most obvious way to generate such a dual-purpose contraceptive method would be to develop safe, effective spermicides that were also active against a wide range of pathogenic organisms. The currently available formulations such as nonoxynol-9, gramicidin and benzalkonium chloride are effective spermicides but are toxic to the vaginal epithelium and do not provide protection against STDs. Over 60 agents are in clinical trials as potentially safer topical spermicides and/or microbicides. Compounds that have reached this stage of development include acid buffers, detergents, dendrimers, non-nucleoside reverse transcriptase inhibitors and anionic polymers. In addition, a number of potential spermicides/microbicides are the subject of preclinical investigation, including β-cyclodextrin, cyanovirin, porphyrins, cyclotriazadisulfonamides, dermaseptins, short-interfering RNA (siRNA) and HIV antibodies. The chemical principles underlying these disparate approaches and potential avenues for future investigation are discussed.

Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease but current predictions are that it will continue to rise as an important cause of mortality and morbidity worldwide. COPD is a complex inflammatory disease with both airway and parenchymal lung injury. Currently there is growing recognition that the inflammatory response extends beyond the lung, with evidence of systemic inflammation, which may account for the multi-organ effects associated with COPD. Early diagnosis and timely therapeutic intervention are likely to make a significant contribution to tackling this disease. Smoking cessation remains the single most effective means of preventing lung function decline and reducing mortality. At present, no currently available drugs have been shown to slow the progression of the disease. Pharmacological treatment has focused largely on symptomatic relief and short-acting bronchodilators have been the mainstay therapy. Long-acting beta-2 agonists and anti-cholinergics have provided additional benefit and anti-inflammatory agents such as inhaled corticosteroids and theophylline seem to offer benefit in selected patients. Combinations of the different classes of treatment, particularly in the same inhaler device, seem to confer particular advantage with improvements in symptoms, exercise capacity, health status and reductions in exacerbations. More research is needed to unravel the important cellular and molecular processes involved in the pathophysiology of COPD and ultimately to develop new and more effective forms of therapy.

To maintain immune homeostasis, the immune system has evolved two “opposite” mechanisms to regulate the activation or expansion of effectors including potential auto-reactive lymphocytes following an immune response. One is to support the survival of activated effectors and thereby benefit the generation of memory response. However, an inappropriate survival of auto-reactive lymphocytes may lead to autoimmune diseases, e.g. multiple sclerosis (MS) and rheumatoid arthritis (RA). The other is to induce apoptosis of most activated effectors, thereby bringing the immune system to a baseline level after an immune response. It is known that autoimmune diseases are due to uncontrolled growth of auto-reactive lymphocytes, eventually leading to damage of self-tissues or organs. Control of auto-reactive T lymphocytes therefore constitutes an attractive therapeutic strategy. Many studies on accessory cells and their secreted factors have focused on their role in the effector phase of a specific autoimmune disease. Recent data, however, support their causative role in triggering autoimmune diseases. In the past several years, several cytokines from activated accessory cells were demonstrated to promote the survival of pathogenic auto-reactive lymphocytes in animal models of MS, RA, and other autoimmune diseases. This review therefore focuses on the current knowledge regarding the role of those soluble survival factors in the initiation of different autoimmune diseases.

Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies, detected in the sera of patients with both autoimmune and various non-autoimmune diseases. They are also detected in subjects with no overt underlying disease - the primary antiphosphilipid syndrome (PAPS). High titers of APL are associated with arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. There have been many suggestions explaining the potential mechanisms of the procoagulant effect of aPL. These include endothelial cell (EC) activation; increased adhesion molecule expression; inhibition of EC prostacyclin release, increased leucocyte adhesion to EC, downregulation of thrombomodulin expression. APL induce the procoagulant activity of monocytes via increased tissue factor expression and directly stimulate platelet hyperactivity with resultant production of enhanced amounts of the proaggregatory molecule of TXA2. In vitro studies show that prepro-endothelin-1 mRNA is induced by human monoclonal anticardiolipin antibodies and this might contribute to vasospasm, and, ultimately, to arterial occlusion. The hypercoagulable state in APS patients is associated with alterations in the protein C/S pathway. It is suggested that aPL may impair the protein C anticoagulant system. Acquired protein C and protein S deficiency is described in patients with APS. Beta2- glycoprotein I, (Beta2-GPI) a natural anticoagulant, is involved in the regulation of protein S anticoagulant activity by preventing the binding of protein S to C4b-binding protein. APL were shown to inhibit this effect of Beta2- GP I. As the group of aPL is very heterogeneous, it is unlikely that a single mechanism is responsible for the thrombogenic activity of all aPLs associated with thrombosis.

Flavonoids are a group of naturally occurring phytochemicals abundantly present in fruits, vegetables, and beverages such as wine and tea. In the past two decades, flavonoids have gained enormous interest because of their beneficial health effects such as anti-inflammatory, cardio-protective and anticancer activities. These findings have contributed to the dramatic increase in the consumption and use of dietary supplements containing high concentrations of plant flavonoids. The pharmacological effect of flavonoids is mainly due to their antioxidant activity and their inhibition of certain enzymes. In spite of abundant data, structural requirements and mechanisms underlying these effects have not been fully understood. This review presents the current knowledge about structure-activity relationships (SARs) and quantitative structure- activity relationships (QSARs) of the antioxidant activity of flavonoids. SAR and QSAR can provide useful tools for revealing the nature of flavonoid antioxidant action. They may also help in the design of new and efficient flavonoids, which could be used as potential therapeutic agents.