Current Medicinal Chemistry - Volume 13, Issue 15, 2006

Can cancer be cured or will it have to be controlled as a chronic disease? Despite a better understanding of the biology of tumour cells, the treatment of most cancers has not significantly changed for the past three decades. Are current cancer drugs targeted at the wrong kind of cells? Accumulating evidence has implicated that cancer is a disease of stem cells. In this context, a small fraction of cancer cells adopt the properties of stem cells. In some cases, the cancer stem cells (CSC) could be the close derivative of normal tissue stem cells. In either situation, the net result will be the same, in that CSC are the cells to be used as targets in the development of molecular and pharmaceutical therapies to treat and prevent human cancer. This could be a paradigm shift in the treatment of cancer, away from targeting the blast cells and towards the targeting of the CSC. A challenge to this approach will be to find a way to specifically target CSC without toxicity to normal cells. In this article, we propose how CSC can be used in therapy programs (target identification, drug discovery, etc.). Therefore, in the future, it might be possible to rid a patient of all his/her cancer cells, including the cancer stem cells.

Intravascular ultrasound (IVUS) imaging within the coronary arteries has emerged as the gold standard for the quantitation of the extent of atherosclerosis plaque. Studies that have utilized IVUS have enhanced our understanding of the in vivo natural history of atherogenesis. As IVUS can be performed within the same coronary artery at different time points it has become an attractive tool for the assessment of the effect of experimental anti-atherosclerotic strategies on plaque burden. This review will review the evolution of IVUS as an imaging modality and highlight its use to assess a number of interventions that are directed at both modification of existing risk factors and novel targets that are thought to play a pivotal role in the pathogenesis of atheroma formation.

The study of protein target families, as opposed to single targets, has become a very powerful tool in chemogenomics-led drug discovery. By integrating comprehensive chemoinformatics and bioinformatics databases with customised analytical tools, a 'Toolkit' approach for the target family is possible, thus allowing predictions of the ligand class, affinity, selectivity and likely off-target issues to be made for the guidance of the medicinal chemist. In this review, we highlight the development and application of the Toolkit approach to the protein kinase superfamily, drawing on examples from lead optimisation studies and the design of focused libraries for lead discovery.

Reduced glutathione (GSH) is present in millimolar concentrations in mammalian cells. It is involved in many cellular functions such as detoxification, amino acid transport, production of coenzymes, and the recycling of vitamins E and C. GSH acts as a redox buffer to preserve the reduced intracellular environment. Decreased glutathione levels have been found in numerous diseases such as cancer, viral infections, and immune dysfunctions. Many antioxidant molecules, such as GSH and N-acetylcysteine (NAC), have been demonstrated to inhibit in vitro and in vivo viral replication through different mechanisms of action. Accumulating evidence suggests that intracellular GSH levels in antigen-presenting cells such as macrophages, influence the Th1/Th2 cytokine response pattern, and more precisely, GSH depletion inhibits Th1-associated cytokine production and/or favours Th2 associated responses. It is known that GSH is not transported to most cells and tissues in a free form. Therefore, a number of different approaches have been developed in the last years to circumvent this problem. This review discusses the capacity of some new molecules with potent pro- GSH effects either to exert significant antiviral activity or to augment GSH intracellular content in macrophages to generate and maintain the appropriate Th1/Th2 balance. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to treat antiviral infections and Th2-mediated diseases such as allergic disorders and AIDS.

This review aims to summarize the non-invasive approaches employed in delivering drugs to the central nervous system which is severely hindered by the presence of the blood-brain barrier (BBB) that limits molecular permeation. Particular attention will be placed on the several available strategies for delivering drugs into the brain, through circumvention of the BBB, in order to critically address the medicinal chemistry and the pharmaceutical technology contributions.

Diabetic patients have a two- to four-fold increased risk for the development of microvascular (renal, neuronal and retinal) and macrovascular complications. Unfortunately, these complications may develop in both Type 1 and Type 2 diabetic patients even with careful glycaemic, blood pressure and lipid control. With the worldwide increase in the incidence diabetes, new strategies to prevent the complications are urgently needed. Mediators of vascular damage of diabetes include poor glycemic control, lipoprotein abnormalities, hypertension, oxidative stress, inflammation and advanced glycation end-products (AGEs), which are modified proteins formed by non-enzymatic glycation. AGEs are resistant to enzymatic degradation and therefore very stable, thus their accumulation continues throughout aging. AGE accumulation causes arterial stiffening in the vessel wall, glomerulosclerosis in the kidney, and vascular hyperpermeability in the retina. Through their interaction with their putative receptor the so-called receptor for AGEs (RAGE), AGEs activate endothelial cells and macrophages, generate reactive oxygen species (ROS), induce overexpression of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1), and quench nitric oxide (NO). The pharmacological treatment currently available for either Type 1 or Type 2 diabetic patients does not directly address the excess accumulation of AGEs. Novel compounds that inhibit AGE formation, cleave AGE crosslinks or reverse their interaction with RAGE are now accessible and could prove useful in meeting this challenge. Other strategies such as inhibition of the hexosamine pathway, vitamin therapy to reduce oxidation and AGE accumulation, reduction of the ROS, or blocking the actions of growth factors or intracellular messengers of cell differentiation are also currently under research. This review will recount recent advances in the development of therapeutic approaches for inhibiting and treating the development of diabetic end-organ damage.

Carbon nanotubes are considered as molecular wires exhibiting novel properties for diverse applications including medicinal and biotechnological purposes. Surface chemistry on carbon nanotubes results on their solubilization in organic solvents and/or aqueous/physiological media. Herein, we will present how interfacing such novel carbon-based nanomaterials with biological systems may lead to new applications in diagnostics, vaccine and drug delivery. Recent developments in this rapidly growing field will be presented thus suggesting exciting opportunities for the utilization of carbon nanotubes as useful tools for biotechnological applications. Emphasis will be placed in the integration of biomaterials with carbon nanotubes, which enables the use of such hybrid systems as biosensor devices, immunosensors and DNAsensors.

Complex polysaccharides, hyaluronic acid or hyaluronan (HA), keratan sulfate (KS), chondroitin sulfates (CSs) and heparin (Hep)/heparan sulfate (HS), are a class of ubiquitous molecules exhibiting a wide range of biological functions. They are widely distributed as glycosaminoglycans (GAGs) sidechains of proteoglycans (PGs) in the extracellular matrix and at cellular level. The recent emergence of improved enzymatic and analytical tools for the study of these complex sugars has produced a virtual explosion in the field of glycomics. In particular, the study of the GAG family of polysaccharides has shed considerable light on the way in which specific carbohydrate structures modulate cellular phenotypes. In addition to the wellknown therapeutic applications of some of these macromolecules, such as HA and derivatives as structure modifying molecules and possessing gel-like properties able to provide functional support for tissues, Hep as an anticoagulant and antithrombotic drug and CS in the treatment of osteoarthritis (OA), this increased understanding of GAG structure-function relationship has led to the discovery of novel pharmaceuticals for the possible treatment of serious diseases, such as cancer. In this paper, the structure and the therapeutic applications of several complex natural polysaccharides, including HA, CS/DS, Hep and their derivatives, are presented and discussed also in the light of the many questions still left unanswered, such as improved preparation and GAG-based drugs with improved properties and new possible therapeutic applications.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The production and accumulation of β-amyloid peptides (Aβ) from the β-amyloid precursor protein (APP) are believed to play a key role in the onset and progression of AD. BACE1 (β-site APP cleaving enzyme 1) is the protease responsible for the N-terminal cleavage of APP leading to the production of Aβ peptides and the development of BACE1 inhibitors as potential therapeutic agents for AD has generated tremendous interests from both academia and the pharmaceutical industry. A wide variety of BACE1 inhibitors have been reported, several of which have demonstrated highly promising efficacy in animal models of AD. This review focuses on recent disclosures of BACE1 inhibitors in the patent and scientific literature, covering the period from approximately May 2004 to November 2005.

Protein microarrays are an emerging class of nanotechnology for tracking many different proteins simultaneously. Much progress has been made for applications in basic sciences. Translation of these methods for the treatment of patients, however, is slow, because the realities in the clinic are rarely taken into account, and proteomic changes in cultured cell lines might not fully reflect human diseases due to the lack of the tissue microenvironment. In this review, we summarise current protein microarray approaches that are being developed for profiling tissues and histopathologically defined cell populations from cancer patients. We provide an overview of clinical applications for protein lysate microarrays and discuss the power of this technology for the discovery of disease markers for cancer diagnosis and individualised treatment.

Glucokinase (GK) is a molecular sensor that regulates glucose induced insulin secretion in pancreatic β-cells and glucose homeostasis in the liver via catalysis of glucose to glucose-6-phosphate. The recent discovery and development of small molecule glucokinase activators represents a potentially important development for the management of type 2 diabetes. Since the discovery of the first orally active small molecule GK activator RO0281675, a number of research groups have reported the identification of potent activators. In this review, the biological significance of GK in whole body glucose homeostasis is briefly described coupled with the recent progress regarding the identification of novel small molecule GK activators.