Current Medicinal Chemistry - Volume 15, Issue 18, 2008

Properties of benzimidazole and its derivatives have been studied for over hundred years; special interest of researchers triggered by the fact that 5,6-dimethylbenzimidazole is a component of naturally occurring vitamin B12. Several antihelminthic, antacid and antibacterial drugs are known which have benzimidazole moiety as their essential constituent. Additionally, several bis- and trisbenzimidazole based systems are well-known for their interaction with DNA and interference with several DNA associated processes. This account gives an overview of the benzimidazole based systems and their relevance in medicinal chemistry.

Natural killer T (NKT) cells represent a unique T cell lineage. The NKT cells bearing an invariant TCR (iNKT cells) recognize a small variety of glycolipid antigens in the context of CD1d (non-classical MHC-I) presentation. CD1d-restricted iNKT cells play a regulatory role during an immune response by producing cytokines (IFN-γ, and IL-4). The identification of α-galactosyl-ceramide (α- GalCer), a marine sponge derivative as a potent stimulator of iNKT cells has raised the potential of therapeutic iNKT cell activation. Invariant NKT cells have been implicated in several different autoimmune diseases in mice and humans, including systemic lupus erythematosus (SLE). Abnormalities in the number and functions of NKT cells have been observed in SLE patients and mouse strains genetically predisposed to lupus (MRL/lpr, NZB/W F1). Moreover, inverse correlation between the frequency of NKT cells and IgG levels has been observed. Elevated IgG levels in relatives of patients with lupus as well as in patients with lupus were associated with low frequencies of NKT cells. This review focuses on the potential roles of NKT cells in the pathogenesis of SLE. It summarizes recent advances in glycolipid therapy for murine lupus. First, it has been demonstrated, that repeated administration of α-GalCer to MRL/lpr mice alleviated inflammatory dermatitis but did not influence kidney disease. Treatment of NZB/W mice with α-GalCer resulted in amelioration of SLE symptoms in young mice, but treatment of older animals resulted in disease exacerbation. The effects of NKT cell activation using α -GalCer, on disease progression, were influenced by a variety of parameters, including the genetic background of mice, the α -GalCer dose, number of injections and the stage of the disease process when treatment was performed. Manipulation of NKT cells in the human system may be a promising treatment alternative for the future, however possible deleterious effects have to be carefully investigated first.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron diseases (MND) characterized by progressive selective degeneration of motor neurons. Although several mutations underlying rare cases of familial ALS were identified during the last decade, the pathogenesis of ALS remains poorly understood. Various mechanisms have been suggested to contribute to disease pathology such as excitotoxicity, oxidative stress, protein aggregation, and inflammation. Accordingly, several candidate biochemical markers related to these pathomechanisms were investigated in cerebrospinal fluid (CSF). Although none of these markers gained clinical importance so far, CSF might reflect pathophysiological alterations in the course of the disease and could therefore provide an insight into pathomechanisms in vivo. It is suggested that cellular and proteinchemical processes are better reflected in the CSF than in other body fluids such as blood or urine due to the proximity of the affected motor neurons to the CSF compartment. Accordingly, alterations in protein expression, post-translational modification or turnover within the tissue of the central nervous system may be mirrored in corresponding changes in CSF protein content. Research on biomarkers in CSF using novel discovery technologies such as proteomics allows to search for a set of proteins that reflect different disease specific molecular pathways and might therefore be of relevance for the establishment of biomarkers for therapeutic monitoring and the development of novel therapies. In this review, an updated overview is given on CSF biomarkers related to the pathomechanisms supposed to be participating in the complex disease process of ALS.

Anticancer drugs are often nonselective antiproliferative agents (cytotoxins) that preferentially kill dividing cells by attacking their DNA at some level. The lack of selectivity results in significant toxicity to noncancerous proliferating cells. These toxicities along with drug resistance exhibited by the solid tumors are major therapy limiting factors that result into poor prognosis for patients. Prodrug and conjugate design involves the synthesis of inactive drug derivatives that are converted to an active form inside the body and preferably at the site of action. Classical prodrug and conjugate design have focused on the development of prodrugs that can overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs. The recent targeted prodrug and conjugate design, on the other hand, hinge on the selective delivery of anticancer agents to tumor tissues thereby avoiding their cytotoxic effects on noncancerous cells. Targeting strategies have attempted to take advantage of low extracellular pH, elevated enzymes in tumor tissues, the hypoxic environment inside the tumor core, and tumor-specific antigens expressed on tumor cell surfaces. The present review highlights recent trends in prodrug and conjugate rationale and design for cancer treatment. The various approaches that are currently being explored are critically analyzed and a comparative account of the advantages and disadvantages associated with each approach is presented.

SSAO/VAP-1 is not only involved in the metabolism of biogenic and xenobiotic primary amines and in the production of metabolites with cytotoxic effects or certain physiological actions, but also plays a role, for example, as an adhesion molecule, in leukocyte trafficking, in regulating glucose uptake and in adipocyte homeostasis. Interest in the enzyme has been stimulated by the findings that the activities of the SSAOs are altered (mostly increased) in various human disorders, including diabetes, congestive heart failure, liver cirrhosis, Alzheimer's disease and several inflammatory diseases, although the underlying causes are often unknown. On the basis of their insulin-mimicking effect, SSAO substrates are possibly capable of ameliorating metabolic changes in diabetes, while SSAO inhibitors (somewhat of a contradiction) are of potential benefit in preventing diabetes complications, atherosclerosis and oxidative stress contributing to several disorders or modulating inflammation, and hence may be of substantial therapeutic value. Great efforts have been made to develop novel compounds which may lead to future drugs useful in therapy, based on their effects on SSAO/VAP-1, and some of the results relating to novel substrates and inhibitors are surveyed in the present review.

Epidemiological, clinical and experimental studies have established a positive correlation between green tea consumption and cardiovascular health. Catechins, the major polyphenolic compounds in green tea, exert vascular protective effects through multiple mechanisms, including antioxidative, anti-hypertensive, anti-inflammatory, anti-proliferative, anti-thrombogenic, and lipid lowering effects. (1) Tea catechins present antioxidant activity by scavenging free radicals, chelating redox active transition-metal ions, inhibiting redox active transcription factors, inhibiting pro-oxidant enzymes and inducing antioxidant enzymes. (2) Tea catechins inhibit the key enzymes involved in lipid biosynthesis and reduce intestinal lipid absorption, thereby improving blood lipid profile. (3) Catechins regulate vascular tone by activating endothelial nitric oxide. (4) Catechins prevent vascular inflammation that plays a critical role in the progression of atherosclerotic lesions. The anti-inflammatory activities of catechins may be due to their suppression of leukocyte adhesion to endothelium and subsequent transmigration through inhibition of transcriptional factor NF-kB-mediated production of cytokines and adhesion molecules both in endothelial cells and inflammatory cells. (5) Catechins inhibit proliferation of vascular smooth muscle cells by interfering with vascular cell growth factors involved in atherogenesis. (6) Catechins suppress platelet adhesion, thereby inhibiting thrombogenesis. Taken together, catechins may be novel plant-derived small molecules for the prevention and treatment of cardiovascular diseases. This review highlights current developments in green tea extracts and vascular health, focusing specifically on the role of tea catechins in the prevention of various vascular diseases and the underlying mechanisms for these actions. In addition, the possible structure- activity relationship of catechins is discussed.

Visfatin is a newly discovered adipocyte hormone with a direct relationship between plasma visfatin level and type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from that of insulin and causes hypoglycaemia by reducing glucose release from liver cells and stimulating glucose utilization in adipocytes and myocytes. Visfatin is upregulated by hypoxia, inflammation and hyperglycaemia and downregulated by insulin, somatostatin and statins. This hormone is found in the cytoplasm as well as the nucleus of cells and has been identified in many tissues and organs including the brain, kidney, lung, spleen and testis but preferentially expressed in visceral adipose tissue and upregulated in some animal models of obesity. Visceral adipose tissue is regarded to be more pernicious than subcutaneous adipose tissue. Visfatin is an endocrine, autocrine as well as paracrine peptide with many functions including enhancement of cell proliferation, biosynthesis of nicotinamide mono- and dinucleotide and hypoglycaemic effect. Visfatin, also known as a pre-B cell colony-enhancing factor, consists of 491 amino acids (aa) in human, chimpanzee, cattle, pig, rat and mouse, 490 aa in rhesus monkey, 285 aa in sheep, 587 in opposum and 588 aa in canines. Visfatin gene is well preserved during evolution. For example, the canine visfatin protein sequence is 96% and 94% identical to human and rodent visfatin, respectively. Since evidence of a direct link between visfatin genotype and human type 2 diabetes mellitus is still weak, more molecular, physiological and clinical studies are needed to determine the role of visfatin in the etiology and pathogenesis of type 2 diabetes mellitus.