Mini Reviews in Medicinal Chemistry - Volume 8, Issue 7, 2008

Chemokines play a key role in immune processes by controlling leukocyte recruitment in physiological and pathological condition. This review discusses the regulation of the chemokine system, its role in human diseases, and its potential relevance as a new pharmacological target.

Leukotrienes (LTs), including LTB4 and cysteinyl-LTs (CysLTs) (LTC4, LTD4, and LTE4), are potent inflammatory lipid mediators which are derived from 5-lipoxygenase activity. CysLTs, which stimulate CysLT1 and CysLT2 receptor subtypes, are functionally involved in the pathophysiology of asthma. Selective CysLT1 receptor antagonists are effective anti-asthmatic drugs. CysLT1 receptor antagonists have been developed from leukotriene structural analogs, analogs of FPL 55712, a chromone carboxylic acid, and by random screening of corporate compound banks. This review will examine the biosynthesis, metabolism and mechanism of action of leukotrienes, their role in asthma, the therapeutic implications of the leukotriene pathway inhibition for asthma, and the medicinal chemistry strategies that have been exploited in the design of potent and selective CysLT1 receptor antagonists.

Selenium is an important trace element involved in different physiological functions of human body. Knowledge of selenium in biology of cancer has increased at rapid rate especially during last two decades. Basic research and clinical studies involving animal models and more recently studies in human strongly support the protective role of selenium against various types of cancer. Selenium's role as an essential nutrient is as a result of its unique chemistry enabled by the presence of selenium in selenoproteins. Epidemiological findings have linked inadequate status of selenium to increased risk of cancer. The protective action of selenium is a combination of various mechanisms. Amongst all the diverse mechanism that have been proposed some important ones are (a) Protective role of selenoproteins / selenoenzymes (b) induction of apoptosis (c) immune system effects (d) detoxification of antagonistic metals (e) inactivation of nuclear transcription factor (f) regulation of lipoxygenases (g) effect on advanced cancer condition (h) reduction of oxidative stress (i) induction of Phase II enzymes (j) androgen receptor down regulation (k) inhibition of DNA adduct formation (l) cell cycle arrest. The purpose of this review is to focus the recent development in the field of cancer prevention utilizing selenium. The metabolism of selenium compounds , carcinogenesis studies, epidemiological data, and various proposed chemopreventive mechanisms of selenium compounds along with results of human intervention trials have been discussed.

The possibility to make precise modifications to the genome at high frequency holds tremendous potential for biotechnology, conventional drug development and gene therapy. Homologous recombination is a powerful method for introducing such modifications in organisms such as mice. However, in mammals and plants, the frequency of gene modification by homologous recombination is quite low, precluding the therapeutic use of this methodology. In the past few years, tremendous progress has been made in overcoming one of primary barriers to efficient recombination, namely the introduction of a targeted double-strand break near the intended recombination site. This review will discuss the advances in engineering custom zinc-finger nucleases and their application in stimulating homologous recombination in higher eukaryotic cells at efficiencies approaching 1 in 2 cells.

Tumor invasion and cancer metastasis are interrelated processes involving cell growth, cell adhesion, cell migration and proteolytic degradation of tissue barriers, which are mediated by aberrant intracellular signaling in cancer cells. Natural (green tea polyphenols, soy isoflavones) or dietary compounds (mushroom G. lucidum) markedly decreased AP-1 and NF-κB signaling and suppressed invasiveness of cancer cells. This review will summarize alternative approaches for the inhibition of invasive behavior of cancer cells by dietary compounds, which can be considered in adjuvant or combination therapy for the prevention and treatment of cancer metastasis.

Traumatic brain injury affects over a million Americans annually, but pharmacological therapy remains limited. Current standards of care in acute, subacute and chronic phases of injury are primarily supportive. This review discusses pharmacological strategies and future directions in patient treatment emphasizing pleiotropic agents targeting inflammation, oxidative damage, and glutamate excitotoxicity.

Glucocorticoid action is linked to the development of obesity and insulin resistance. Inhibition of 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a strategy to suppress glucocorticoid action in a tissue-specific manner. A large variety of 11β-HSD1 inhibitor classes are under investigation by the pharmaceutical industry to treat type 2 diabetes and obesity.

Resistance to apoptosis is one of the fundamental hallmarks of cancer. Recently, the selective induction of apoptosis in cancer cells has emerged as an exciting possibility for the development of future selective cancer therapy. This review will summarise the development of the major classes of small molecule “pro-apoptotic” antitumour agents.

Numerous studies implicate the prolyl peptidase, fibroblast activation protein (FAP) in tumorigenesis; however, FAP-selective inhibitors have not yet been developed to fully validate FAP as a therapeutic target. Herein, we review recent efforts aimed at validating and inhibiting FAP for cancer therapy and highlight future directions for successful targeting of this prolyl peptidase.

Over the last two decades, numerous attempts have been made to develop 11C- and 18F-labeled radiotracers in order to study glucocorticoid receptor (GR)-mediated abnormalities of the hypothalamus-pituitary-adrenocortical (HPA) axis function and regulation in vivo by means of positron emission tomography (PET). The present review addresses the research efforts dealing with the design, radiosynthesis and radiopharmacological evaluation of PET radiotracers for brain GR imaging. The underlying problems such as metabolic instability, insufficient blood-brain-barrier penetration and/or high non-specific binding will be discussed.