Current Medicinal Chemistry - Volume 15, Issue 7, 2008

Malignant Mesothelioma is an aggressive and fatal type of tumor. The incidence of mesothelioma has increased in the past 30 years and is now common as male cancers of the liver, bone and bladder, especially in Europe and Australia. The main risk factor is asbestos exposure even if other co-factor, such as simian virus 40 (SV40) could be implied in its etiology. Unfortunately, its incidence is expected to continue to increase for the next decades, also in rapidly industrializing countries, such as India, where it is not recognised as an occupational disease. Furthermore, some disastrous events, such as the World Trade Center Disaster, may contribute to increase future risk for mesothelioma. The treatment-resistant phenotype of mesothelioma is largely due to its ability to escape from the highly regulated apoptotic machinery. The understanding of the molecular mechanisms responsible of the malignant mesothelioma resistance to apoptosis is now advancing, allowing developing new therapeutic strategies to change the natural history and improve survival of patients. This review gives an overview of the main anti-apoptotic strategies devised by malignant mesothelioma and the therapeutic implication and opportunities for this cancer.

Glucocorticoids play an essential role in the regulation of multiple physiological processes, including energy metabolism, maintenance of blood pressure and stress responses, as well as cognitive functions. On a tissue-specific level, glucocorticoid action is controlled by 11beta-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme (11beta-HSD1) is a NADP(H)-dependent bidirectional enzyme in vitro and reduces cortisone to active cortisol in vivo. 11beta-HSD1 is expressed in many tissues including the liver, adipose and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity has been associated with the metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that the inhibition of 11beta-HSD1 mitigates the adverse effects of excessive glucocorticoid levels on metabolic parameters and provides promising opportunities for the development of therapeutic interventions. This review discusses recently disclosed 11beta-HSD1 inhibitors and their potential for the treatment of metabolic disorders.

Nicotinamide adenine dinucleotide (NAD), generally considered a key component involved in redox reactions, has been found to participate in an increasingly diverse range of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. In recent years, medicinal chemists have become interested in the therapeutic potential of molecules affecting interactions of NAD with NAD-dependent enzymes. Also, enzymes involved in de novo biosynthesis, salvage pathways, and down-stream utilization of NAD have been extensively investigated and implicated in a wide variety of diseases. These studies have bolstered NAD-based therapeutics as a new avenue for the discovery and development of novel treatments for medical conditions ranging from cancer to aging. Industrial and academic groups have produced structurally diverse molecules which target NAD metabolic pathways, with some candidates advancing into clinical trials. However, further intensive structural, biological, and medical studies are needed to facilitate the design and evaluation of new generations of NAD-based therapeutics. At this time, the field of NAD-therapeutics is most likely at a stage similar to that of the early successful development of protein kinase inhibitors, where analogs of ATP (a more widely utilized metabolite than NAD) began to show selectivity against target enzymes. This review focuses on key representative opportunities for research in this area, which extends beyond the scope of this article.

Metabotropic glutamate (mGlu) receptors have received much attention, driven by a strong belief in the potential of these modulatory glutamate receptors as drug targets. So far, major drug discovery programs have largely focused on group I (mGlu1 and 5) and II (mGlu2 and 3) mGlu receptors, which have been implicated in neuropathological and various psychiatric disorders. The four group III representatives (mGlu4, mGlu6, mGlu7 and mGlu8) are less understood, mainly due to the paucity of specific compounds. Recent advances in the identification of selective or specific compounds, and the generation of transgenic animals have, however, revealed important insights into the potential role of group III receptors in the pathophysiology of neurological and mood disorders. Activation of the mGlu4 receptor seems to be beneficial for treating Parkinson-like symptoms and a potential role in the treatment of mood disorders is slowly growing. Similarly, genetic inactivation studies and usage of relatively selective agonists strongly support the involvement of the mGlu8 receptor for anxiety disorders. In contrast, controversial data have been obtained for the mGlu7 receptor. While mGlu7 receptordeficient animals show an anxiolytic profile in several in vivo readouts, the first selective allosteric agonist AMN082 has also been reported to improve anxiety-like behaviour despite activating the stress axis. The least investigated receptor remains the mGlu6 receptor, which is mostly based on its predominant expression in the retina.

Polyelectrolyte multilayer films have been well characterized for almost two decades and there is now a growing interest for the development of biomimetic films that could be used in vitro or in vivo to control cellular behaviors. In this review, the important properties of multilayer films designed for cell/surface interactions will be highlighted. The first part will deal with the physico-chemical properties of polypeptide and polysaccharide multilayer films, including their growth, swellability, stability and mechanical properties. In the second part, we will focus on important properties influencing cellular behaviors: i) film biodegradability, ii) film mechanical properties, iii) film bioactivity achieved by either the intrinsic properties of the film components or the insertion of small peptides, proteins, or DNA. In particular, films thicker than one micron are particularly well suited for loading bioactive molecules due to their reservoir capacities.

Oxytocin (OT) is a neurohypophysial hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Although OT-like substances have been identified in all vertebrates, OT has been found only in mammals where it plays a major role in the onset and maintaining of behaviors which are typical of these animals, such as labour and lactation. Recently, several data have suggested the involvement of OT in the formation of infant attachment, maternal behavior, pair bonding and, more generally, in linking social signals with cognition, behaviors and reward. The aim of this paper was to review critically the role of OT in the regulation of different physiological functions and complex behaviors, as well as its possible involvement in the pathophysiology of some neuropsychiatric disorders. MEDLINE and PubMed (1972-2007) databases were searched for English language articles by using the following keywords: oxytocin, physiology, cognitive functions, attachment, psychopathology, psychiatric disorders. Papers were examined that addressed the following aspects of the OT system: synthesis and localization, receptors, physiology: In addition, latest findings showing abnormalities of OT and OT system in several neuropsychiatric disorders, including autism, obsessive-compulsive disorder, eating disorders, addiction, schizophrenia, post-traumatic stress disorder and Prader-Willy syndrome, will be also discussed together with the possible clinical use of OT or its analogues and/or antagonists.

Platensimycin was recently discovered by Merck Research Laboratories and has created considerable interest given its potent antibacterial activity and mode of action. The use of RNA gene-silencing techniques and screening libraries of natural products allowed Merck to find this antibiotic which may have otherwise been missed using conventional methods. Interestingly, platensimycin has shown good activity against a panel of Gram positive organisms which included various resistant strains. Platensimycin works by inhibiting β- ketoacyl synthases I/II (FabF/B) which are key enzymes in the production of fatty acids required for bacterial cell membranes. So far, a number of groups have explored synthetic strategies for platensimycin and this work has subsequently lead to the synthesis of active analogues. Given its mode of action, it is intriguing as to why Merck themselves patented only a single compound and have not apparently sought to generate further libraries. This review will discuss the origins of platensimycin, its mechanism of action, synthetic schemes and where the future may take us following this fascinating discovery.

Despite its clinical importance, the mechanism of preeclampsia is unclear; however, many believe placental pathology might be related to maternal systemic disease. If this is true, a factor which mediates information from the placenta to the maternal circulation can be hypothesized. Among a variety of such reported factors, soluble fms-like tyrosine kinase-1 (sFlt1) will be the focus of this review. The hypoxic placenta, which is commonly found in preeclampsia, produces sFlt1; furthermore, animal experiments suggest its overexpression leads to preeclampsia-like symptoms.

Bronchiolitis obliterans syndrome (BOS) is the leading cause of death in lung transplant recipients (LTR). BOS is thought to result from chronic immunologic/inflammatory insults leading to peri-bronchiolar leukocyte infiltration, with a subsequent exuberant tissue re-modelling and fibro-obliteration of the luminal space of the allograft airways. Diagnosis is based on functional criteria and severity is graded on the degree of Forced Expiratory Volume in 1 second (FEV1) impairment. Current strategies to improve pulmonary function once BOS is established have demonstrated little or no impact on disease progression and re-transplantation remains the only therapeutic option. Among the alternative treatments which have been attempted in the last few years, long-term azithromycin treatment seems to be the most promising therapeutic device for BOS treatment. Azithromycin is a macrolide antibiotic, endowed with a broad spectrum of anti-inflammatory/immunomodulatory activities. Long-term oral azithromycin therapy can significantly improve FEV1 in about 42% of patients with established BOS. Moreover, reduced neutrophilia, chemokine release and bacterial exacerbations have been demonstrated. These observations suggest that the drug can downregulate pulmonary inflammation, even if the precise underlying mechanisms still need to be determined.

Asporin is an extracellular matrix protein that belongs to the small leucine-rich repeat proteoglycan (SLRP) family of proteins. It is unique among SLRPs in that it lacks a glycosaminoglycan attachment site and contains an asparatic acid (D) repeat at its amino terminus. Its biological role has been unclear, but recent genetic studies have demonstrated association between asporin and various bone and joint diseases, including osteoarthritis, rheumatoid arthritis and lumbar disc disease. Each of these common diseases presents a substantial medical, social and economical burden to societies worldwide. This paper reviews recent progress in the study of asporin, focusing on its expression, regulation and function as well as its role in the molecular pathogenesis of common bone and joint diseases. Asporin is found primarily in regions surrounding skeletal tissue and is up-regulated in disease states. It binds to various growth factors, including TGF-β and BMP-2, and negatively regulates their activity. By inhibiting binding of TGF-β1 to its type II receptor, asporin forms a functional feedback loop with TGF-β1 and regulates its chondrogenic potential. As an extracellular, tissue-specific protein, asporin represents a promising target for phamacogenomic approaches to common bone and joint diseases.