Current Medicinal Chemistry - Volume 17, Issue 28, 2010

The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regulators, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53- MDM2 interaction, and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.

Histone H2A variant, H2A.Z, plays an essential role in transcriptional activation of ERα-dependent genes, cell proliferation, development, and differentiation. High expression of H2A.Z is ubiquitously detected in the progression of breast cancer, and is significantly associated with lymph node metastasis and patient survival. This makes H2A.Z an excellent target for diagnostic and therapeutic interventions. A recent study provides a new insight into the role of H2A.Z within the context of cancer-related genes and further corroborates the emerging link between dysfunction of this histone variant and cancer. Interestingly, the depletion of H2A.Z also causes defective in the stability and integrity of the human genome. These abnormalities include defective chromosome segregation, activation of LINE-1 retrotransposable elements, and changes in cell cycle-related genes. This article also presents the molecular pathways linking H2A.Z to breast cancer and mechanisms have been proposed to explain how altered H2A.Z leads to tumorigenesis. Two strategies are proposed here for anti-tumor treatments of H2A.Z-defective breast cancer. One is to restore H2A.Z function by targeting c- Myc transcription factor and the other is to find potential drug treatment by blocking the activity of H2A.Z-remodelling complex, p400/Tip60.

Thromboxane A2 (TxA2), a bioactive metabolite of the Arachidonic acid (AA), is a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. It plays an important role in major human diseases, such as myocardial infraction, unstable angina, pregnancy-induced hypertension and preeclampsia, thrombosis and thrombotic disorders, pulmonary hypertension, asthma, septic shock, atherosclerosis, lupus nephritis, and Raynaud's phenomenon. Thus, TxA2 is a therapeutic target for many research groups. A number of TXA(2) receptor antagonists as well as thromboxane synthase inhibitors have been developed. In this research we review and evaluate new quantitative structure activity relationships of thromboxane synthase inhibitors and thromboxane receptor antagonists, using the C-QSAR program of Biobyte. Lipophicity, as Clog P is a significant physicochemical parameter for this biological response. CMR/MR molar refractivity as well as sterimol parameters seemed to be important as well Molecular Volume. Electronic effects with the exception of σ Hammett's constant are not found to govern the biological activity. The derived equations will be very helpful for the design of new potent molecules.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although most studies have emphasized the role of T cells in the pathogenesis of MS, increasing evidence supports the concept that B cells play a key role in the pathogenesis of MS, mainly in association with the deposition of antibodies and the activation of complement. Emerging pathophysiological findings of B-cell, follicle-like structures in the meninges of patients and observations of decreased interleukin (IL)-10 production from naive B cells in MS have recently been reported. As more knowledge is gained of the pathophysiology of B cells in MS, the mechanisms of B-cell-mediated neuropharmacology of current therapy had been clarified as well. In this article, we review the increasing evidence that points to a link between B cells and MS, and also discuss the potential of B-cell-targeted therapy in MS.

Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expressions of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9, and chymase also converts precursors of TGF-β and MMP-9 to their active forms. All of angiotensin II, TGF-β and MMP-9 are considered to be closely involved in the development and progression of metabolic syndrome and its complications. In a diabetic animal model, chymase induced pancreatic disorganization via attack of oxidative stress induced by augmentation of chymase-forming angiotensin II. In atherosclerotic lesions in patients, accumulation of chymase-positive cells was observed, and chymase inhibition prevented the development of atherosclerosis in an animal model. In Apo E-deficient mice, chymase inhibition prevents the development of angiotensin II-induced abdominal aneurysmal aorta (AAA). In this model, the AAA development on an increase in MMP-9 activities induced by angiotensin II, but the inhibition of MMP-9 activation by chymase inhibitor resulted in attenuation of the AAA development. Cardiac dysfunction after myocardial infarction was also attenuated by chymase inhibition. Steatosis and fiblosis in liver were strongly prevented by chymase inhibition in an animal model with nonalcoholic steatohepatitis which is involved in metabolic syndrome. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful preventions of organ damages. In this review, we propose the significance of chymase as a target to prevent complications of metabolic syndrome.

Abscisic acid (ABA) is a plant hormone involved in stress tolerance, stomatal closure, seed dormancy, and other physiological events. Although ABA is registered as a farm chemical (plant growth regulator), its practical use has been limited, mainly due to its weak effect in field trials, which is considered to be due to its rapid inactivation through biodegradation. Catabolic inactivation of ABA is mainly controlled by ABA 8'-hydroxylase (CYP707A), which is the cytochrome P450 catalyzing the C8'-hydroxylation of ABA into 8'-hydroxy-ABA and its more stable tautomer, phaseic acid, which has much lower hormonal activity than ABA. Thus, a specific inhibitor of CYP707A is promising not only as a chemical probe for the mechanism of ABA action, but also because of its potential use in agriculture and horticulture. This review article focuses on our recent research on the development of two types of specific inhibitors of CYP707A: the ABA analogue-type inhibitors that were designed on the basis of differences between the structural requirements for CYP707A and for ABA activity, and the azole-type P450 inhibitors that were developed by conformational restriction or enlargement of the plant growth retardant uniconazole.

The human body is composed of 60 trillion cells, which have their origin in a fertilized egg. During development, the potential of a cell or tissue can be achieved by environmental manipulation. Then, what molecular determinants underlie or accompany the potential of the cells? To obtain a broader understanding of these problems, it is important to analyze all transcripts / genes in a wide selection of cell types. The development of microarray technologies, which allow us to undertake parallel analyses of many genes, has led to a new era in medical science. In this review, we show that the global expression data have clearly elucidated discernible major trends of the phenomenon in preimplantation development and epithelial-mesenchymal transition, and of the character of marrow stromal cells, which are attracting a great deal of attention as they represent a valuable source of cells for regenerative medicine. One of the interesting results is obtained from microarray data of marrow stromal cells: OP9 cells that have been recognized as a type of niche-constituting preadipocyte derived from marrow stroma, are found to be chondroblasts. We also describe what effect each type of expression data would bring to reproductive and regenerative medicine, as well as offering an excellent model of cell differentiation in biology.

Background: Hyperhomocysteinemia has been associated with cognitive dysfunction and dementia. The incidence of dementia in Parkinson's Disease (PD) patients is higher than in the general population and plasma Homocysteine concentrations are increased in L-dopa treated PD patients. Objective: We evaluated the possible correlations between L-Dopa related hyperhomocysteinemia and cognitive dysfunction in PD. Methods: A Medline literature search was performed to identify all published studies on Homocysteine and cognitive dysfunction and dementia during the course of PD from 1966 to 31/03/2010. Results: Sixteen studies were found for review; ten studies focused on homocysteine and cognitive dysfunction in PD patients, five on homocysteine and PD dementia and two on homocysteine and markers of neurodegeneration in PD. The design of the study was retrospective in 14 studies, while 2 had a prospective design, with a variable follow-up period (from 24-weeks to 2 years). In most of the studies plasma homocysteine levels significantly correlated with cognitive functions, dementia and markers of neurodegeneration in PD patients. However, some studies did not confirm these findings. Several factors may concur to explain these partially conflicting results, including the retrospective design of the studies, their small sample size, their high percentage of excluded patients, and the use of a wide range of neuropsychological tasks in assessment of cognitive dysfunctions across the available studies. Conclusions: Available data seem to indicate a potential role of L-dopa related hyperhomocysteinemia on cognitive impairment and dementia during the course of PD.

Reactive oxygen species (ROS) generated in the presence of O2 by mitochondria, phagocytic cells, peroxisomes, and cytochrome P450 enzymes under physiological conditions, may play a dual function in the human organism. On the one hand, they participate in cell signal transduction cascades, leading to the activation of some transcription factors responsible for regulating of the expression of genes relevant for cell growth and differentiation. On the other hand, they cause oxidative damage of cellular DNA, protein and lipids, resulting in the initiation or development of numerous diseases such as cancer, cardiovascular diseases, type 2 diabetes mellitus, cataract, rheumatoid arthritis, or different neurodegenerative diseases. Both endogenous compounds (glutathione, ubiquinol, urate, bilirubin) and enzymes (superoxide dismutase, catalase, glutathione peroxidase) are engaged in the detoxification of ROS. In addition, numerous dietary components such as vitamin C, vitamin E, carotenoids, and polyphenols are thought to be involved in the antioxidant defense system. The present review article is focused on the summary and the assessment of research on the impact of dietary antioxidants in the prevention of chronic diseases, particularly cancer and cardiovascular diseases.

The aim of this study was to verify the existence of synergistic antibacterial effect between four essential oils (Aniba rosaeodora, Melaleuca alternifolia, Origanum vulgare, and Pelargonium graveolens) individually combined with the antibacterial drug Gentamicin. We investigated the effectiveness in vitro of the association of essential oil/Gentamicin, against fifteen different strains of Gram positive and Gram negative bacteria. The antibacterial effects of these oils in combination with Gentamicin were evaluated by using the MHB microdilution method, while gas chromatography (GC) and GC/Mass spectrometry were used to analyze the chemical composition of the oils. A synergistic interaction was observed against all tested strains with the associations between the essential oils Aniba rosaeodora/Gentamicin and Pelargonium graveolens/Gentamicin. In particular a very strong synergistic interaction was observed against Acinetobacter baumannii ATCC 19606 (FIC index = 0.11). In contrast, the essential oils Origanum vulgare and Melaleuca alternifolia in association with Gentamicin were less effective on bacterial species growth. In vitro interaction can improve the antimicrobial effectiveness of the Gentamicin and may contribute to reduce its dose correlated to side effects.