Current Medicinal Chemistry - Volume 14, Issue 2, 2007

The learning and memory deficits have been recognized as severe and consistent neurological disorders associated with numerous neurodegenerative states. Research in this area has gained momentum only in the recent past after the biochemical and physiological basis of these processes have been understood. A considerable alteration in the neurotransmission is a consistent finding in cognitive disorders. Therefore, many therapeutic strategies to augment the concentration of neurotransmitters in brain such as cholinergic agents, biogenic amines and neuropeptides etc. have been evaluated in cognitive deficits. CNS modulators are the type of antiamnesics that act via modulation of the neurological processes underlying memory storage. These include psychostimulants, excitatory amino acids and most important of all “nootropics”. Nootropics are a heterogeneous group of compounds of diverse chemical composition and biological function that allegedly facilitate learning and memory or overcome natural or induced cognitive impairments. The literature survey incorporated in this article hallmarks the success achieved in the design and development of potential nootropic agents. Additionally, this review is an attempt towards discussing various approaches available to enhance memory, along with the classification of the known memory enhancers, authors research work towards various structural modifications carried out and the biological screening.

ATP-sensitive potassium (KATP) channels have important functions through their coupling of cellular energetic networks and their ability to decode metabolic signals, and they are implicated in diseases of many organs. KATP channels are formed by the physical association between the inwardly rectifier potassium channels (Kir6.x) and the regulatory sulfonylurea receptor subunit (SUR), which form a hetero-octameric complex. Different subtypes of KATP channels exist in various tissues. KATP channel openers (KCOs) are classified into nine chemical families according to their molecular structures: (1) benzopyrans, (2) cyanoguanidines, (3) thioformamides, (4) pyrimidine derivatives, (5) pyridine derivatives, (6) benzothiadiazines, (7) dihydropyridines, (8) nicotinamide derivatives, and (9) aliphatic amines. Although the model also predicts that KCOs have four co-binding areas, it was hypothesized that the main contribution lies in the binding domain of hydrophobicity of the side chain. A series of compounds containing the skeleton of the aliphatic secondary amines as a side chain was designed. It was found that N-isopropyl 2,3-dimethyl-2- butylamine (iptakalim, 91) is a novel KCOs. Iptakalim regulates the pore selectively of the inwardly rectifier potassium channel and dilates smaller arteries, but has little effect on vasodilatation of the aorta. Iptakalim administered p.o. has selective and long-lasting antihypertensive effects in hypertensive animals and does not induce tolerance, but has little effect on blood pressure in normotensive animals. Meanwhile, it also reverses cardiovascular remodeling and protects the brain and kidney against damage caused by hypertension in animal models. Iptakalim is in phase II clinical trials now and has a promising future as a treatment for hypertension.

Observational studies have identified left ventricular hypertrophy (LVH) as a strong, independent risk factor for the development of heart failure (HF), coronary heart disease and stroke. LVH develops in response to hemodynamic overload. Classical conceptualization has it that LVH would start as an adaptive, beneficial response in order to normalize wall stress. With progression of the disease, deterioration to maladaptive hypertrophy, and further on to HF could occur. Recent experiments in animal models of pressureoverload and myocardial infarction now challenge this concept by demonstrating that blunting the hypertrophic response is actually associated with preserved cardiac function, and with improved survival. These findings may have profound therapeutical implications.

Stem cell biology is a promising, fast-growing field that aims to develop cell-based tools for the treatment of a wide range of diseases. Special attention is paid to bone marrow cells that play a role in the musculoskeletal system. Bone marrow contains hematopoietic stem cells (HSCs) and stromal cells that form the reticular network that supports HSCs formation. Stromal cells also contain mesenchymal stem cells (MSCs) that differentiate to various lineages. The major obstacles in utilizing stem cells are identifying these cells and following the signaling pathways that control the cells’ fate. The interactions of stem cells with an extracellular matrix and other cells create a tissue-specific niche that is responsible for regulating cell differentiation. It is important to identify biomarkers that will enable the isolation, selection and expansion of stem cells in vitro to allow their use for cell therapy. The study of stem cells' differentiation is based on various techniques, including the generation of antibodies to specific cellular sub-populations and high throughput analysis at transcriptome and proteome levels. Advances in transcriptome and proteome profiling will establish the molecular signature and will allow the discovery of the cell type specific differentiation programming. Such analysis identified several proteins related to chromatin remodeling factors, cell adhesion molecules and extracellular matrix ligands that localize cells at the specific niche. Detailed interpretation of the transcriptional and translational expression patterns will provide understanding of key properties of MSCs and allow their future use in regenerative medicine.

T helper 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, play an important role in allergic immune disorders, such as bronchial asthma. These cytokines regulate diverse biological functions by binding to receptors at the cell surface to activate complex signal transduction pathways, including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the Ras-extracellular signal-regulated kinase (ERK) signaling pathways. The suppressor of cytokine signaling (SOCS) family proteins has been shown to regulate the JAK-STAT pathway, and the Sprouty-related EVH1-domain-containing protein (SPRED) family proteins regulate the Ras-ERK pathway. SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes. SOCS3 also has a role in Th3 differentiation. SPRED-1 is expressed in hematopoietic cells, including eosinophils, and negatively controls the eosinophil numbers and functions by modulating IL-5 signaling. Here, we discuss the role of SOCS and SPRED proteins in allergic asthma and explore the potential of these proteins as targets for therapeutic strategies in allergic asthma.

MicroRNAs (miRNAs) are non-coding small RNAs that play important roles in a variety of biological pathways including cellular proliferation and apoptosis. Recent studies have linked the expression of selected miRNAs to carcinogenesis and viral pathogenesis. Here, we will discuss examples of roles served by cellular miRNAs and virus-encoded miRNAs in the development of cancers and viral diseases.

In this review we summarize the achievements of medicinal chemistry in the field of pharmacological approaches to the therapy of β-thalassemia using molecules able to stimulate the production of fetal hemoglobin (HbF). We first describe the molecular basis of the pathology and the biochemical rational of using HbF inducers for therapy; we then outlined the in vitro and in vivo experimental systems suitable for screening of such potential drugs, and finally we describe the different classes of compounds with emphasis on their advantages and disadvantages in the treatment. The results of these reviewed studies indicate that: (a) HbF inducers can be grouped in several classes based on their chemical structure and mechanism of action; (b) clinical trials with some of these inducers demonstrate that they are effective in ameliorating the symptoms of β-thalassemia; (c) a good correlation was found between HbF stimulation in vivo and in vitro indicating that in vitro testing might be predictive of the in vivo response; (d) combined use of different inducers might maximize the effect, both in vitro and in vivo. However, (e) the response to HbF inducers, evaluated in vitro and in vivo, is variable, and some patients might be refractory to HbF induction by certain inducers; in addition, (f) several considerations call for caution, including the fact that most of the inducers exhibit in vitro cytotoxicity, predicting side effects in vivo following prolonged treatments.

The lung is a unique organ in terms of its direct exposure to high levels of oxygen and reactive compounds. Several parenchymal lung diseases (e.g. emphysema associated with smoking and a number of fibrotic lung disorders) have been proposed to be due to the exposure of the lung to exogenous irritants leading to local redox imbalance in the alveolar epithelium. The disease progression of emphysema/chronic obstructive pulmonary disease (COPD) and fibrosis share several common factors, such as the role of reactive oxygen species, disturbances of the pulmonary thiol status and activation of growth factors and tissue destructing proteases. Importantly in COPD or fibrosis, medication does not provide any significant therapeutic effect. This review concentrates on the key thiol (-SH)-regulated mechanisms leading to the development of COPD and/or pulmonary fibrosis and the major redox-regulated defense/oxidant repair mechanisms, thioredoxin/peroxiredoxin and glutaredoxin protein families in the lung. Redox-regulated proteins, both proteases and oxidant repair enzymes, undergo conformational changes during oxidative stress, a process that modulates their activation or inactivation. In addition, some of the redox-regulated proteins influence the metabolism of glutathione (GSH), a major small molecular antioxidant of human lung, and participate in the crosstalk between numbers of GSH associated enzymes functioning in the detoxification pathways of human lung. An understanding of the processes involved in oxidant-mediated lung damage may provide the key to devising interventional strategies that can actually prevent the progression of lung parenchymal disease.

Hsp90 is a chaperone that is critically important for both cancer progression and tumor survival. Hsp90 is an exciting target for anti-cancer drugs because most of the proteins that interact with Hsp90 are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Recent work in fungi has shown that reduction of Hsp90 activity dramatically increases the efficacy of many fungicides. Furthermore, in studies on the evolution of drug resistance in fungi, it has been shown that high levels of Hsp90 increase the rate of the development of fungicide resistance, whereby low levels of Hsp90 decrease the rate of fungicide resistance. Similarly, in humans and mammalian models, Hsp90 inhibitors have been shown to act additively or synergistically with many other cancer therapies for killing both solid tumors and leukemias. Also, several recent studies have shown that Hsp90 inhibitors potentiate the activity of drugs in cancer cells lines that are otherwise resistant to the drug. However, during the evolution of drug resistance in cancer cells, it has not yet been determined whether early exposure to Hsp90 inhibitors slows the rate of developing resistance to other anti-cancer drugs, as would be expected from the fungal studies. In this review, we summarize the effects of the Hsp90 inhibitors geldanamycin and its derivatives with other anti-cancer drugs on killing cancer cells. We also discuss other basic science and clinical studies that need to be done to determine the optimum exposure regimens for Hsp90 inhibitor treatments to maximize its cancer-killing activities, and to minimize the evolution of resistance to other anti-cancer drugs.

In this review we discuss the features of a new class of antiretroviral combinations, namely “Virostatics”. Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combination of hydroxyurea and didanosine against HIV-1. Hydroxyurea and didanosine synergize to control viral replication and present with a favorable resistance profile, suppressing several resistant quasi-species. Because virostatics target essential cellular proteins, they exert an immune modulating activity and reduce viral targets (CD4 T cells), possibly with limited immunosuppressive effects. Importantly, a dose-finding clinical study has shown that decreasing the dose of hydroxyurea not only diminishes toxicity but also increases antiviral potency. Therefore, the combination of hydroxyurea and didanosine strikes a balance between viral suppression, drug-related toxicity and viral escape, and could have a role both in induction and maintenance therapy. In this review we would like to appraise what is known about hydroxyurea and didanosine and specifically address the major advantages, i.e. novel mechanism of action leading to a new class of drugs and resistance profile providing durability, as well as the major criticisms of this combination, i.e. toxicity and reasons for prescribing a perceived immune suppressant to immune compromised patients.

Atherosclerosis and its complications represent the major cause of death in developed countries. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase and consequently inhibitors of cholesterol biosynthesis. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. In clinical trials, statins are beneficial in primary and secondary prevention of coronary heart disease. Statins, were initially designed as cholesterol-lowering drugs. However, these drugs, besides their lipid-lowering properties, exert a number of protective effects on the cardiovascular system that emerged over the past years. The benefits observed with statin treatment appear to be greater than that might be expected from reduction in lipid levels alone, suggesting effects beyond cholesterol lowering. These cholesterol-independent effects have been called “pleiotropic”. The cholesterol-independent or “pleiotropic” effects of statins involve improvement of endothelial function, stability of atherosclerotic plaques, decrease of oxidative stress and inflammation, and inhibition of thrombogenic response. These pleiotropic effects of statins have been proposed as key properties of these drugs to reduce cardiovascular morbidity and mortality. The present review will emphasize the molecular mechanisms underlying the effects of statins on endothelial function and oxidative stress. In particular, inhibition of small GTP-binding proteins, Rho, Ras and Rac, which are regulated by isoprenoids [farnesyl pyrophosphate and geranylgeranyl pyrophosphate], seems to play an important role in mediating the pleiotropic effects of statins.