Current Medicinal Chemistry (v.17, #27)

Beta Amyloid Aggregation Inhibitors: Small Molecules as Candidate Drugs for Therapy of Alzheimer's Disease by F. Re, C. Airoldi, C. Zona, M. Masserini, B. La Ferla, N. Quattrocchi, F. Nicotra (2990-3006).
The progressive production and subsequent accumulation of and#946;-amyloid (Aand#946;), a proteolytic fragment of the membrane-associated amyloid precursor protein (APP), plays a central role in Alzheimer's Disease (AD). Aand#946; is released in a soluble form that may be responsible for cognitive dysfunction in the early stages of the disease, then progressively forms oligomeric, multimeric and fibrillar aggregates, triggering neurodegeneration. Eventually, the aggregation and accumulation of Aand#946; culminates with the formation of extracellular plaques, one of the morphological hallmarks of the disease, detectable post-mortem in AD brains. In this review we report the known structural features of amyloid peptides and fibrils, and we give an overview of all small molecules that have been found to interact with Aand#946; aggregation. Deeper knowledge of the mechanism leading to amyloid fibrils along with their molecular structure and the molecular interactions responsible for activity of small molecules could supply useful information for the design of new AD therapeutic agents.

Genistein Aglycone: A Dual Mode of Action Anti-Osteoporotic Soy Isoflavone Rebalancing Bone Turnover Towards Bone Formation by A. Bitto, F. Polito, F. Squadrito, H. Marini, R. D'Anna, N. Irrera, L. Minutoli, R. Granese, D. Altavilla (3007-3018).
Osteoporosis is characterized by reduced bone mass and structural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. Bone loss further increases in postmenopausal women when the ovaries stop making estrogens. Women undergoing treatment for osteoporosis require long-term dosing therapeutic regimens, that offer no symptomatic relief, and may cause side effects. To avoid this problem, many therapeutic alternatives have been proposed. Epidemiological data support a robust relationship between soy isoflavones, fracture incidence and bone mineral density in osteoporotic, postmenopausal women. These suggest that a high isoflavone intake, restores the metabolic balance of bone formation and resorption. However, this matter is still controversial and several reports show negative results, probably because different doses and/or isoflavones have been used. Although it is difficult to identify the specific isoflavone most involved in preventing or restoring bone loss, a review of current literature based on new encouraging preclinical and clinical data, indicates that aglycone genistein appears to be the most effective isoflavone in preserving bone health. Genistein aglycone, through a peculiar anti-osteoporotic dual mode of action, can positively regulate bone cell metabolism rebalancing bone turnover towards bone formation. Genistein in fact stimulates osteoblast and inhibits osteoclast function, mainly through the osteoprotegerin-sRANKL system. The positive results achieved by genistein aglycone intake, in terms of efficacy and safety, have stimulated the development of specially formulated medical food products for the clinical management of postmenopausal bone loss.

CXCR4-CXCL12-Dependent Inflammatory Network and Endothelial Progenitors by P. Salvatore, C. Pagliarulo, R. Colicchio, C. Napoli (3019-3029).
The endothelial progenitor cells (EPCs) are angiogenic cells having properties similar to those of embryonal angioblasts. The number and function of EPCs are affected by a variety of conditions, including cytokines and chemokines, which are pivotal inflammatory signaling molecules. The purpose of this paper is to review current knowledge about the role of these progenitor in different vascular diseases, emphasizing the important biological role played from the CXCR4-CXCL12 axis in the cellular trafficking. Indeed, as described in detail in this review, the CXCR4/CXCL12 interaction produces pleiotropic effects in stem cells and plays a pivotal role in several processes related to development, tissue regeneration and development/progression of malignancies.

The renaissance of cell- or organism-based phenotypic assays has made subsequent target identification for bioactive small organic molecules an important aspect of current drug discovery. Among the many strategies available for target identification, derivatizing bioactive small molecules into activity-based probes has the main advantage of determining small molecule-protein interactions directly in the native environment where the target proteins maintain their three-dimensional structures, including all the post-translational modifications, as the discrete small molecular probes usually have better access to intracellular compartments. Thus this chemical platform will not only afford a more precise means of understanding the mechanisms of action for bioactive molecules, but shed light onto the specificity of the bioactive small molecules. Here we will provide an overview of the strategies for the design of activity-based small molecular probes and review their applications for target identification using case studies. Special emphasis is placed on logistic concerns for probe's design as well as recent developments in this field.

Biological Rationales and Clinical Applications of Temperature Controlled Hyperthermia - Implications for Multimodal Cancer Treatments by P. Schildkopf, O. J. Ott, B. Frey, M. Wadepohl, R. Sauer, R. Fietkau, U. S. Gaipl (3045-3057).
Hyperthermia (HT) - heating the tumor in the range of 40.0 - 44.0 and#176;C - combined with radiation (RT) and/or chemotherapy (CT) is a well proven treatment for malignant tumors. The improvement of the techniques for monitoring and adapting of the desired temperatures even in deep seated tumors has led to a renaissance of, now quality-controlled, HT in multimodal tumor therapy approaches. Randomized clinical trials have shown improved disease-free survival and local tumor control without an increase in toxicity for the combined treatment. In this review, we will focus on biological rationales of HT comprising direct cytotoxicity, systemic effects, chemosensitization, radiosensitization, and immune modulation. The latter is a prerequisite for the control of recurrent tumors and micrometastases. Immunogenic tumor cell death forms induced by HT will be introduced. Modulations of the cytotoxic properties of chemotherapeutic agents by HT as well as synergistic effects of HT with RT will be presented in the context of the main aims of anti-tumor therapy. Furthermore, modern techniques for thermal mapping like magnet resonance imaging will be outlined. The effectiveness of HT will be demonstrated by reviewing recent clinical trials applying HT in addition to CT and/or RT. We conclude that hyperthermia is a very potent radio- as well as chemosensitizer, which fosters the induction of immunogenic dead tumor cells leading to local and in special cases also to systemic tumor control.

Protein aggregation is a key mechanism involved in neurodegeneration associated with Alzheimer's, Parkinson's and Huntington's diseases. Nine diseases (including Huntington's) arise from polyglutamine (polyQ) expansion above a repeat threshold of approximately 37 glutamines, and neuronal toxicity correlates with the process of protein aggregation. The similar toxic gain-of-function mechanism of the nine diseases supports the hypothesis that disease onset and progression is dependent upon polyQ expansion. However, there is an increasing body of literature demonstrating that the protein context of the polyQ tract has an essential role in the disease process. The composition of regions flanking repeats can alter the biochemical and biophysical properties of the polyQ region. A number of the disease proteins are proteolytically cleaved, with release of the polyQ-containing fragment initiating aggregation. Interactions of flanking domains with other molecules can also influence aggregation and cellular localization, which are critical factors for toxicity. More recently, there is evidence that domains flanking the polyQ tract can also aggregate independent of the polyQ tract, and that this significantly alters the rate at which the polyQ regions form fibrillar aggregates and the properties of these aggregates. In this review we consider the role of protein context in modulating the polyQ diseases and the therapeutic potential of targeting non-polyQ protein properties.

Will Antiangiogenic Agents be a Future for Mesothelioma Therapy? by C. Belli, S. Anand, M. Panella, M. Giovannini, G. Tassi, D. Fennell, L. Mutti (3069-3079).
Background: Malignant mesothelioma (MM) is an aggressive disease that is diagnosed mostly in locally advanced or metastatic stage. In this condition chemotherapy with the combination cisplatin and pemetrexed or ralitrexed represents the standard treatment as supported by a phase III study. However, chemotherapy has very limited effect on the improvement of survival of patients and very few of the MM patients survive more than 2 years. A better understanding of molecular mechanisms and pathways involved in angiogenesis in MM is the basis for the development of new drugs targeted against these pathways responsible for the proliferation and survival of tumor cells. Objective: This review discusses the role of angiogenic factors in tumourigenesis with a particular focus on MM and it summarizes the results of clinical trials on the drugs targeting angiogenic pathways in MM. Methods: We have used original research articles, abstracts and oral presentations from ASCO (American Society of Clinical Oncology) and the website of clinical trials http://www.ClinicalTrials.gov Results/Conclusions: This review summarizes the results of antiangiogenic agents under evaluation in clinical trials. A better understanding of the angiogenic pathways activated in MM will hopefully provide new therapeutic options for these patients in the future.

Lipopolysaccharide (LPS), the glycolipid of the outer membrane of Gram-negative bacteria, is critically involved in health and diseases. LPS facilitates the survival of pathogens by imposing a permeability barrier against antibiotics and antimicrobial peptides. LPS, also termed as endotoxin, functions as a potent inducer of innate immunity. Interception of endotoxin in systemic circulation by immune cells e.g. macrophages is essential to mount surveillance against invading microbes. However, a hyper-activated immune response may lead to the overwhelming production of tissue damaging cytokines TNF-and#945;, IL-1, IL-6 and free radicals that may cause multiple organ failures or septic shock syndromes. The sepsis or septic shock is the major cause of mortality; 120,000 deaths/year occur in the United States alone, in the intensive care units. To-date, no therapeutic is available to combat sepsis mediated lethality. Furthermore, bacterial resistance against commonly used antibiotics has been increasing at an alarming rate necessitating a search for antibacterial agents with novel mode of actions. LPS could be a valid drug target for the development of antiendotoxic and antimicrobial compounds. In this article, recent advances in structural basis of LPS recognition by its receptor proteins and mode of actions of antimicrobial peptides defensins and cathelicidins are reviewed. Our research has identified, through de novo design, antimicrobial and endotoxin interacting and#946;-boomerang peptides. Structure-activity correlations (SAR) of these peptides have been discussed, highlighting future design to achieve potent LPS neutralizing molecules.

The myriads of molecular pathways that have been measured to understand the physical bases of neuronal and other cellular functions have exceeded classical comprehension. In the tradition of Bohr and Schrodinger, the hypothesis is developed that molecular pathways are simply epiphenomenal transports of quanta with increments in the order of 10-20 J. Experimental measurements of photon emissions from cell cultures and the serial steps of phosphorylation in general molecular pathways and transformations in chromophores supported this contention. This discrete value is also associated with action potentials, intersynaptic events, the biophysical bases of membrane potentials, the numbers of action potentials per cell from magnetic energy potential, and the interionic distances around membranes. Consideration of information as discrete increments of energy may allow greater experimental control and external intervention of pathways relevant to medicinal chemistry.

Decaprenylphosphoryl-β-D-Ribose 2'-Epimerase from Mycobacterium tuberculosis is a Magic Drug Target by G. Manina, M. R. Pasca, S. Buroni, E. De Rossi, G. Riccardi (3099-3108).
Tuberculosis is still a leading cause of death in developing countries and a resurgent disease in developed countries. The selection and soaring spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Currently, there is an urgent need of new drugs for tuberculosis treatment, with novel mechanisms of action and, moreover, the necessity to identify new drug targets. Several enzymes involved in various metabolic processes have been described as potential targets for the development of new drugs. Recently, two different classes of most promising drugs, the benzothiazinones (BTZ) and the dinitrobenzamide derivatives (DNB), have been found to be highly active against M. tuberculosis, including XDR-TB strains. Interestingly, both drugs have the sametarget: the heteromeric decaprenylphosphoryl-and#946;-D-ribose 2'-epimerase encoded by dprE1 (Rv3790) and dprE2 (Rv3791) genes, respectively. DprE1 and DprE2 are involved in the biosynthesis of D-arabinose and, in particular, they are essential to perform the transformation of decaprenylphosphoryl-D-ribose to decaprenylphosphoryl-D-arabinose, which is a substrate for arabinosyltransferases in the synthesis of the cell-envelope arabinogalactan and liporabinomannan polysaccharides of mycobacteria. Arabinogalactan is a fundamental component of the mycobacterial cell wall, which covalently binds the outer layer of mycolic acids to peptidoglycan. The heteromeric decaprenylphosphoryl-and#946;-D-ribose 2'-epimerase thus represents a valid vulnerable antimycobacterial drug target which could result and#x201C;magicand#x201D; for tuberculosis treatment.

Homocysteine, Intracellular Signaling and Thrombotic Disorders by N. Dionisio, I. Jardin, G. M. Salido, J. A. Rosado (3109-3119).
Homocysteine, a sulphur-containing amino acid derived from methionine, has been presented as an independent risk factor for cardiovascular disorders, including atherosclerosis and thrombogenesis. The mechanisms underlying homocysteine-induced effects have been intensively investigated over the last two decades. Homocysteine can induce oxidative stress promoting oxidant injury to vascular and blood cells. Hyperhomocysteinemia often results in intracellular Ca2+ mobilization, endoplasmic reticulum (ER) stress, with the subsequent development of apoptotic events, chronic inflammation leading to endothelial dysfunction and remodeling of the extracellular matrix. Homocysteine has also been reported to induce modulation of gene expression through alteration of the methylation status. The effects of elevated concentrations of circulating homocysteine on the vascular wall, platelet function and coagulation factors promote the development of a pro-coagulant state. The pathophysiological significance of homocysteine in the development of vascular disorders through the induction of endothelial dysfunction and abnormal platelet activity and blood coagulation is discussed in this review.

Nanomedicine: Magnetic Nanoparticles and their Biomedical Applications by R. Banerjee, Y. Katsenovich, L. Lagos, M. McIintosh, X. Zhang, C.-Z. Li (3120-3141).
During this past decade, science and engineering have seen a rapid increase in interest for nanoscale materials with dimensions less than 100 nm, which lie in the intermediate state between atoms and bulk (solid) materials. Their attributes are significantly altered relative to the corresponding bulk materials as they exhibit size dependent behavior such as quantum size effects (depending on bulk Bohr radius), optical absorption and emission, coulomb staircase behavior (electrical transport), superparamagnetism and various unique properties. They are active components of ferrofluids, recording tape, flexible disk recording media along with potential future applications in spintronics: a new paradigm of electronics utilizing intrinsic charge and spin of electrons for ultra-high-density data storage and quantum computing. They are used in a gamut of biomedical applications: bioseparation of biological entities, therapeutic drugs and gene delivery, radiofrequency-induced destruction of cells and tumors (hyperthermia), and contrast-enhancement agents for magnetic resonance imaging (MRI). The magnetic nanoparticles have optimizable, controllable sizes enabling their comparison to cells (10-100 and#956;m), viruses (20-250 nm), proteins (3-50 nm), and genes (10-100 nm). Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) provide necessary characterization methods that enable accurate structural and functional analysis of interaction of the biofunctional particles with the target bioentities. The goal of the present discussion is to provide a broad review of magnetic nanoparticle research with a special focus on the synthesis, functionalization and medical applications of these particles, which have been carried out during the past decade, and to examine several prospective directions.