Current Medicinal Chemistry (v.15, #30)
Different Synthetic Strategies of Oseltamivir Phosphate: A Potent Influenza Neuraminidase Inhibitor by Jianzhi Gong, Wenfang Xu (3145-3159).
Oseltamivir phosphate (Tamifluand#174;) is the only orally active anti-influenza drug that potently inhibit neuraminidase. The recent emergence of avian flu, especially the H5N1 type, makes the situation of Tamiflu supply and demand increasingly serious. Further optimization of the current commercial approach and exploration of new synthetic routes are urgent. Here, different synthetic strategies of oseltamivir phosphate are reviewed, including discovery and improved synthetic route from (-)-quinic acid or (-)-shikimic acid, new asymmetric synthesis via catalytic desymmetrization of a mesoaziridine (CDMA), Diels-Alder Reaction and from other available materials.
Trends in Cell-Based Electrochemical Biosensors by Lin Ding, Dan Du, Xueji Zhang, Huangxian Ju (3160-3170).
Cell-based electrochemical biosensors have contributed tremendously to the fields of biology, medicine, chemistry, pharmacology, and environmental science. With electrochemical transducers and whole cells as the recognition elements, these biosensors provide new horizons for biosensing and life science research. This review focuses on the research accomplishments on this topic over the last three years, and is divided into three sections according to the types of cellular responses. Our aim is to highlight how simple and sensitive electrochemical methods can be coupled with cells by virtue of the integration of interface control, nanotechnology and genetic engineering to generate new enabling technologies. Some specific examples to demonstrate how these sensors are useful in medicinal chemistry and drug design have also been discussed. It is hoped that this review can provide inspiration for the development of fast, selective, sensitive, and convenient detection and diagnosis platforms.
Cancer Stem Cells: How can we Target them? by Ivan Ischenko, Hendrik Seeliger, Moshe Schaffer, Karl-Walter Jauch, Christiane Bruns (3171-3184).
One of the most exciting concepts being explored in cancer research today is the idea of cancer stem cells. Evidence for the existence of such cells was first proposed for haematological malignancies and, more recently, for solid tumors, including breast, brain, colon and pancreatic cancer. The cancer stem cell hypothesis states that a minority of transformed stem cells, or progenitors with acquired self-renewal properties, are the source of tumor cell renewal and thereby determine the behaviour of tumors, including proliferation, spreading and response to chemo- and radiotherapy. Indeed, just as somatic stem cells may be resistant to the induction of apoptosis by cytotoxic agents and radiation therapy, cancer stem cells may display increased resistance to these agents as compared with the more differentiated cells that comprise the mass of tumors. More specifically, the reactivation of varied developmental signalling cascades (epidermal growth factor (EGF)/EGFR, stem cell factor (SCF)/KIT, sonic hedgehog, Notch, and/or Wnt/and#946;-catenin) combined with the increased DNA repair mechanisms and ABC transporter-mediated drug efflux in cancer stem cells may be responsible for their resistance to conventional therapies. Furthermore, changes in the local microenvironment of cancer stem cells may also influence their behaviour. Thus, the molecular targeting of such highly tumorigenic cancer cells must be considered for improving the efficacy of the current anti-cancer strategies with the aim to sensitize tumors toward conventional therapies and effectively abrogate tumorigenesis. This review provides a summary of some developments in the field of cancer stem cell targeting and highlights aspects where it could be of help in the drug discovery process.
Prevention and Treatment of Staphylococcus Biofilms by Pietro Speziale, Livia Visai, Simonetta Rindi, Giampiero Pietrocola, Giulio Provenza, Maria Provenzano (3185-3195).
Staphylococcus growth on medical devices represents a common occurrence that can lead to serious illness and death. Biomaterial-associated infection, mostly caused by Staphylococcus epidermidis and Staphylococcus aureus, is fairly complicated by the organism'development of a biofilm, which provides a microenvironment that protects from attack by the host immune system and antibiotics. In this review we present recent insights regarding S. aureus and S. epidermidis structural and functional factors that are effective in biofilm development and describe the regulation of their expression. On the basis of the knowledge gained, we also present the potential and limits of current biochemical and biophysical strategies aimed at preventing biofilm formation or at the treatment of established mature biofilms.
Application of Drug Repositioning Strategy to TOFISOPAM by P. Bernard, C. Dufresne-Favetta, P. Favetta, Q.-T. Do, F. Himbert, S. Zubrzycki, T. Scior, C. Lugnier (3196-3203).
Drug repositioning strategy is an interesting approach for pharmaceutical companies ; especially to increase their productivity. SELNERGYtm is a reverse docking based-program able to virtually screen thousands of compounds on more than 2000 3D biological targets. This program was successfully applied to tofisopam and revealed that the isomers of tofisopam are able to fit with phosphodiesterase 4. This old drug was used as a racemic mixture to treat anxiety in the eighties and was recently shown to act as a PDE4 inhibitor. Thanks to this strategy we demonstrated that tofisopam acts via the inhibition of PDE4 in the submicromolar range. Moreover, we firstly showed that the S-enantiomer of tofisopam is ten times more active than R-enantiomer. The identification of the biochemical mechanism of tofisopam isomers now allows to reposition this drug in new therapeutic indications where modulation of cAMP via PDE4 inhibitors are possible.
Alternative Pharmacological Interventions that Limit Myocardial Infarction by I. Andreadou, E. Iliodromitis, M. Koufaki, D. Farmakis, A. Tsotinis, D. Kremastinos (3204-3213).
Despite current optimal treatment, the morbidity and mortality of coronary heart disease remain significant worldwide and open the way for the development of novel cardioprotective therapies. In the last two decades, a remarkable scientific effort has focused on the limitation of infarct size. Important input from experimental studies has led the way in this direction. However, clinical and preclinical results using various cardioprotective strategies to attenuate reperfusion injury have generally not been applicable for every day clinical practice. Protection of the ischemic myocardium is known to occur as a result of ischemic preconditioning (PC), in which repetitive brief periods of ischemia protect the heart from a subsequent prolong ischemic insult. Although PC is a powerful form of protection, it is of limited clinical application for obvious ethical and practical reasons. Another endogenous form of cardioprotection, similar to PC but applicable at the time of reperfusion, termed postconditioning (PostC), has been recently described. Short series of repetitive cycles of brief reperfusion and re-occlusion of the coronary artery applied at the onset of reperfusion, reduce the infarct size and coronary artery endothelial dysfunction. At present, pharmacological PC and PostC are possible alternative methods that may substitute pharmaceutical treatments the short ischemic insults. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. We summarize the recent research efforts on novel therapeutic strategies and on the design of new compounds, based on the accumulated knowledge of the ligands, receptors and intracellular signaling pathways of PC and PostC.
Computational Approaches for the Study of Serotonin and Its Membrane Transporter SERT: Implications for Drug Design in Neurological Sciences by J. Pratuangdejkul, B. Schneider, J-M. Launay, O. Kellermann, P. Manivet (3214-3227).
Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter of the central nervous and peripheral systems (CNS), plays a critical role in a wide variety of physiological and behavioral processes. In the serotonergic system, deregulation of the tightly controlled extracellular concentration of 5-HT appears to be at the origin of a host of metabolic and psychiatric disorders. A key step that regulates 5-HT external level is the re-uptake of 5-HT into cells by the 5-HT transporter (SERT), which is besides the target of numerous drugs interacting with the serotonergic system. Therapeutic strategies have mainly focused on the development of compounds that block the activity of SERT, for instance reuptake inhibitors (e.g. tricyclics, and#x201C;selectiveand#x201D; serotonin reuptake inhibitors) and in the past, specific substrate-type releasers (e.g. amphetamine and cocaine derivatives). Today, generation of new drugs targetting SERT with enhanced selectivity and reduced toxicity is one of the most challenging tasks in drug design. In this context, studies aiming at characterizing the physicochemical properties of 5-HT as well as the biological active conformation of SERT are a prerequisite to the design of new leads. However, the absence of a high-resolution 3D-structure for SERT has hampered the design of new transporter inhibitors. Using computational approaches, numerous efforts were made to shed light on the structure of 5-HT and its transporter. In this review, we compared several in silico methods dedicated to the modeling of 5-HT and SERT with an emphasis on i) quantum chemistry for study of 5-HT conformation and ii) ligand-based (QSAR and pharmacophore models) and transporter-based (homology models) approaches for studying SERT molecule. In addition, we discuss some methodological aspects of the computational work in connection with the construction of putative but reliable 3D structural models of SERT that may help to predict the mechanisms of neurotransmitter transport.
(Neuro)Transmitter Systems in Circulating Immune Cells: A Target of Immunopharmacological Interventions? by Seyed Tayebati, Francesco Amenta (3228-3247).
Increasing evidence indicates the existence of an association between nervous and immune systems. The two systems communicate with each-other to maintain immune homeostasis. Activated immune cells secrete cytokines that influence central nervous system activity. Nervous system, through its peripheral and/or autonomic divisions activates output regulating levels of immune cell activity and the subsequent magnitude of an immune response. On the other hand, neurotransmitters, which represent the main substances involved in nerve cell communications, can influence immune function. Immune organs and circulating immune cells express several (neuro)transmitter systems that can be involved in regulating their activity. The expression of neurotransmitter systems by different subsets of circulating immune cells was reviewed. The regulatory role of different families of (neuro)transmitters (catecholamines, 5-hydroxytryptamine, acetylcholine, histamine and neuropeptides) in modulating levels of immune mediators or specific immune responses is discussed.
Alkannins and Shikonins: A New Class of Wound Healing Agents by V. Papageorgiou, A. Assimopoulou, A. Ballis (3248-3267).
Alkannins and Shikonins (A/S) are chiral-pairs of naturally occurring isohexenylnaphthazarins. They are found in the external layer of the roots of at least a hundred and fifty species that belong mainly to the genera Alkanna, Lithospermum, Echium, Onosma and Arnebia of the Boraginaceae family. Their occurrence in Jatropha glandulifera, a member of the Euphorbiaceae, should be considered as an exception. Pharmaceutical formulations with wound healing properties based on A/S have been in the market for many years. Although their wound-healing, anti-inflammatory, antimicrobial, antioxidant, antithrombotic and antitumor properties have been extensively documented, significant insight into their specific molecular pathways and mechanisms was hindered until recently. With the establishment of viable synthetic and biosynthetic routes of A/S and the synthesis of specific derivatives that were discovered the last few years, the effects of those compounds in the molecular-cell biology of human tissues in health and diseas have just started being explored in depth, revealing a new class of drugs that hold promise as the basis for many valuable therapeutic targets. In the recent years, a wealth of new information arising from research efforts, on the wound healing properties of A/S has been accumulated. In this paper we review the findings and advances on the molecular and biological properties of A/S that promote wound healing.
Copper Transport Systems are Involved in Multidrug Resistance and Drug Transport by Tatsuhiko Furukawa, Masaharu Komatsu, Ryuji Ikeda, Kazutake Tsujikawa, Shin-ichi Akiyama (3268-3278).
Copper is an essential trace element and several copper containing proteins are indispensable for such processes as oxidative respiration, neural development and collagen remodeling. Copper metabolism is precisely regulated by several transporters and chaperone proteins. Copper Transport Protein 1 (CTR1) selectively uptakes copper into cells. Subsequently three chaperone proteins, HAH1 (human atx1 homologue 1), Cox17p and CCS (copper chaperone for superoxide dismutase) transport copper to the Golgi apparatus, mitochondria and copper/zinc superoxide dismutase respectively. Defects in the copper transporters ATP7A and ATP7B are responsible for Menkes disease and Wilson's disease respectively. These proteins transport copper via HAH1 to the Golgi apparatus to deliver copper to cuproenzymes. They also prevent cellular damage from an excess accumulation of copper by mediating the efflux of copper from the cell. There is increasing evidence that copper transport mechanisms may play a role in drug resistance. We, and others, found that ATP7A and ATP7B are involved in drug resistance against the anti-tumor drug cis-diamminedichloroplatinum (II) (CDDP). A relationship between the expression of ATP7A or ATP7B in tumors and CDDP resistance is supported by clinical studies. In addition, the copper uptake transporter CTR1 has also been reported to play a role in CDDP sensitivity. Furthermore, we have recently found that the effect of ATP7A on drug resistance is not limited to CDDP. Using an ex vivo drug sensitivity assay, the histoculture drug response assay (HDRA), the expression of ATP7A in human surgically resected colon cancer cells correlated with sensitivity to 7-ethyl-10-hydroxy-camptothecin (SN-38). ATP7Aoverexpressing cells are resistant to many anticancer drugs including SN-38, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), vincristine, paclitaxel, etoposide, doxorubicin (Dox), and mitoxantron. The mechanism by which ATP7A and copper metabolism modulate drug transport appears to involve modulation of drug cellular localization via modulation of the vesicle transport system. In ATP7A overexpressing cells, Dox accumulates in the Golgi apparatus. In contrast, in the parental cells, Dox is localized in the nuclei, where the target molecules of Dox, topoisomerase II and DNA, are found. Disruption of the intracellular vesicle transport system with monensin, a Na+/H+ ionophore, induced the relocalization of Dox from the Golgi apparatus to the nuclei in the ATP7A overexpressing cells. These data suggested that ATP7A-related drug transport is dependent on the vesicle transport system. Thus copper transport systems play important roles in drug transport as well as in copper metabolism. Components of copper metabolism are therefore likely to include target molecules for the modulation of drug potency of not only anti-cancer agents but also of other drugs.
Erratum-I by Hongyu Cao, Ran Cao, Huabei Zhang, Xuefang Zheng, Dabin Gao (3279-3279).
In our review entitled and#x2018;Non-nucleoside inhibitors of NS5B polymerase binding to allosteric sites: 3D- QSAR and molecular docking studiesand#x2019; in the Current Medicinal Chemistry, 2008, 15(15), 1462-77. We wish to correct mistakes in the authorship and their units of the manuscript.
Erratum-II by Jelena Ivanovic, Emanuele Nicastri, Paolo Ascenzi, Rita Bellagamba, Elisabetta De Marinis, Stefania Notari, Leopoldo Pucillo, Valerio Tozzi, Giuseppe Ippolito, Pasquale Narciso (3280-3280).
In our review entitled and#x2018;Therapeutic Drug Monitoring in the Management of HIV-Infected Patientsand#x2019; in the Current Medicinal Chemistry, 2008, 15(19), 1925-39.