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- Volume 3, Issue 7, 2003
Mini Reviews in Medicinal Chemistry - Volume 3, Issue 7, 2003
Volume 3, Issue 7, 2003
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Preface [Hot topic: Carbohydrates (Executive Editor: Istvan Toth)]
By Istvan TothThe last few years have witnessed an explosion of interest in the area of carbohydrates in biology and medicinal chemistry. Carbohydrates are among the most important class of molecules in biological systems and are at the centre of an enormous amount of modern pharmaceutical research, particularly in the areas of cancer, immunotherapy, infection and inflammation. Glycoproteins, because they are localized on the cell surface, play key roles in cell-cell and cell-pathogen interactions, recognition events and signal transduction. Mimetics of these glycoconjugates are therefore likely to be important candidates for future drug development. Carbohydrates represent one of the major components of the outer surface of mammalian cells, the outer cell membrane being studded with glycoproteins and glycolipids. While the roles of most of these species remain to be elucidated, we already know that different glycosylation patterns are associated with different stages of cell development, and that pathological states, such as cancers, can lead to abnormal alterations in cell-surface glycosylation. The appending of sugars onto proteins alters many of their biochemical properties, such as secondary and tertiary conformations, and resistance to proteases. The introduction of faster computers and better software has seen an increase in interest in the modelling of these highly flexible carbohydrates and glycoconjugates, with the aim of designing new carbohydrate-based drugs. The chemical synthesis of carbohydrates and carbohydrate-like molecules, particularly complex polysaccharides and glycoconjugates, is often very challenging. Nevertheless, chemical synthesis allows us to secure pure and homogeneous material that is otherwise very difficult to obtain from biological sources. Additionally, we can obtain by synthesis molecules with modified physicochemical characteristics, with resulting improvements in stability towards degrading enzymes and to the gastric environment. The synergistic interactions between synthetic chemists and glycoscientists have resulted in advances in both areas. Some of the disadvantages of using carbohydrates as drugs are well known, such as their (often) poor uptake, low affinity for receptors and poor biostability. However, in spite of the perception that carbohydrates do not make good drugs, there are in fact many such drugs currently used as therapeutics, and many more in clinical trials. These include pharmaceuticals used to treat conditions such as influenza, arthritis, inflammatory diseases, cancer and epilepsy. The advantages of using carbohydrates as therapeutics relative to, say, peptides, are their lower toxicity and immunogenicity. Advances in our understanding of carbohydrate-mediated biological processes, the design and synthesis of biologically active carbohydrate-based molecules, and efforts to overcome some of the current limitations of this class of compound, will undoubtedly lead to increased numbers of drugs in the pharmaceutical pipeline, for the treatment of a wide range of diseases. This issue of MRMC reviews the following aspects: - Molecular modelling of carbohydrates; - The effects of glycosylation on the conformations of peptides; - The identification of polysaccharide biosynthesis inhibitors as new anti-tuberculosis agents; - The design of inhibitors of the carbohydrate-binding proteins, selectins; - A survey of the diverse structural types of glycosidase inhibitors; - The physicochemical characteristics of carbohydrate-based drugs; - Chemoselective synthesis of neoglycoconjugates; - Drug development based on heparin-protein interactions.
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Aspects of the Stability and Bioavailability of Carbohydrates and Carbohydrate Derivatives
Authors: N. B. Drinnan and Frank VariCarbohydrates play a critical role in many biological processes and disease states including cancer, inflammation and infection. The development of carbohydrates as therapeutics continues to gain interest, as the biological roles of these biopolymers are further elucidated and understood. However, many carbohydrates display poor affinity, stability and bioavailability characteristics, which has led to a widely held view that this class of molecules make poor drugs. As there are already a significant number of carbohydrate-based drugs presently being employed by physicians, it is clear that some carbohydrates do make effective drugs. Recent advances in (a) the understanding of carbohydrate specific transport mechanisms, and (b) the development of novel carbohydrate based bioactives which may overcome many of the previous limitations of stability and bioavailability, suggest that carbohydrate-based compounds may provide a rich source of new drug candidates for a variety of diseases.
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Extending Chemoselective Ligation to Sugar Chemistry: Convergent Assembly of Bioactive Neoglycoconjugates
More LessGlycoproteins and glycolipids play central roles in human health and disease, and their mimetics are primary candidates for drug development. Our understanding of the molecular level of phenomena based on molecular recognition of oligosaccharides by specific receptors has taken tremendous advantage from their chemical synthesis, which provides homogeneous material not attainable from biosynthetic systems. This review summarizes chemoselective approaches for the assembly of neoglycoconjugates. The objective of these methods is to make glycoconjugate synthesis accessible to a broader community, thus accelerating progress in biotechnology.
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The Potential of the Molecular Diversity of Heparin and Heparan Sulfate for Drug Development
By Peter FugediHeparin and heparan sulfate have been shown to interact with a large number of biologically important proteins regulating important physiological processes. Specific oligosaccharide structures within the heterogeneous polysaccharide chains are responsible for the binding to individual proteins. Identification of specific protein-binding oligosaccharides provides lead compounds in pharmaceutical development and in one case has already resulted in an approved drug. The chemical and biosynthetic basis of the molecular diversity of heparin and heparan sulfate, its manifestation in heparin-protein interactions, and recent progress for drug development offered by this diversity are reviewed.
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Back to (non)-Basics: Recent Developments in Neutral and Charge- Balanced Glycosidase Inhibitors
Authors: Todd A. Houston and Joanne T. BlanchfieldCertain glycosidase inhibitors possess potent antiviral, antitumour and antidiabetic properties. Glyconic acid lactones, the earliest glycosidase inhibitors identified, have planar anomeric carbons that mimic the transition state of glycoside hydrolysis. Other classes include lactams, glycals, epoxides, halides and sulfonium ions, the latter based on the natural product salacinol from an antidiabetic herb.
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Recent Progress in the Design of Selectin Inhibitors
Authors: Siri R. Chhabra, Aisyah S. Abdul Rahim and Barrie KellamThe selectins are a family of cell-adhesion proteins that mediate the early stages of leukocyte recruitment from the blood stream to sites of tissue damage through recognition of the carbohydrate epitope sialyl Lewis-x (sLe-x). Current development of small molecule based inhibitors of this process and their clinical potential to address numerous acute and chronic diseases are explored.
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Recent Progress Towards the Identification of Inhibitors of Mycobacterial Cell Wall Polysaccharide Biosynthesis
More LessMycobacterial infections have recently attracted significant attention from international health agencies due to the resurgence of these diseases worldwide. This review summarizes the recent work directed towards the identification of new anti-tuberculosis agents that act by inhibiting mycobacterial cell wall polysaccharide biosynthesis.
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Conformation of Glycopeptides
Authors: Laszlo Otvos Jr. and Mare CudicThe presence of carbohydrate side-chains in native glycoproteins alters a number of biochemical properties of the peptide backbone. One of the most frequently studied questions is the conformationmodifying effect of sugar incorporation into asparagine, serine and threonine residues. When N-glycosylation modifies the conformation, the resulting structures are more ordered than the peptide chain without sugar addition. For O-glycopeptides the final conformations can be either more ordered or less ordered. In any event, only the innermost carbohydrates make contact with the peptide backbone. Through-space structural changes are mostly found downstream of the O-glycosylation site. In the repeat unit of epithelial mucin-1 protein, clustering of the carbohydrates results in an easily observable stabilization of the poly-proline II helix.
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Recent Trends in Carbohydrate Modeling
Authors: Jane D. Dyekjaer and Kjeld RasmussenThe exploding activities in modeling of carbohydrates during the past few years is reviewed with emphasis on advances in improving force fields, coupling of NMR measurements with molecular dynamics simulations, direct calculation of thermodynamic properties, application of quantum chemical methods on a large scale, and web-access to modeling.
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Preface [Hot topic: Neuropathic Pain: Some Clues for the Future (Executive Editor: Ana Martinez)]
By Ana MartinezPeople usually think of pain as having some physical cause. Get rid of the cause, and the pain goes away. However, nerves themselves can also generate pain, and this pain often doesn't go away easily. It is called neuropathic pain (from the Greek neuro, meaning nerves, and pathy, meaning abnormality). It can be puzzling and frustrating for people who have it and for doctors who treat it. Currently there is no proven treatment to prevent or cure neuropathic pain, but recent research has seen great progress in understanding its causes and in finding new drugs that promise great benefit. The first goal of this monographic issue is to review current knowledge of the targets, mechanisms, new drugs and treatments of neuropathic pain and prospects for the future with the aim of helping the scientific community in the search for effective therapies for this widespread disability. Dr. J.E. Banos and co-workers summarise the current understanding of the potential targets for neuropathic pain drug design and / or intervention in their complete concise revision. The state-of-the-art of the new drugs for neuropathic pain from a medicinal chemistry point of view is considered by the group of Dr. M.L. Lopez in its review focused on VR1 receptor modulators, Dr. A. Ferrer-Montiel et al., describing excellent analysis of small molecules targeting the NMDA receptor, my colleagues Drs. S. Morales and L. Rubio, focusing on AMPA glutamate receptor, and Dr. P. Goya and co-workers shedding light on the progress towards cannabinoids and neuropathic pain. Antidepressant drugs that have been used for over 30 years to cure neuropathic pain were accurately update by Drs. C. Mattia and F. Coluzzi. Finally, the oceans hold further promising compounds that might lead to new drugs. Conotoxins obtained from the predatory snails of the genus Conus probably describe a new era in the future treatment of neuropathic pain. A brief introduction of conotoxins by my colleague Diana Alonso precedes the complete table prepared by Dr. B. Livett and co-workers, focusing on therapeutic conopeptides. All the drugs belonging to the conopeptide family currently developing for treatment of neuropathic pain are described herein. I am very grateful to all the above-mentioned contributors for their excellent work and their willingness in the prompt submission of their manuscript. I signally hope readers will enjoy this issue and will find new clues to accelerate their own research
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Neuropathic Pain: Some Clues for Future Drug Treatments
Authors: J. E. Banos, G. Sanchez, F. Berrendero and R. MaldonadoNeuropathic pain is still far from being adequately dealt with. Under this name, several clinical entities have been considered and most of them only share several painful ailments. At present, the available treatments can only alleviate the pain of roughly half of the patients, and their effectiveness is often limited by the appearance of the intolerable side effects. In this review, we will consider the pathophysiology of neuropathic pain to understand the basis of pharmacological treatments that are currently being investigated. Some examples of these drugs will also be considered.
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VR1 Receptor Modulators as Potential Drugs for Neuropathic Pain
Authors: Maria L. Lopez-Rodriguez, Alma Viso and Silvia Ortega-GutierrezThe involvement of VR1 in the endogenous pain signalling has converted this receptor into a promising therapeutic target for the development of a new family of potent analgesics devoid of the shortcomings of other analgesics commonly used. The desensitisation induced after VR1 activation points to the utility of VR1 agonists for the treatment of various nociceptive disorders including mitigation of neuropathic pain, inhibition of neurogenic inflammation and suppression of urinary bladder hyperreflexia, whereas VR1 antagonists have been described as valuable agents for the treatment of inflammatory hyperalgesia and pain. Structure of the main classes of VR1 ligands developed to date, their molecular mechanisms of action and their promising utility for the management of diverse nociceptive alterations, specially neuropathic pain, are discussed in this review.
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Small Molecules Targeting the NMDA Receptor Complex as Drugs for Neuropathic Pain
Pain is a complex disease that usually remains poorly treated or undertreated, especially the neuropathic pain caused by injury to the peripheral or central nervous system. Antagonists of the NMDA receptor complex have emerged as potential drugs for pain management. A strong case is being raised for noncompetitive or uncompetitive antagonists with low-to-moderate affinity and fast on / offset kinetics as drugs with good therapeutic profiles, because of their reduced side effects.
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AMPA Glutamate Receptors and Neuropathic Pain
Authors: Susana Morales-Alcelay, Laura Rubio and Ana MartinezGlutamate receptors are implicated in many actions in the central nervous system, as an excitatory amino acid, and one of the more relevant is its role in excitotoxicity. Apart from this, it also has a role as pronociceptive agent, so that antagonizing its actions could be of interest for developing new analgesic agents. Furthermore, between the analgesics agents, it is of outstanding interest the fact that there is no specific therapy against the neuropathic pain, and glutamate receptor subunits have elicited as new potential targets for this disturbance.
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Cannabinoids and Neuropathic Pain
Authors: P. Goya, N. Jagerovic, L. Hernandez-Folgado and M. I. MartinAfter a brief overview of the endocannabinoid system (CB receptors, and endocannabinoids) and of the cannabinergic ligands, some general issues related to cannabinoids and pain are commented. Finally, the most important findings regarding cannabinoids and neuropathic pain are discussed in detail.
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Antidepressants in Chronic Neuropathic Pain
Authors: Consalvo Mattia and Flaminia ColuzziThis review presents available clinical studies and new insights into mechanisms of analgesic effect and possible new routes of administration of antidepressant drugs. Older TCAs continue to be superior treatments. We focused on recent findings on newer antidepressants as analgesics. Their use should be supported by further controlled trials.
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Drugs From the Sea: Conotoxins as Drug Leads for Neuropathic Pain and Other Neurological Conditions
Authors: D. Alonso, Z. Khalil, N. Satkunanthan and B. G. LivettThe oceans are a source of a large group of structurally unique natural products that are mainly found in invertebrates such as sponges, tunicates, bryozoans, and molluscs. It is interesting to note that the majority of marine compounds currently in clinical trials or under preclinical evaluation are produced by these species rather than as secondary metabolites by marine algae [1]. Through the combined efforts of marine natural products chemists and pharmacologists a number of promising compounds have been identified that are either already at advanced stages of clinical trials such as the new anti-cancer drug marine alkaloid ecteinascidin 743 [2], or have been selected as promising candidates for extended preclinical evaluation [3]. This is the case for conotoxins, (Table 1) where a number of conopeptides are currently being developed as analgesics for the treatment of neuropathic pain.
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Volumes & issues
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)