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Showing papers in "ChemInform in 1999"


Journal ArticleDOI

582 citations


Journal ArticleDOI
TL;DR: In this article, a review summarizes current knowledge about the in vitro pharmacological properties of important CB 1 and CB 2 receptor ligands, focusing on the binding properties of these ligands.
Abstract: Mammalian tissues contain at least two types of cannabinoid receptor, CB 1 and CB 2 , both coupled to G proteins. CB 1 receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB 2 receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this 'endogenous cannabinoid system' has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB 1 or CB 2 receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB 1 and CB 2 receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [ 35 S]GTPγS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB 1 or CB 2 receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such 'inverse cannabimimetic effects' are inverse agonists rather than pure antagonists is discussed.

468 citations


Journal ArticleDOI

461 citations


Book ChapterDOI
TL;DR: In this article, an overview of the field of carbon-carbon bond breaking is presented, including stoichiometric and catalytic reactions, especially those related to organic synthesis, and the first part deals with stochastic reactions involving carbon carbon bond breaking.
Abstract: Cleavage of carbon-carbon bonds by transition metals under homogeneous conditions has recently received much scientific and technological interest. In this review, an overview of this field is presented. The first part deals with stoichiometric reactions involving carbon-carbon bond breaking. The second part features catalytic reactions, especially those related to organic synthesis.

307 citations


Journal ArticleDOI
TL;DR: The spontaneous Raman effect has attracted attention from a basic research point of view as well as a powerful spectroscopic technique with many practical applications as discussed by the authors, however, it has not yet advanced the field of ultrasensitive trace detection.
Abstract: In the Raman effect, incident light is inelastically scattered from a sample and shifted in frequency by the energy of its characteristic molecular vibrations. Since its discovery in 1927, the effect has attracted attention from a basic research point of view as well as a powerful spectroscopic technique with many practical applications. The advent of laser light sources with monochromatic photons at high flux densities was a milestone in the history of Raman spectroscopy and resulted in dramatically improved scattering signals (for a general overview of modern Raman spectroscopy, see refs 1-5). In addition to this so-called spontaneous or incoherent Raman scattering, the development of lasers also opened the field of stimulated or coherent Raman spectroscopies, in which molecular vibrations are coherently excited. Whereas the intensity of spontaneous Raman scattering depends linearly on the number of probed molecules, the coherent Raman signal is proportional to the square of this number (for an overview, see refs 6 and 7). Coherent Raman techniques can provide interesting new opportunities such as vibrational imaging of biological samples,8 but they have not yet advanced the field of ultrasensitive trace detection. Therefore, in the following article, we shall focus on the spontaneous Raman effect, in the following simply called Raman scattering. Today, laser photons over a wide range of frequencies from the near-ultraviolet to the near-infrared region are used in Raman scattering studies, allowing selection of optimum excitation conditions for each sample. By choosing wavelengths which excite appropriate electronic transitions, resonance Raman studies of selected components of a sample or parts of a molecule can be performed.9 In the past few years, the range of excitation wavelengths has been extended to the near-infrared (NIR) region, in which background fluorescence is reduced and photoinduced degradation from the sample is diminished. High-intensity NIR diode lasers are easily available, making this region attractive for compact, low cost Raman instrumentation. Further, the development of low noise, high quantum efficiency multichannel detectors (chargecoupled device (CCD) arrays), combined with highthroughput single-stage spectrographs used in combination with holographic laser rejection filters, has led to high-sensitivity Raman spectrometers (for an overview on state-of-the-art NIR Raman systems, see ref 10). As we shall show in section 2, the nearinfrared region also has special importance for ultrasensitive Raman spectroscopy at the singlemolecule level. As with optical spectroscopy, the Raman effect can be applied noninvasively under ambient conditions in almost every environment. Measuring a Raman spectrum does not require special sample preparation techniques, in contrast with infrared absorption spectroscopy. Optical fiber probes for bringing excitation laser light to the sample and transporting scattered light to the spectrograph enable remote detection of Raman signals. Furthermore, the spatial and temporal resolution of Raman scattering are determined by the spot size and pulse length, respectively, of the excitation laser. By using a confocal microscope, Raman signals from femtoliter volumes (∼1 μm3) can by observed, enabling spatially resolved measurements in chromosomes and cells.11 Techniques such as multichannel Hadamard transform Raman microscopy12,13 or confocal scanning Fourier transform Raman microscopy14 allow generation of high-resolution Raman images of a sample. Recently, Raman spectroscopy was performed using near-field optical microscopy.15-17 Such techniques overcome the diffraction limit and allow volumes significantly smaller than the cube of the wavelength to be investigated. In the time domain, Raman spectra can be measured on the picosecond time scale, providing information on short-lived species such as excited 2957 Chem. Rev. 1999, 99, 2957−2975

251 citations



Journal ArticleDOI
TL;DR: General aspects on NO and NO donors are reviewed, major focus is placed on recent developments of novel NO donors, NO releasing device(s) as well as innovative improvements to current NO donors.
Abstract: Nitric oxide (NO) is an important messenger molecule involved in many pathological and physiological processes within the mammalian body. Exogenous NO sources constitute a powerful way to supplement NO when the body can not generate enough for normal biological functions. In this article, general aspects on NO and NO donors are reviewed. Major focus is placed on recent developments of novel NO donors, NO releasing device(s) as well as innovative improvements to current NO donors. Finally, an outlook on future NO donor development is provided.

206 citations


Journal ArticleDOI
TL;DR: In this article, the authors present both continuous and discrete mathematical models which describe the formation of the capillary sprout network in response to chemical stimuli (tumor angiogenic factors, TAF) supplied by a solid tumor.
Abstract: Angiogenesis, the formation of blood vessels from a pre-existing vasculature, is a process whereby capillary sprouts are formed in response to externally supplied chemical stimuli. The sprouts then grow and develop, driven initially by endothelial-cell migration, and organize themselves into a dendritic structure. Subsequent cell proliferation near the sprout tip permits further extension of the capillary and ultimately completes the process. Angiogenesis occurs during embryogenesis, wound healing, arthritis and during the growth of solid tumors. In this paper we present both continuous and discrete mathematical models which describe the formation of the capillary sprout network in response to chemical stimuli (tumor angiogenic factors, TAF) supplied by a solid tumor. The models also take into account essential endothelial cell-extracellular matrix interactions via the inclusion of the matrix macromolecule fibronectin. The continuous model consists of a system of nonlinear partial differential equations describing the initial migratory response of endothelial cells to the TAF and the fibronectin. Numerical simulations of the system, using parameter values based on experimental data, are presented and compared qualitatively with in vivo experiments. We then use a discretized form of the partial differential equations to develop a biased random-walk model which enables us to track individual endothelial cells at the sprout tips and incorporate anastomosis, mitosis and branching explicitly into the model. The theoretical capillary networks generated by computer simulations of the discrete model are compared with the morphology of capillary networks observed in in vivo experiments.

187 citations



Journal ArticleDOI
TL;DR: In this article, the authors present an approach to size reduction using topographically directed etching with neutral metastable atoms (NMT) and near field phase-shifting photolithography.
Abstract: 4.1. Nanomachining with Scanning Probes 1831 4.2. Soft Lithography 1832 4.3. Embossing with Rigid Masters 1835 4.4. Near-Field Phase-Shifting Photolithography 1835 4.5. Topographically Directed Photolithography 1837 4.6. Topographically Directed Etching 1837 4.7. Lithography with Neutral Metastable Atoms 1838 4.8. Approaches to Size Reduction 1839 5. Techniques for Making Regular or Simple Patterns 1839

169 citations


Journal ArticleDOI
TL;DR: The origin of ions in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry is currently a matter of active research as discussed by the authors, and a number of chemical and physical pathways have been suggested for MALDI ion formation, including gas-phase photoionization, ion-molecule reactions, disproportionation, excited-state proton transfer, energy pooling, thermal ionization, and preformed ions.
Abstract: The origin of ions in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry is currently a matter of active research. A number of chemical and physical pathways have been suggested for MALDI ion formation, including gas-phase photoionization, ion–molecule reactions, disproportionation, excited-state proton transfer, energy pooling, thermal ionization, and desorption of preformed ions. These pathways and others are critically reviewed, and their varying roles in the wide variety of MALDI experiments are discussed. An understanding of ionization pathways should help to maximize ion yields, control analyte charge states and fragmentation, and gain access to new classes of analytes. © 1999 John Wiley & Sons, Inc. Mass Spec Rev 17: 337–366, 1998

Journal ArticleDOI
TL;DR: In this article, the authors discuss the development of a general approach to rational synthesis of crystalline nanowires of arbitrary composition, and illustrate solutions to these challenges with measurements of the atomic structure and electronic properties of carbon nanotubes.
Abstract: Dimensionality plays a critical role in determining the properties of materials due to, for example, the different ways that electrons interact in three-dimensional, twodimensional (2D), and one-dimensional (1D) structures.1-5 The study of dimensionality has a long history in chemistry and physics, although this has been primarily with the prefix “quasi” added to the description of materials; that is, quasi-1D solids, including square-planar platinum chain and metal trichalcogenide compounds,2,6 and quasi2D layered solids, such as metal dichalcogenides and copper oxide superconductors.3-5,7,8 The anisotropy inherent in quasi-1D and -2D systems is central to the unique properties and phases that these materials exhibit, although the small but finite interactions between 1D chains or 2D layers in bulk materials have made it difficult to address the interesting properties expected for the pure low-dimensional systems. Are pure low-dimensional systems interesting and worth pursuing? We believe that the answer to this question is an unqualified yes from the standpoints of both fundamental science and technology. One needs to look no further than past studies of the 2D electron gas in semiconductor heterostructures, which have produced remarkably rich and often unexpected results,9,10 and electron tunneling through 0D quantum dots, which have led to the concepts of the artificial atom and the creation of single electron transistors.11-15 In these cases, lowdimensional systems were realized by creating discrete 2D and 0D nanostructures. 1D nanostructures, such as nanowires and nanotubes, are expected to be at least as interesting and important as 2D and 0D systems.16,17 1D systems are the smallest dimension structures that can be used for efficient transport of electrons and optical excitations, and are thus expected to be critical to the function and integration of nanoscale devices. However, little is known about the nature of, for example, localization that could preclude transport through 1D systems. In addition, 1D systems should exhibit density of states singularities, can have energetically discrete molecularlike states extending over large linear distances, and may show more exotic phenomena, such as the spin-charge separation predicted for a Luttinger liquid.1,2 There are also many applications where 1D nanostructures could be exploited, including nanoelectronics, superstrong and tough composites, functional nanostructured materials, and novel probe microscopy tips.16-29 To address these fascinating fundamental scientific issues and potential applications requires answers to two questions at the heart of condensed matter chemistry and physics research: (1) How can atoms or other building blocks be rationally assembled into structures with nanometer-sized diameters but much longer lengths? (2) What are the intrinsic properties of these quantum wires and how do these properties depend, for example, on diameter and structure? Below we describe investigations from our laboratory directed toward these two general questions. The organization of this Account is as follows. In section II, we discuss the development of a general approach to the rational synthesis of crystalline nanowires of arbitrary composition. In section III, we outline key challenges to probing the intrinsic properties of 1D systems and illustrate solutions to these challenges with measurements of the atomic structure and electronic properties of carbon nanotubes. Last, we discuss future directions and challenges in section IV.

Book ChapterDOI
TL;DR: In this article, a review of the recent advances in the field of transition metal-catalyzed functionalization of carbon-hydrogen bonds is presented, with a focus on the use of homogeneous transition metal complexes.
Abstract: Direct use of the carbon-hydrogen bond in organic synthesis with the aid of the homogeneous transition metal complexes has been the subject of recent interest. This review surveys some of the recent advances in the field of the transition metal-catalyzed functionalization of carbon-hydrogen bonds.

Journal ArticleDOI
Susan M. Ludeman1
TL;DR: Among the topics covered are: perturbations to metabolite distributions and half-lives effected by buffer, structure, pH and nucleophiles; effects of pH on mechanism; alkylation versus P-N bond hydrolysis; the influence ofucleophiles on alkylated product distributions; and preactivated forms of cyclophosphamide as metabolite precursors (4-hydroperoxycycloph phosphamide and mafosfamide).
Abstract: This is primarily an overview of the spontaneous (non-enzymatic) chemistry of the metabolites of cyclophosphamide, viz., cis- and trans-4-hydroxycyclophosphamide, aldophosphamide (and its hydrate), iminophosphamide, phosphoramide mustard, acrolein, and chloroethylaziridine. A brief description of detoxification products obtained through enzyme catalyzed reactions appears. Included as the historical basis for the development of cyclophosphamide is the chemistry of nitrogen mustards. Among the topics covered are: perturbations to metabolite distributions and half-lives effected by buffer, structure, pH and nucleophiles; effects of pH on mechanism; alkylation versus P-N bond hydrolysis; the influence of nucleophiles on alkylation product distributions; the influence of substituents on alkylation rates; and preactivated forms of cyclophosphamide as metabolite precursors (4-hydroperoxycyclophosphamide and mafosfamide). A review with 66 references.

Journal ArticleDOI
TL;DR: Many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.
Abstract: Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.

Journal ArticleDOI
TL;DR: This review presents various aspects of beta-peptides (oligomers of Beta-amino acids): synthesis, structure detn.
Abstract: With 71 refs., this review presents various aspects of beta-peptides (oligomers of beta-amino acids): synthesis, structure detn. by NMR and CD, thermal stability properties, helical and beta-pleated secondary structures, peptide folding, biol. and pharmacokinetic activities.



Journal ArticleDOI
B. L. Chenard1, Frank S. Menniti1
TL;DR: The wide range of potential therapeutic targets for NMDA antagonists coupled with the hope that NR2B selective agents might possess an improved clinical safety profile compared to non-selective compounds has supported an aggressive effort to develop the structure-activity relationships (SAR) of NR2 B selective antagonists.
Abstract: In the late 1980s, a new class of N-methyl-D-aspartate (NMDA) receptor antagonists, exemplified by the phenylethanolamine ifenprodil (1), was identified. Initially, the mechanism of action of ifenprodil was a mystery as it was not a competitive antagonist at the glutamate or glycine (co-agonist) binding sites, nor was it a blocker of the calcium ion channel associated with the NMDA receptor. Early studies with a novel polyamine binding site associated with the NMDA receptor and functional studies in various brain regions suggested a unique and selective activity profile for 1. However, it was not until the NMDA receptor subunits were identified and expressed that ifenprodil was shown to be a selective antagonist for a subset of NMDA receptors containing the NR2B subunit. The wide range of potential therapeutic targets for NMDA antagonists coupled with the hope that NR2B selective agents might possess an improved clinical safety profile compared to non-selective compounds has supported an aggressive effort to develop the structure-activity relationships (SAR) of NR2B selective antagonists. This SAR and the basic physiology of the NMDA receptor form the basis of this review.

Journal ArticleDOI
TL;DR: The structure basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors and the structure based exploitation of additional highly validated targets from a variety of therapeutic areas is now ripe.
Abstract: The protein kinase family represents both a huge opportunity and a challenge for drug development. The conservation of structural features within the ATP binding cleft initially led to the belief that specificity would be difficult to achieve. This dogma has now been clearly dispelled with the discovery and clinical testing of a group of first generation compounds, which are characterized by a high degree of selectivity towards a variety of oncology targets. The structural basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors. The protein kinase inhibitor field is now ripe for the structure based exploitation of additional highly validated targets from a variety of therapeutic areas.

Journal ArticleDOI
TL;DR: A review of the currently most compelling beta-amino acid targets can be found in this article, with a special emphasis on catalytic and enzymatic processes, as well as methods based on "chiral pool", self-regeneration of stereogenic centers, diastereoselective nucleophilic additions to prochiral double bonds, and enanti-lective reactions in the presence of chiral additives.
Abstract: The introductory section of this review presents some of the currently most compelling beta-amino acid targets, according to their structural types: alpha- and beta-aryl substituted, olefinic and alkynyl, alpha, alpha- and alpha,beta-disubstituted, cyclic and conformationally restricted, fluorine-containing, and phosphonic analogous beta-amino acids. The main section highlights some of the very new (1996-1998), promising methodology for the enantioselective synthesis of beta-amino acids, with especial emphasis on catalytic and enzymatic processes, as well as methods based on "chiral pool", self-regeneration of stereogenic centers , diastereoselective nucleophilic additions to prochiral double bonds, and enantioselective reactions in the presence of chiral additives.

Journal ArticleDOI
Ryong Ryoo1, Sang Hoon Joo1, Shinae Jun1
TL;DR: Ordered carbon molecular sieves exhibiting Bragg diffraction of X-ray lines have been synthesized for the first time, using mesoporous silica sieves as the template as mentioned in this paper.
Abstract: Ordered carbon molecular sieves exhibiting Bragg diffraction of X-ray lines have been synthesized for the first time, using mesoporous silica molecular sieves as the template. Sucrose was converted to carbon inside the mesopores of the silica molecular sieves through a mild carbonization process using a sulfuric acid catalyst. The carbon molecular sieves were obtained after the removal of the silica framework using an aqueous solution of sodium hydroxide. The X-ray diffraction, transmission electron microscopy, and pore size analysis showed that the structure of the carbon molecular sieves consisted of a three-dimensional regular array of uniform mesopores 3 nm in diameter. The structure was not simply a negative replica of the used silica template, but the synthesis mechanism involved the unique transformation into a new ordered array that was triggered by the removal of the silica frameworks. The highly ordered mesoporous texture suggested its scientific and technological importance as a new shape-selec...



Journal ArticleDOI
TL;DR: Protein kinase C (PKC) is a family of enzymes that play a ubiquitous role in intracellular signal transduction as discussed by the authors, and the development of potent and selective PKC inhibitors, including isozyme-selective inhibitors, has opened new avenues for biochemical and pharmaceutical studies.
Abstract: Protein kinase C (PKC) is a family of enzymes that play a ubiquitous role in intracellular signal transduction. Our understanding of the precise role of PKC has evolved considerably as a result of improved methodology and a better understanding of the signal transduction pathways. A number of primary pathways previously attributed to PKC have been re-examined and found to involve other kinases as our understanding of the PKC isozymes has evolved. PKC isozymes appear to play distinct, and in some cases opposing roles in the transduction of intracellular signals. The development of potent and selective PKC inhibitors, including isozyme-selective inhibitors, has opened new avenues for biochemical and pharmaceutical studies. The role of PKC in some of the pathways relevant to cardiovascular, peripheral microvascular, CNS, oncology, immune and infectious disease states are surveyed. A survey of the current generation of potent and selective ATP-competitive inhibitors is provided. The progress of PKC inhibitors currently in clinical development, including LY333531, ISIS 3521 (CGP 64128A), bryostatin 1, GF109203x, Ro 32-0432 and Ro 31-8220, Go 6976 and Go 7611, CPR 1006, and balanol (SPC 100840) are discussed.

Journal ArticleDOI
TL;DR: This review summarizes the biochemistry of the 5-lipoxygenase pathway, the pharmacology of FLAP and 5 lipoxygenases inhibitors and discusses possible criteria for the development of these drugs.
Abstract: Arachidonate 5-lipoxygenase is the key enzyme in leukotriene biosynthesis and catalyzes the initial steps in the conversion of arachidonic acid to biologically active leukotrienes. Leukotrienes are considered as potent potent mediators of inflammatory and allergic reactions which are locally released by leukocytes and other 5-LO expressing cells and exert their effects via binding to specific membrane receptors and, as suggested recently, the nuclear receptor PPARa. Because of the proinflammatory profile of leukotrienes it was assumed that leukotriene biosynthesis inhibitors and leukotriene receptor antagonists have a therapeutical potential in a variety of inflammatory diseases. Clinical studies confirmed the therapeutic value of the antileukotriene therapy in asthma but the results with leukotriene biosynthesis inhibitors in psoriasis, arthritis and inflammatory bowel disease were more or less disappointing. This review summarizes the biochemistry of the 5-lipoxygenase pathway, the pharmacology of FLAP and 5 lipoxygenase inhibitors and discusses possible criteria for the development of these drugs.

Journal ArticleDOI
TL;DR: The latest developments in the search for new inhibitors will be reported as well as the discovery of new natural substrates for DPP IV such as the glucagon-like peptides and the chemokines.
Abstract: This review deals with the properties and functions of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). This membrane anchored ecto-protease has been identified as the leukocyte antigen CD26. The following aspects of DPP IV/CD26 will be discussed : the structure of DPP IV and the new family of serine proteases to which it belongs, the substrate specificity, the distribution in the human body, specific DPP IV inhibitors and the role of CD26 in the intestinal and renal handling of proline containing peptides, in cell adhesion, in peptide metabolism, in the immune system and in HIV infection. Especially the latest developments in the search for new inhibitors will be reported as well as the discovery of new natural substrates for DPP IV such as the glucagon-like peptides and the chemokines. Finally the therapeutical perspectives for DPP IV inhibitors will be discussed.



Journal ArticleDOI