bluuebunny/crossref_metadata_2025 huggingface dataset:
Building ontologies in DAML + OIL
Authors: Stevens Robert , Wroe Chris , Bechhofer Sean , Lord Phillip , Rector Alan , Goble Carole
Published: February 2003

In this article we describe an approach to representing and building ontologies advocated by the Bioinformatics and Medical Informatics groups at the University of Manchester. The hand‐crafting of ontologies offers an easy and rapid avenue to delivering ontologies. Experience has shown that such approaches are unsustainable. Description logic approaches have been shown to offer computational support for building sound, complete and logically consistent ontologies. A new knowledge representation language, DAML + OIL, offers a new standard that is able to support many styles of ontology, from hand‐crafted to full logic‐based descriptions with reasoning support. We describe this language, the OilEd editing tool, reasoning support and a strategy for the language's use. We finish with a current example, in the Gene Ontology Next Generation (GONG) project, that uses DAML + OIL as the basis for moving the Gene Ontology from its current hand‐crafted, form to one that uses logical descriptions of a concept's properties to deliver a more complete version of the ontology. Copyright © 2003 John Wiley & Sons, Ltd.
The MGED ontology: a framework for describing functional genomics experiments
Authors: Stoeckert Christian J. , Parkinson Helen
Published: February 2003

The Microarray Gene Expression Data (MGED) society was formed with an initial focus on experiments involving microarray technology. Despite the diversity of applications, there are common concepts used and a common need to capture experimental information in a standardized manner. In building the MGED ontology, it was recognized that it would be impractical to cover all the different types of experiments on all the different types of organisms by listing and defining all the types of organisms and their properties. Our solution was to create a framework for describing microarray experiments with an initial focus on the biological sample and its manipulation. For concepts that are common for many species, we could provide a manageable listing of controlled terms. For concepts that are species‐specific or whose values cannot be readily listed, we created an ‘OntologyEntry’ concept that referenced an external resource. The MGED ontology is a work in progress that needs additional instances and particularly needs constraints to be added. The ontology currently covers the experimental sample and design, and we have begun capturing aspects of the microarrays themselves as well. The primary application of the ontology will be to develop forms for entering information into databases, and consequently allowing queries, taking advantage of the structure provided by the ontology. The application of an ontology of experimental conditions extends beyond microarray experiments and, as the scope of MGED includes other aspects of functional genomics, so too will the MGED ontology. Copyright © 2003 John Wiley & Sons, Ltd.
A relational database for the discovery of genes encoding amino acid biosynthetic enzymes in pathogenic fungi
Authors: Giles Peter F. , Soanes Darren M. , Talbot Nicholas J.
Published: February 2003

Fungal phytopathogens continue to cause major economic impact, either directly, through crop losses, or due to the costs of fungicide application. Attempts to understand these organisms are hampered by a lack of fungal genome sequence data. A need exists, however, to develop specific bioinformatics tools to collate and analyse the sequence data that currently is available. A web‐accessible gene discovery database (http://cogeme.ex.ac.uk/biosynthesis.html) was developed as a demonstration tool for the analysis of metabolic and signal transduction pathways in pathogenic fungi using incomplete gene inventories. Using Bayesian probability to analyse the currently available gene information from pathogenic fungi, we provide evidence that the obligate pathogen Blumeria graminis possesses all amino acid biosynthetic pathways found in free‐living fungi, such as Saccharomyces cerevisiae. Phylogenetic analysis was also used to deduce a gene history of succinate‐semialdehyde dehydrogenase, an enzyme in the glutamate and lysine biosynthesis pathways. The database provides a tool and methodology to researchers to direct experimentation towards predicting pathway conservation in pathogenic microorganisms. Copyright © 2003 John Wiley & Sons, Ltd.
An approach to inferring transcriptional regulation among genes from large‐scale expression data
Authors: Herrero Javier , Díaz‐Uriarte Ramón , Dopazo Joaquín
Published: February 2003

The use of DNA microarrays opens up the possibility of measuring the expression levels of thousands of genes simultaneously under different conditions. Time‐course experiments allow researchers to study the dynamics of gene interactions. The inference of genetic networks from such measures can give important insights for the understanding of a variety of biological problems. Most of the existing methods for genetic network reconstruction require many experimental data points, or can only be applied to the reconstruction of small subnetworks. Here we present a method that reduces the dimensionality of the dataset and then extracts the significant dynamic correlations among genes. The method requires a number of points achievable in common time‐course experiments. Copyright © 2003 John Wiley & Sons, Ltd.
Early gene expression in wounded human keratinocytes revealed by DNA microarray analysis
Authors: Dayem Manal A. , Moreilhon Chimène , Turchi Laurent , Magnone Virginie , Christen Richard , Ponzio Gilles , Barbry Pascal
Published: February 2003

Wound healing involves several steps: spreading of the cells, migration and proliferation. We have profiled gene expression during the early events of wound healing in normal human keratinocytes with a home‐made DNA microarray containing about 1000 relevant human probes. An original wounding machine was used, that allows the wounding of up to 40% of the surface of a confluent monolayer of cultured cells grown on a Petri dish (compared with 5% with a classical ‘scratch’ method). The two aims of the present study were: (a) to validate a limited number of genes by comparing the expression levels obtained with this technique with those found in the literature; (b) to combine the use of the wounding machine with DNA microarray analysis for large‐scale detection of the molecular events triggered during the early stages of the wound‐healing process. The time‐courses of RNA expression observed at 0.5, 1.5, 3, 6 and 15 h after wounding for genes such as c‐Fos, c‐Jun, Egr1, the plasminogen activator PLAU (uPA) and the signal transducer and transcription activator STAT3, were consistent with previously published data. This suggests that our methodologies are able to perform quantitative measurement of gene expression. Transcripts encoding two zinc finger proteins, ZFP36 and ZNF161, and the tumour necrosis factor α‐induced protein TNFAIP3, were also overexpressed after wounding. The role of the p38 mitogen‐activated protein kinase (p38MAPK) in wound healing was shown after the inhibition of p38 by SB203580, but our results also suggest the existence of surrogate activating pathways. Copyright © 2003 John Wiley & Sons, Ltd.
Genomics and ethics: the case of cloned and/or transgenic animals
Authors: de Montera Béatrice
Published: February 2003

The point of the present study is to illustrate and, if possible, promote the existing link between genomics and ethics, taking the example of cloned and transgenic animals. These ‘new animals’ raise theoretical and practical problems that concern applied ethics. We will explore more particularly an original strategy showing that it is possible, starting from philosophical questioning about the nature of identity, to use a genomic approach, based on amplification fragment length polymorphism (AFLP) and methylation‐sensitive amplification polymorphism (MSAP) detection, to provide useful tools to define more rigorously what cloned animals are, by testing their genetic and epigenetic identity. We expect from the future results of this combined approach to stimulate the creativity of the philosophical and ethical reflection about the impact of biotechnology on animals, and to increase scientific involvement in such issues. Copyright © 2003 John Wiley & Sons, Ltd.
Why chloroplasts and mitochondria contain genomes
Authors: Allen John F.
Published: February 2003

Chloroplasts and mitochondria originated as bacterial symbionts. The larger, host cells acquired genetic information from their prokaryotic guests by lateral gene transfer. The prokaryotically‐derived genes of the eukaryotic cell nucleus now function to encode the great majority of chloroplast and mitochondrial proteins, as well as many proteins of the nucleus and cytosol. Genes are copied and moved between cellular compartments with relative ease, and there is no established obstacle to successful import of any protein precursor from the cytosol. Yet chloroplasts and mitochondria have not abdicated all genes and gene expression to the nucleus and to cytosolic translation. What, then, do chloroplast‐ and mitochondrially‐encoded proteins have in common that confers a selective advantage on the cytoplasmic location of their genes? The proposal advanced here is that co‐location of chloroplast and mitochondrial genes with their gene products is required for rapid and direct regulatory coupling. Redox control of gene expression is suggested as the common feature of those chloroplast and mitochondrial proteins that are encoded in situ. Recent evidence is consistent with this hypothesis, and its underlying assumptions and predictions are described. Copyright © 2003 John Wiley & Sons, Ltd.
Pressures in archaeal protein coding genes: a comparative study
Authors: Chattopadhyay Sujay , Sahoo Satyabrata , Kanner William A. , Chakrabarti Jayprokas
Published: February 2003

Our studies on the bases of codons from 11 completely sequenced archaeal genomes show that, as we move from GC‐rich to AT‐rich protein‐coding gene‐containing species, the differences between G and C and between A and T, the purine load (AG content), and also the overall persistence (i.e. the tendency of a base to be followed by the same base) within codons, all increase almost simultaneously, although the extent of increase is different over the three positions within codons. These findings suggest that the deviations from the second parity rule (through the increasing differences between complementary base contents) and the increasing purine load hinder the chance of formation of the intra‐strand Watson–Crick base‐paired secondary structures in mRNAs (synonymous with the protein‐coding genes we dealt with), thereby increasing the translational efficiency. We hypothesize that the AT‐rich protein‐coding gene‐containing archaeal species might have better translational efficiency than their GC‐rich counterparts. Copyright © 2003 John Wiley & Sons, Ltd.
Turning informal thesauri into formal ontologies: a feasibility study on biomedical knowledge re‐use
Authors: Hahn Udo
Published: February 2003

This paper reports a large‐scale knowledge conversion and curation experiment. Biomedical domain knowledge from a semantically weak and shallow terminological resource, the UMLS, is transformed into a rigorous description logics format. This way, the broad coverage of the UMLS is combined with inference mechanisms for consistency and cycle checking. They are the key to proper cleansing of the knowledge directly imported from the UMLS, as well as subsequent updating, maintenance and refinement of large knowledge repositories. The emerging biomedical knowledge base currently comprises more than 240 000 conceptual entities and hence constitutes one of the largest formal knowledge repositories ever built. Copyright © 2003 John Wiley & Sons, Ltd.
Building a cell and anatomy ontology of Caenorhabditis elegans
Authors: Lee Raymond Y. N. , Sternberg Paul W.
Published: February 2003

We are endowed with a rich knowledge about Caenorhabditis elegans. Its stereotyped anatomy and development has stimulated research and resulted in the accumulation of cell‐based information concerning gene expression, and the role of specific cells in developmental signalling and behavioural circuits. To make the information more accessible to sophisticated queries and automated retrieval systems, WormBase has begun to construct a C. elegans cell and anatomy ontology. Here we present our strategies and progress. Copyright © 2003 John Wiley & Sons, Ltd.
Bringing ontology to the Gene Ontology
Authors: Williams Jennifer , Andersen William
Published: February 2003

We present an analysis of some considerations involved in expressing the Gene Ontology (GO) as a machine‐processible ontology, reflecting principles of formal ontology. GO is a controlled vocabulary that is intended to facilitate communication between biologists by standardizing usage of terms in database annotations. Making such controlled vocabularies maximally useful in support of bioinformatics applications requires explicating in machine‐processible form the implicit background information that enables human users to interpret the meaning of the vocabulary terms. In the case of GO, this process would involve rendering the meanings of GO into a formal (logical) language with the help of domain experts, and adding additional information required to support the chosen formalization. A controlled vocabulary augmented in these ways is commonly called an ontology. In this paper, we make a modest exploration to determine the ontological requirements for this extended version of GO. Using the terms within the three GO hierarchies (molecular function, biological process and cellular component), we investigate the facility with which GO concepts can be ontologized, using available tools from the philosophical and ontological engineering literature. Copyright © 2003 John Wiley & Sons, Ltd.
The S. cerevisiae HAP complex, a key regulator of mitochondrial function, coordinates nuclear and mitochondrial gene expression
Authors: Buschlen S. , Amillet J‐M , Guiard B. , Fournier A. , Marcireau C. , Bolotin‐Fukuhara M.
Published: February 2003

We have compared Saccharomyces cerevisiae global gene expression in wild‐type and mutants (Δhap2 and Δhap4) of the HAP transcriptional complex, which has been shown to be necessary for growth on respiratory substrates. Several hundred ORFs are under positive or negative control of this complex and we analyse here in detail the effect of HAP on mitochondria. We found that most of the genes upregulated in the wild‐type strain were involved in organelle functions, but practically none of the downregulated ones. Nuclear genes encoding the different subunits of the respiratory chain complexes figure in the genes more expressed in the wild‐type than in the mutants, as expected, but in this group we also found key components of the mitochondrial translation apparatus. This control of mitochondrial translation may be one of the means of coordinating mitochondrial and nuclear gene expression in elaborating the respiratory chain. In addition, HAP controls the nuclear genes involved in several other mitochondrial processes (import, mitochondrial division) that define the metabolic state of the cell, but not mitochondrial DNA replication and transcription. In most cases, a putative CCAAT‐binding site is present upstream of the ORF, while in others no such sites are present, suggesting the control to be indirect. The large number of genes regulated by the HAP complex, as well as the fact that HAP also regulates some putative transcriptional activators of unknown function, place this complex at a hierarchically high position in the global transcriptional regulation of the cell. Copyright © 2003 John Wiley & Sons, Ltd.
An upper‐level ontology for the biomedical domain
Authors: McCray Alexa T.
Published: February 2003

At the US National Library of Medicine we have developed the Unified Medical Language System (UMLS), whose goal it is to provide integrated access to a large number of biomedical resources by unifying the vocabularies that are used to access those resources. The UMLS currently interrelates some 60 controlled vocabularies in the biomedical domain. The UMLS coverage is quite extensive, including not only many concepts in clinical medicine, but also a large number of concepts applicable to the broad domain of the life sciences. In order to provide an overarching conceptual framework for all UMLS concepts, we developed an upper‐level ontology, called the UMLS semantic network. The semantic network, through its 134 semantic types, provides a consistent categorization of all concepts represented in the UMLS. The 54 links between the semantic types provide the structure for the network and represent important relationships in the biomedical domain. Because of the growing number of information resources that contain genetic information, the UMLS coverage in this area is being expanded. We recently integrated the taxonomy of organisms developed by the NLM's National Center for Biotechnology Information, and we are currently working together with the developers of the Gene Ontology to integrate this resource, as well. As additional, standard, ontologies become publicly available, we expect to integrate these into the UMLS construct. Published in 2003 by John Wiley & Sons, Ltd.
What is the Nature of the First‐Formed Intermediates in the Electrophilic Halogenation of Alkenes, Alkynes, and Allenes?
Authors: Lenoir Dieter , Chiappe Cinzia
Published: February 2003

The π complexes first formed as essential intermediates from alkenes, alkynes, and allenes with bromine have been investigated in different solvents by UV‐spectroscopy in combination with stopped‐flow techniques allowing the determination of the equilibrium constants, Kf. Using alkenes with sterically protected double bonds, such as di‐tert‐butylstilbene and tetraneopentylethylene, the reaction stops at the stage of the 1:1 and 1:2 π complex of the alkene with bromine as persistent species in 1,2‐dichlorethane as solvent. Calculations by state‐of‐art ab initio and DFT methods reproduces the experimentally determined thermodynamic values quite well, and reveal the preferred structures and nature of both complexes for ethene, ethyne, and allene. Consideration of the entropy term reveals that complexes are stabilized in solution owing to reduction of the entropy loss by restricted translations and rotation. According to calculations these species are Mulliken‐outer‐type complexes with no or little charge transfer from bromine to the double or triple bond, respectively. The 1:2 complex has a close structural relationship to the bromonium‐ or bromirenium ion, which is the subsequent intermediate on the reaction coordinate. Steric influences show a strong effect on the Kf value, which can be explained by the polarizibility of the parent system. Addition–elimination often occurs. In bromination of adamantylidenadamantane and its derivatives the reaction stops at the stage of the bromonium ion. The effect of various polar groups situated in equatorial homoallyl positions on the stability of corresponding π complex and bromonium ion has been studied in this series.
Catalytic Hydrogenation by Triruthenium Clusters: A Mechanistic Study with Parahydrogen‐Induced Polarization
Authors: Blazina Damir , Duckett Simon B. , Dyson Paul J. , Lohman Joost A. B.
Published: February 2003

The reactivity of the cluster family [Ru3(CO)12−x(L)x] (in which L=PMe3, PMe2Ph, PPh3 and PCy3, x=1–3) towards hydrogen is described. When x=2, three isomers of [Ru3(H)(μ‐H)(CO)9(L)2] are formed, which differ in the arrangement of their equatorial phosphines. Kinetic studies reveal the presence of intra‐ and inter‐isomer exchange processes with activation parameters and solvent effects indicating the involvement of ruthenium‐ruthenium bond heterolysis and CO loss, respectively. When x=3, reaction with H2 proceeds to form identical products to those found with x=2, while when x=1 a single isomer of [Ru3(H)(μ‐H)(CO)10(L)] is formed. Species [Ru3(H)(μ‐H)(CO)9(L)2] have been shown to play a kinetically significant role in the hydrogenation of an alkyne substrate through initial CO loss, with rates of H2 transfer being explicitly determined for each isomer. A less significant secondary reaction involving loss of L yields a detectable product that contains both a pendant vinyl unit and a bridging hydride ligand. Competing pathways that involve fragmentation to form [Ru(H)2(CO)2(L)(alkyne)] are also observed and shown to be favoured by nonpolar solvents. Kinetic data reveal that catalysis based on [Ru3(CO)10(PPh3)2] is the most efficient although [Ru3(H)(μ‐H)(CO)9(PMe3)2] corresponds to the most active of the detected intermediates.
A Novel Extended Covalent Tripod for Assembling Nine‐Coordinate Lanthanide(III) Podates: A Delicate Balance between Flexibility and Rigidity
Authors: Koeller Sylvain , Bernardinelli Gérald , Bocquet Bernard , Piguet Claude
Published: February 2003

The introduction of long semirigid spacers between the capping carbon atom of the tripod and the unsymmetrical tridentate binding units provides the novel, extended covalent podand tris‐{2‐[2‐(6‐diethylcarbamoylpyridin‐2‐yl)‐1‐ethyl‐1H‐benzoimidazol‐5‐yl‐methoxy]ethyl}methane (L15). Reaction of L15 with lanthanide(III) in acetonitrile produces stable podates [Ln(L15)]3+ (Ln=La–Lu) in which three tridentate binding units are facially organized. These wrap around the nine‐coordinate pseudo‐tricapped trigonal‐prismatic metal ions. The crystal structure of [La(L15)](ClO4)3 (18, LaC67H82N12O18Cl3, trigonal, R3c, Z=6) reveals the formation of a C3‐symmetrical triple‐helical podate. Two slightly different arrangements of the flexible ethylenoxy parts of the spacer are observed in the solid state in agreement with the formation of two conformational isomers (M:m) in a 4:1 ratio. A qualitative analysis of the aromatic diamagnetic anisotropies affecting the NMR signals of [Ln(L15)]3+ (Ln=La, Y, Lu) in solution, combined with the quantitative determination of electron‐induced relaxation in the paramagnetic complex [Nd(L15)]3+, demonstrate that the solid state structure is maintained in solution. This leads to a mixture of two triple‐helical conformers of similar stabilities and that do not interconvert on the NMR timescale between 243 and 343 K. Particular attention has been given to the structural programming of extended covalent tripods for facially organizing unsymmetrical tridentate binding units around LnIII. Photophysical measurements show that L15 efficiently protects the metallic coordination spheres and sensitizes EuIII and TbIII upon UV irradiation.
Experimental and Theoretical Charge Density Study of the Neurotransmitter Taurine
Authors: Hibbs David E. , Austin‐Woods Charles J. , Platts James A. , Overgaard Jacob , Turner Peter
Published: February 2003

The experimental electron density distribution in taurine, 2‐aminoethane sulfonic acid,1, has been determined from high‐resolution X‐ray diffraction data collected at a temperature of 100 K. Taurine crystallizes as a zwitterion in the monoclinic space groupP21/c.Topological analysis of the experimental electron density and a comparison with high‐level theoretical gas‐phase calculations show that the crystal environment has a significant influence on the electronic configuration of the sulfonate moiety in1, which in the crystal is more delocalized than in the gas phase. This crystal effect is mainly due to hydrogen bonding.
Synthesis of α‐(2→5)Neu5Gc Oligomers
Authors: Ren Chien‐Tai , Chen Chien‐Sheng , Yu Yi‐Ping , Tsai Yow‐Fu , Lin Ping‐Yu , Chen Yu‐Ju , Zou Wei , Wu Shih‐Hsiung
Published: February 2003

A facile synthesis of the sialic acid oligomers α‐(2→5)Neu5Gc (1) is presented. Monosaccharides 2–4 with suitable functionality were used as the building blocks. After selective removal of the paired carboxyl and amine protecting groups, the fully protected oligomers were assembled through consecutive coupling of the building blocks by well established peptide coupling techniques. By this approach, fully protected oligomers as large as an octasaccharide were synthesized. Deprotection of these fully protected oligomers was conducted in two steps (LiCl in refluxing pyridine and 0.1 n NaOH) to afford the desired products in high yield. Enzymatic degradation of the octamer with neuraminidase, monitored by capillary electrophoresis (CE), was also accomplished. The stepwise exo‐cleavage adducts were all well separated and identified in the CE spectrum. The strategy described here for solution‐phase synthesis also provides the basis for future solid‐phase synthesis of poly‐α‐(2→5)Neu5Gc.
Cover Picture: Structural Regulation of a Peptide‐Conjugated Graft Copolymer: A Simple Model for Amyloid Formation (Chem. Eur. J. 5/2003)
Authors: Koga Tomoyuki , Taguchi Kazuhiro , Kobuke Yoshiaki , Kinoshita Takatoshi , Higuchi Masahiro
Published: February 2003

The cover picture shows the self‐organization process of the poly(γ‐methyl‐L‐glutamate)‐conjugated graft copolymer in aqueous media. The self‐assembling property and high‐order structure of the peptide derivative can be easily controlled by manipulating the environmental conditions (pH, solution composition, and salt concentration etc.). Only under the condition of low pH or that of low salt concentration did the electrostatic repulsive force based on the protonated amino groups permit the controlled growth of the peptide assembly and the tight packing of hydrophobic peptide chains, resulting in induction of highly‐ordered nanofibril formation with α‐to‐β structural transition. For details see the article by M. Higuchi et al. on p. 1146 ff.
Solid‐Phase Synthesis of the Cyclic Lipononadepsipeptide [N‐Mst(Ser1), D‐Ser4, L‐Thr6, L‐Asp8, L‐Thr9]Syringotoxin
Authors: Bayó Nuria , Jiménez Jose C. , Rivas Luis , Nicolás Ernesto , Albericio Fernando
Published: February 2003

An optimized solid‐phase strategy for the preparation of the cyclic lipononadepsipeptide [N‐Mst(L‐Ser1), D‐Ser4, L‐Thr6, L‐Asp8, L‐Thr9]syringotoxin is reported. The strategy is based on the use of a mild orthogonal protection scheme and the incorporation of the nonproteinogenic amino acid (Z)‐Dhb into the peptide chain as the dipeptide Fmoc‐Thr(tBu)‐(Z)‐Dhb‐OH. The didehydrodipeptide was synthesized by a water‐soluble carbodiimide‐induced β‐elimination of a protected dipeptide containing a residue of Thr with its free hydroxy side chain unprotected.
A New Cryptophane Receptor Featuring Three endo‐Carboxylic Acid Groups: Synthesis, Host Behavior and Structural Study
Authors: Roesky Christian E. O. , Weber Edwin , Rambusch Torsten , Stephan Holger , Gloe Karsten , Czugler Mátyás
Published: February 2003

Examples of a new type of cryptophane molecule incorporating aromatic groups in the bridges (1–4) and, for the first time, being also supplied with three endo‐positional ionizable carboxylic acid functions (1) have been synthesized and characterized. The cryptophane triester 2 yielded a solvate (channel inclusion compound) with trichloromethane and water, the X‐ray crystal structure of which is reported. The complexation of 1 with low‐molecular‐weight alcohols in solution was studied, and the liquid–liquid extraction of different metal ions including alkali (Na+, Cs+), alkaline earth (Mg2+, Ca2+, Sr2+, Ba2+), and the lanthanide metal ions Eu3+ and Yb3+ in an extraction system containing metal nitrate buffer/H2O/1/CHCl3 was examined. Molecular modeling calculations of the cryptophanes 1 and 2, and of the Eu3+ complex of 1 were carried out contributing to the discussion.
An Insight into the Local Aromaticities of Polycyclic Aromatic Hydrocarbons and Fullerenes
Authors: Poater Jordi , Fradera Xavier , Duran Miquel , Solà Miquel
Published: February 2003

In this work we quantify the local aromaticity of six‐membered rings in a series of planar and bowl‐shaped polycyclic aromatic hydrocarbons (PAHs) and fullerenes. The evaluation of local aromaticity has been carried out through the use of structurally (HOMA) and magnetically (NICS) based measures, as well as by the use of a new electronically based indicator of aromaticity, theparadelocalization index (PDI), which is defined as the average of all the Bader delocalization indices betweenpara‐related carbon atoms in six‐membered rings. The series of PAHs selected includes C10H8, C12H8, C14H8, C20H10, C26H12, and C30H12, with benzene and C60taken as references. The change in the local aromaticity of the six‐membered rings on going from benzene to C60is analyzed. Finally, we also compare the aromaticity of C60with that of C70, open [5,6]‐ and closed [6,6]‐C60NH systems, and C60F18.
Instantaneous SmI2/H2O/Amine‐Mediated Reductions in THF
Authors: Dahlén Anders , Hilmersson Göran
Published: February 2003

The SmI2‐mediated reductions of ketones, imines, and α,β‐unsaturated esters have been shown to be instantaneous in the presence of H2O and an amine in THF. The SmI2‐mediated reductions are not only shown to be fast and quantitative by the addition of H2O and an amine, but the workup procedures are also simplified. Competing experiments with SmI2/H2O/amine confirmed that α,β‐unsaturated esters could be selectively reduced in the presence of ketones or imines. Comparison of analogue ligands showed that nitrogen and phosphorus ligands are superior to oxygen and sulfur ligands in these reductions. The trialkylphosphine 1,2‐bis(dimethylphosphino)ethane (DMPE) provided a primary kinetic isotope effect, yielding a kH/kD of 4.5.
The Total Synthesis of (−)‐Callystatin A
Authors: Kalesse Markus , Chary Khandavalli P. , Quitschalle Monika , Burzlaff Arne , Kasper Cornelia , Scheper Thomas
Published: February 2003

Callystatin A is a prominent member of a class of natural products which display promising growth inhibition of cancer cells in their biological profile. The challenging structure and the interesting biological activity of (−)‐callystatin A fueled our interest in the synthesis of this marine natural product. We achieved the total synthesis using a highly convergent approach joining four subunits together with a Wittig olefination, a selective Heck reaction and an aldol reaction as the pivotal steps. The aldol reaction as one of the final transformations during the synthesis opens fast access to a variety of structural analogues and circumvents tedious protecting group manipulations. Here we report an improved synthesis utilizing a modified vinyl iodide which shortens the synthesis by two steps. Additionally, first biological results will be reported.
Highly Sensitive Amplified Electronic Detection of DNA By Biocatalyzed Precipitation of an Insoluble Product onto Electrodes
Authors: Patolsky Fernando , Lichtenstein Amir , Willner Itamar
Published: February 2003

The amplified detection of a target DNA, based on the alkaline phosphatase oxidative hydrolysis of the soluble 5‐bromo‐4‐chloro‐3‐indoyl phosphate to the insoluble indigo product as an amplification path, is addressed by two different sensing configurations. The accumulation of the insoluble product on Au electrodes or Au/quartz crystals alters the interfacial electron‐transfer resistance at the Au electrode or the mass associated with the piezoelectric crystal, thus enabling the quantitative transduction of the DNA sensing by Faradaic impedance spectroscopy or microgravimetric quartz crystal microbalance measurements, respectively. One sensing configuration involves the association of a complex consisting of the target DNA and a biotinylated oligonucleotide to the functionalized transducers. The binding of the avidin/alkaline phosphatase conjugate to the sensing interface followed by the biocatalyzed precipitation provides the amplification path for the analysis of the target DNA. This analysis scheme was used to sense the target DNA with a sensitivity limit that corresponds to 5×10−14 M. The second amplified detection scheme involves the use of a nucleic‐acid‐functionalized alkaline phosphatase as a biocatalytic conjugate for the precipitation of the insoluble product. Following this scheme, the functionalized transducers are interacted with the analyzed sample that was pretreated with the oligonucleotide‐modified alkaline phosphatase, followed by the biocatalyzed precipitation as the amplification route for the analysis of the target DNA. By the use of this configuration, a detection limit corresponding to 5×10−13 M was achieved. Real clinical samples of the Tay–Sachs genetic disorder were easily analyzed by the developed detection routes.
Structural Regulation of a Peptide‐Conjugated Graft Copolymer: A Simple Model for Amyloid Formation
Authors: Koga Tomoyuki , Taguchi Kazuhiro , Kobuke Yoshiaki , Kinoshita Takatoshi , Higuchi Masahiro
Published: February 2003

The self‐assembly of peptides and proteins into β‐sheet‐rich high‐order structures has attracted much attention as a result of the characteristic nanostructure of these assemblies and because of their association with neurodegenerative diseases. Here we report the structural and conformational properties of a peptide‐conjugated graft copolymer, poly(γ‐methyl‐L‐glutamate) grafted polyallylamine (1) in a water‐2,2,2‐trifluoroethanol solution as a simple model for amyloid formation. Atomic force microscopy revealed that the globular peptide 1 self‐assembles into nonbranching fibrils that are about 4 nm in height under certain conditions. These fibrils are rich in β‐sheets and, similar to authentic amyloid fibrils, bind the amyloidophilic dye Congo red. The secondary and quaternary structures of the peptide 1 can be controlled by manipulating the pH, solution composition, and salt concentration; this indicates that the three‐dimensional packing arrangement of peptide chains is the key factor for such fibril formation. Furthermore, the addition of carboxylic acid‐terminated poly(ethylene glycol), which interacts with both of amino groups of 1 and hydrophobic PMLG chains, was found to obviously inhibit the α‐to‐β structural transition for non‐assembled peptide 1 and to partially cause a β‐to‐α structural transition against the 1‐assembly in the β‐sheet form. These findings demonstrate that the amyloid fibril formation is not restricted to specific protein sequences but rather is a generic property of peptides. The ability to control the assembled structure of the peptide should provide useful information not only for understanding the amyloid fibril formation, but also for developing novel peptide‐based material with well‐defined nanostructures.
Complexation Behavior of a Highly Preorganized 7,7‐Diphenylnorbornane‐Derived Macrocycle: Towards the Design of Molecular Clocks
Authors: García Martínez Antonio , Osío Barcina José , del Rosario Colorado Heras María , de Fresno Cerezo Álvaro , del Rosario Torres Salvador María
Published: February 2003

The syntheses of two new cyclophane hosts, 4 and 6, are described. The main difference between them is the higher degree of preorganization of 4 as a consequence of the inclusion of the 7,7‐diphenylnorbornane (DPN) subunit. The inner cavity of 4 adopts a belt‐shaped structure, while 6 has a twisted geometry. In the solid state, the molecules of macrocycle 6 are stacked along an axis to form nanotubular structures. Compounds 4 and 6 form two of the strongest complexes between arene cyclophanes and Ag+ reported up to date. The silver cation is located inside the cavity of the macrocycles. The stability of 4⋅Ag+ is considerably higher than that of 6⋅Ag+. The additional stabilization of 4⋅Ag+ is attributed to higher preorganization of macrocycle 4. DNMR experiments as well as theoretical calculations carried out with 4⋅Ag+ show evidence of Ag+‐hopping between two different binding sites inside the macrocycle. This phenomenon could be the basis for the design of molecular clocks.
A Theoretical Study on the Complete Catalytic Cycle of the Hetero‐Pauson–Khand‐Type [2+2+1] Cycloaddition Reaction of Ketimines, Carbon Monoxide and Ethylene Catalyzed by Iron Carbonyl Complexes
Authors: Imhof Wolfgang , Anders Ernst , Göbel Angela , Görls Helmar
Published: February 2003

The [2+2+1] cycloaddition reaction of 1,4‐diazabutadienes, carbon monoxide and ethylene catalyzed by iron carbonyl complexes produces pyrrolidin‐2‐one derivatives. Only one of the two imine moieties is activated during the catalysis. The mechanism of this cycloaddition reaction is studied by density functional theory at the B3LYP/6‐311++G(d,p) level of theory. In accordance with experimental results, a [(diazabutadiene)Fe(CO)3] complex of square‐pyramidal geometry is used as the starting compound S of the catalytic cycle. Based on experimental experience, the reaction with ethylene is considered to take place before any interaction with carbon monoxide. According to the computational results, the reaction does not proceed by ligand dissociation followed by addition of ethylene and subsequent intramolecular activation steps but by the approach of an ethylene molecule from the base of the square‐pyramidal complex. This reaction yields an intermediate I4 in which ethylene is coordinated to the iron centre and a new CC bond between ethylene and one of the imine groups is formed. The insertion of a terminal carbon monoxide ligand into the metal–carbon bond between ethylene and iron produces the key intermediate I7. The reaction proceeds by metal‐assisted formation of a lactam P. The catalytic cycle is closed by a ligand‐exchange reaction in which the diazabutadiene ligand substitutes P with reformation of S. This reaction pathway is found to be energetically favored over a reductive elimination. It leads to the experimentally observed heterocyclic product P and a reactive [Fe(CO)3] fragment.
A Theoretical Case Study of Type I and Type II β‐Turns
Authors: Czinki Eszter , Császár Attila G. , Perczel András
Published: February 2003

NMR chemical shielding anisotropy tensors have been computed by employing a medium size basis set and the GIAO‐DFT(B3LYP) formalism of electronic structure theory for all of the atoms of type I and type II β‐turn models. The models contain all possible combinations of the amino acid residues Gly, Ala, Val, and Ser, with all possible side‐chain orientations where applicable in a dipeptide. The several hundred structures investigated contain either constrained or optimized ϕ, ψ, and χ dihedral angles. A statistical analysis of the resulting large database was performed and multidimensional (2D and 3D) chemical‐shift/chemical‐shift plots were generated. The 1Hα‐13Cα, 13Cα‐1Hα‐13Cβ, and 13Cα‐1Hα‐13C′ 2D and 3D plots have the notable feature that the conformers clearly cluster in distinct regions. This allows straightforward identification of the backbone and side‐chain conformations of the residues forming β‐turns. Chemical shift calculations on larger For‐(L‐Ala)n‐NH2 (n=4, 6, 8) models, containing a single type I or type II β‐turn, prove that the simple models employed are adequate. A limited number of chemical shift calculations performed at the highly correlated CCSD(T) level prove the adequacy of the computational method chosen. For all nuclei, statistically averaged theoretical and experimental shifts taken from the BioMagnetic Resonance Bank (BMRB) exhibit good correlation. These results confirm and extend our previous findings that chemical shift information from selected multiple‐pulse NMR experiments could be employed directly to extract folding information for polypeptides and proteins.
Vilsmeier Formylation of 5,10,15‐Triphenylcorrole: Expected and Unusual Products
Authors: Paolesse Roberto , Nardis Sara , Venanzi Mariano , Mastroianni Marco , Russo Michele , Fronczek Frank R. , Vicente Maria Graça H.
Published: February 2003

5,10,15‐Triphenylcorrole (1) reacts with the Vilsmeier reagent (POCl3/DMF) to give the corresponding 3‐formyl derivative 3 as the major product. The regioselectivity of the reaction was proven by X‐ray crystallography and only traces of the 2‐formyl isomer were observed. A more polar product is also observed and this compound becomes the major product when an excess of DMF is used for the preparation of the Vilsmeier reagent, while the formation of the 3‐formyl isomer is almost completely suppressed. X‐ray crystallography allowed us to identify this compound as the fully substituted N‐ethane bridged derivative 4, formed from the attack of the Vilsmeier reagent at the inner core of the macrocycle. This compound is unique among porphyrinoid macrocycles, and further confirms the peculiarity of corrole chemistry.
Supramolecular Control of Two‐Dimensional Phase Behavior
Authors: De Feyter Steven , Larsson Mattias , Schuurmans Norbert , Verkuijl Bas , Zoriniants George , Gesquière André , Abdel‐Mottaleb Mohamed M. , van Esch Jan , Feringa Ben L. , van Stam Jan , De Schryver Frans
Published: February 2003

We have used directed two‐component self‐assembly to “pattern” organic monolayers on the nanometer scale at the liquid/solid interface. The ability of the scanning tunneling microscope to investigate structural details in these adlayers was used to gain insight into the two‐component two‐dimensional phase behavior. The components are symmetrically alkylated bisurea derivatives (R1‐urea‐spacer‐urea‐R2; R1, R2=alkyl, spacer=alkyl or bisthiophene). The bisthiophene unit acts as a marker and its bisurea derivative (T2) is a component in all the mixtures investigated. By varying the position of the hydrogen‐bond forming urea groups along the molecule and the length of the alkyl chains of the other components, the effect of 1) hydrogen bonding, 2) molecule length, 3) odd–even effects, and 4) shape complementarity on the two‐dimensional phase behavior was investigated. Insight into the effect of these parameters leads to the control of the two‐dimensional patterning: from randomly intermixed systems to phase separation.
Atomic Properties of Selected Biomolecules: Quantum Topological Atom Types of Hydrogen, Oxygen, Nitrogen and Sulfur Occurring in Natural Amino Acids and Their Derivatives
Authors: Popelier Paul L. A. , Aicken Fiòna M.
Published: February 2003

Molecular electron densities are generated at B3LYP/6‐311+G(2d,p)//HF/6‐31G(d) level for 57 molecules, including one conformation of each naturally occurring amino acid and smaller derived molecules. The electron densities are partitioned into atomic fragments according to the approach of quantum chemical topology (QCT). A set of 547 unique topological atoms is obtained, containing 421 hydrogens, 63 oxygens, 57 nitrogens and 6 sulfurs. Each atom is described by seven properties: volume, kinetic energy, monopole, dipole, quadrupole, octupole and hexadecapole moment. Cluster analysis groups atoms into atom types based on their similarity expressed in the discrete 7D space of atomic properties. Using a separation criterion we distinguish seven hydrogen, six oxygen, two nitrogen and six sulfur atom types.
Ni0‐Catalyzed Cyclotrimerization of 1,3‐Butadiene: A Comprehensive Density Functional Investigation on the Origin of the Selectivity
Authors: Tobisch Sven
Published: February 2003

A comprehensive theoretical investigation of the mechanism for the Ni0‐catalyzed cyclotrimerization of 1,3‐butadiene by the [Ni0(η2‐butadiene)3] active catalyst complex is presented by employing a gradient‐corrected DFT method. All critical elementary processes of the catalytic cycle have been scrutinized, namely, oxidative coupling of two butadienes, butadiene insertion into the allyl–NiII bond, allylic isomerization in both octadienediyl–NiII and dodecatrienediyl–NiII species, and reductive elimination under ring closure. For each of these elementary steps several conceivable routes and also the different stereochemical pathways have been probed. The favorable route for oxidative coupling start from the prevalent [Ni0(η2‐butadiene)3] form of the active catalyst through coupling between the terminal non‐coordinated carbon atoms of two reactive η2‐butadiene moieties; this is assisted by an ancillary butadiene in η2‐mode. The initial η3,η1(C1)‐octadienediyl–NiII product is the active precursor for subsequent butadiene insertion, which preferably takes place into the η3‐allyl–NiII bond. The insertion is driven by a strong thermodynamic force. Therefore, the dodecatrienediyl–NiII products, with the most favorable bis(η3‐allyl),Δ‐trans isomers in particular, represent a thermodynamic sink. Commencing from a preestablished equilibrium between the various bis(η3‐allyl),Δ‐trans forms of the [NiII(dodecatrienediyl)] complex, the major cyclotrimer products, namely all‐t‐CDT, c,c,t‐CDT and c,t,t‐CDT, are formed along competing paths by reductive elimination under ring closure, which is shown to be rate‐controlling. The all‐c‐CDT‐generating path is completely precluded by both thermodynamic and kinetic factors, giving rise to negligibly populated bis(η3‐allyl),Δ‐cis precursor isomers. The regulation of the selectivity of the CDT formation as well as the competition between the two reaction channels for generation of C12‐ and C8‐cycloolefins is elucidated.
Acetylenic Quinoxalinoporphyrazines as Photosensitisers for Photodynamic Therapy
Authors: Mitzel Frieder , FitzGerald Simon , Beeby Andrew , Faust Rüdiger
Published: February 2003

A range of lipo‐ and hydrophilic derivatives of the new class of octaalkynyl tetra‐[6,7]‐quinoxalinoporphyrazines (TQuiPors), analogues of the naphthalocyanines, were prepared in two steps starting from functionalised hexa‐1,5‐diyne‐3,4‐diones. Divalent zinc and magnesium ions were introduced into the macrocyclic core. Whereas the triisopropylsilyl‐, 3,5‐di‐tert‐butylphenyl‐ and 4‐triisopropylsilyloxyphenyl‐terminated acetylenic TQuiPors are lipophilic and hence soluble in standard organic solvents, a polyethylene glycol‐substituted derivative was found to dissolve in DMSO as well as in ethanol/water mixtures. The new chromophores are characterised by intense UV/Vis/NIR absorptions, most notably by bands at 770 nm with extinction coefficients exceeding 500 000 M−1 cm−1. With a view to possible photodynamic therapy applications, the potency of the chromophores to sensitise the formation of singlet oxygen was examined, both qualitatively using a 1,3‐diphenylisobenzofuran assay, and quantitatively by the determination of the singlet oxygen quantum yields. It was found that all TQuiPors produce singlet oxygen when irradiated in the presence of air. In particular, the octaalkynyl Zn‐TQuiPor generates singlet oxygen with a quantum yield of 56 %, thereby rivalling, and, in conjunction with its absorption profile, even exceeding the standards set by established PDT agents. The photostabilities of the TQuiPors were assessed and generally found to be satisfactory, but dependent on the solvent and the wavelength of the incident light.