bluuebunny/crossref_metadata_2025 huggingface dataset:
Catalysis through Induced Intramolecularity: What Can Be Learned by Mimicking Enzymes with Carbonyl Compounds that Covalently Bind Substrates?
Authors: Pascal Robert
Published: May 2003

Protein engineering and the use of catalytic antibodies have given substance to the possibility of making artificial enzymes, whereas chemical design has provided functional, though not yet useful, enzyme mimics. This article is devoted to a class of mimics that uses covalent binding to substrates at a site different from the reaction center and that exhibits turnover. These molecular devices are capable of converting the bimolecular reaction of a substrate into a fast intramolecular one and may be defined by the concept of catalysis by induced intramolecularity. As examples of such systems, several reactions of bifunctional substrates that involve catalysis by carbonyl compounds are brought together in this review. Their ability to catalyze difficult reactions such as the hydrolysis of unactivated amides by mimicking enzyme−substrate complementarity is the result of a uniform stabilization of bound species, including both the transition state and also encounter complexes, which is the specific feature of these systems. They allow quantitative analysis of differences between intramolecular and bimolecular processes and support the explanation based on the entropic disadvantage of bimolecular reactions that can be compensated by binding energy as in enzymes. Three‐dimensional energy diagrams are proposed as valuable tools to describe these systems, as well as enzymatic mechanisms and other catalytic mechanisms that take advantage of induced intramolecularity. Unexpectedly, these diagrams are appropriate to a wide field of applications, such as the description of intramolecular and bimolecular reactions, resulting in a dynamic description of the notion of “tight” binding. In addition, the high efficiency of catalysts that covalently bind substrates raises the question of what their contribution may have been in early enzyme evolution. Their potential association with primitive enzymes as catalytic cofactors is considered. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Using the COSYMA System for the Discovery of Synthesis Strategies by Analogy
Authors: Jauffret Philippe , Ostermann Claude , Kaufmann Gérard
Published: May 2003

COSYMA is a computer program whose use is to suggest synthesis strategies for complex organic molecules. During a learning stage, which has been presented in previous papers, strategies (sequences of key reaction steps) are automatically extracted from total syntheses, described in the literature, and stored in a knowledge base. This paper presents the storage of strategies and the use of COSYMA to solve synthetic problems: how strategies applicable to a submitted target molecule are selected, and “instanciated” according to the structural specificities of this target. We provide an example of using COSYMA for discovering synthesis strategies for acromelic acid. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Stereoselective Synthesis of myo‐, neo‐, L‐chiro, D‐chiro, allo‐, scyllo‐, and epi‐Inositol Systems via Conduritols Prepared from p‐Benzoquinone
Authors: Podeschwa Michael , Plettenburg Oliver , vom Brocke Jochen , Block Oliver , Adelt Stephan , Altenbach Hans‐Josef
Published: May 2003

A practical route is described for the flexible preparation of a wide variety of inositol stereoisomers and their polyphosphates. The potential of this approach is demonstrated by the synthesis of myo‐, L‐chiro‐, D‐chiro‐, epi‐, scyllo‐, allo‐, and neo‐inositol systems. Optically pure compounds in either enantiomeric form can be prepared from p‐benzoquinone via enzymatic resolution of a derived conduritol B key intermediate. High‐performance anion‐exchange chromatography with pulsed amperometric detection permits inositol stereoisomers to be resolved and detected with high sensitivity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Solvent and Temperature Effects on Diastereofacial Selectivity: Amines as Co‐Solvents in n‐Butyllithium Addition to α‐Chiral Aldehydes
Authors: Cainelli Gianfranco , Giacomini Daria , Galletti Paola , Quintavalla Arianna
Published: May 2003

Temperature‐dependent selectivity in nucleophilic additions to α‐chiral aldehydes is affected by solvent mixtures. In this context, we investigated the effect on diastereoselectivity of tertiary amines as co‐solvents. Addition of 5 mol% of an amine to hexane strongly influences the anti/syn ratio in the additions of nBuLi to 2‐phenylpropanal and to (2S)‐2‐[(tert‐butyl)dimethylsilyloxy]‐2‐propanal. In these hexane/amine mixtures as reaction solvents, we observed diastereoselectivities higher than those obtained in hexane. In the corresponding Eyring plots of ln(anti/syn) against the reciprocal temperature, we observed inversion temperatures (Tinv), these generally occurring at higher temperatures in the hexane/amine mixtures than in pure hexane. The presence of the inversion temperatures confirms that these tertiary amines take part in the solvation of the starting aldehyde, thus contributing to a solvent effect on facial selectivity. In some cases, the differential entropy of activation is the predominant factor in differentiating the diastereoselectivity among these hexane/amine mixtures. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Stereochemistry of Polyethylated Aromatic Systems
Authors: Marks Vered , Gottlieb Hugo E. , Biali Silvio E.
Published: May 2003

Hexaethylbenzene adopts a conformation with the ethyl groups perpendicular to the aromatic ring and oriented in a fully alternated up‐down arrangement. The synthesis, stereochemistry and rotational barriers of systems possessing two polyethylaryl rings in spatial proximity (e.g., decaethylbiphenyl, octaethylbiphenylene) are reviewed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Synthesis of Ruthenium‐Labelled Tripeptoids with Alternating Amide and Diaryl Ether Bonds
Authors: Leone‐Stumpf Danielle , Lindel Thomas
Published: May 2003

Free‐amino forms of 4‐O‐methyldopamine and 4‐O‐methyltyramine react as nucleophiles in a chemoselective manner with [RuCp]+‐complexed p‐substituted chloroarenes. As a consequence, it is not necessary to use protecting groups for the synthesis of peptoids with alternating amide and diaryl ether bonds. [RuCp]+‐labelled diaryl ether tripeptoids containing DOPA‐ and tyrosine‐derived subunits have been assembled as model compounds. The purification of the charged complexes was conveniently achieved employing aminopropyl‐functionalised silica as a stationary phase. The free‐amino form of tripeptoid 2 resembles the ABB′ partial structure of the macrocyclic bastadins, biologically active natural products from the marine sponge Ianthella. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Knoevenagel Adducts from Reactions between Glutaconate Moieties and Aldehydes and Their Adducts with Primary Amines and Enamines
Authors: Giral Angela Lopez , Mahuteau‐Betzer Florence , Gateau‐Olesker Alice , Marazano Christian
Published: May 2003

Evaluation of an hypothesis regarding the biomimetic synthesis of manzamine alkaloids from the stepwise condensation of malonate, aldehydes and primary amine derivatives is presented. The first part of this study was concentrated on the Knoevenagel reaction, with various aldehydes, of glutaconaldehydes 7 and their ester analogues 17 and 23, in order to prepare stable derivatives of dienes 8. This reaction, previously reported to work only with salicylaldehyde and glutaconic esters, appeared to be difficult to control in the case of the glutaconaldehyde derivative 7a, but was successful when starting from esters 17 and 23. This result allowed the preparation of new dienes 21, 22a−c, and 25. The second part of this paper reports preliminary results concerning the reactivity of diene 21 towards primary amines and aldehyde equivalents. Dienals such as 21 were found to react with primary amines to afford 1,2‐dihydropyridines such as 26 or 27. Diene 21 was also shown to give diastereoisomeric cycloadducts 30 or 32 with enamines or oxazolidine derivatives. The cycloadducts 30 were finally shown to react with n‐butylamine in acidic medium to give rearranged cyclopentenes 36 and 37. Although the synthesis of derivatives such as 9 or 10, corresponding to the AB ring system of manzamine A, by this approach have yet to be successful, the reported results reveal some new aspects of this multicomponent chemistry, some features of which are related to polyketide‐type condensations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Val‐Ala Dipeptide Isosteres by Hydrocyanation of α′‐Amino α,β‐Unsaturated Ketones − Control of Stereoselectivity by the N‐Protecting Group
Authors: Benedetti Fabio , Berti Federico , Garau Gianpiero , Martinuzzi Ivan , Norbedo Stefano
Published: May 2003

Three diastereoisomeric hydroxyethylene isosters of the Val‐Ala dipeptide were synthesized from α,β‐unsaturated ketones 1 derived from N‐Boc‐ and N,N‐dibenzyl‐L‐valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β‐cyano ketones with the stereoselectivity depending on the protecting group. N‐Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N‐dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N‐Boc and N,N‐dibenzyl compounds. The cyano alcohols thus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val‐Ala dipeptide. In the first series the hydroxy group and the N‐terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C‐terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4‐hydroxy‐5‐amino acid isosters, and three lactones (23−25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach. (© Wiley‐VCH Verlag GmbH & Co KGaA, 69451 Weinheim, Germany, 2003)
Synthesis and Molecular Modeling Studies of SYNPHOS®, a New, Efficient Diphosphane Ligand For Ruthenium‐Catalyzed Asymmetric Hydrogenation
Authors: Paule Sébastien Duprat de , Jeulin Séverine , Ratovelomanana‐Vidal Virginie , Genêt Jean‐Pierre , Champion Nicolas , Dellis Philippe
Published: May 2003

A new, optically active, atropisomeric diphosphane ligand, (2,3,2′,3′‐tetrahydro‐5,5′‐bi(1,4‐benzodioxin)‐6,6′‐diyl)bis‐(diphenylphosphane) (SYNPHOS®), has been synthesized, characterized, and used in ruthenium‐catalyzed asymmetric hydrogenations. This new ligand has been compared with other atropisomeric diphosphanes (BINAP and MeO‐BIPHEP) with respect to their dihedral angles calculated by molecular modeling and the enantioselectivity of their ruthenium‐mediated hydrogenation reactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Substrates for Investigation of DNA Polymerase Function: Synthesis and Properties of 4′‐C‐Alkylated Oligonucleotides
Authors: Detmer Ilka , Summerer Daniel , Marx Andreas
Published: May 2003

In addition to their potential as diagnostic and therapeutic agents, modified oligonucleotides have also been shown to be highly valuable tools for examination of complex biological processes. Carefully designed nucleotide analogues have therefore found considerable application in investigations of DNA polymerase function and mechanism. To examine the contribution of primarily steric constraints on DNA polymerase selectivity, we have developed a new functional strategy based on the use of modified nucleotide analogues that differ primarily in their steric demand. Here we report the efficient synthesis of modified thymidine analogues bearing 4′‐alkyl groups with varying steric demand, the effects of 4′‐alkylation on sugar puckering, and the incorporation of these analogues into oligonucleotides by use of automated solid‐phase DNA synthesis. We also studied the pairing properties of 4′‐alkylated oligonucleotide duplexes in relation to those of their natural counterparts under a range of buffer conditions. In general, our studies indicate that 4′‐alkylation of thymidines has little effect on nucleoside and oligonucleotide conformation. These results have relevance to the previously reported action of 4′‐alkylated nucleotides and oligonucleotides as probes of DNA polymerase function and mechanism. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Theoretical Studies on Cycloaddition Reactions of 2‐Azaallene Cations with Isocyanates
Authors: Yang Si‐Ya , Sun Cheng‐Ke , Fang De‐Cai
Published: May 2003

The mechanisms of cycloaddition reactions between 2‐azaallene cations and isocyanates have been explored at the B3LYP/6‐31G* level. It is found that [2+2] or [2+4] cycloaddition reactions can take place via an intermediate when 2‐azaallene cations react with 1 or 2 equiv. of isocyanates. The effects of substituents are also reported in the present paper, and the results obtained indicate that electron‐attracting groups on 2‐azaallene cations favor the reaction, and electron‐donating groups on 2‐azaallene cations hinder the reaction. Substituents on isocyanates have the opposite effects. These results have been rationalized with FMO interaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Development of a Functionalizable External β‐Turn Mimic Based on a cis‐Fused 1,7‐Naphthyridine Scaffold
Authors: Rombouts Frederik J. R. , Borggraeve Wim M. De , Delaere David , Froeyen Matheus , Toppet Suzanne M. , Compernolle Frans , Hoornaert Georges J.
Published: May 2003

An intramolecular Diels−Alder strategy using 2(1H)‐pyrazinones was applied to generate a substituted perhydro‐1,7‐naphthyridine ring system that served as a scaffold to construct the type VI β‐turn mimic 2, featuring a cis‐amide linkage between the central i+1 and i+2 residues. The synthesis permits mimicking of the amino acid side chains of the central dipeptide, a unique feature for external‐turn mimics. Modeling studies indicated that the cis‐fused bicyclic system adopts a conformation suitable for induction of a β‐turn when the angular position 8a bears a non‐H substituent. Extensive NMR analysis of an 8a‐methyl derivative 25 confirmed its β‐turn‐inducing properties in various solvents, including water. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Structures of Saturated 5H‐Pyrrolo[1,2‐a][3,1]benzoxazin‐1(2H)‐ones Prepared from 4‐Oxopentanoic Acid and Cyclic Amino Alcohols
Authors: Kivelä Henri , Klika Karel D. , Szabó Angela , Stájer Géza , Pihlaja Kalevi
Published: May 2003

Saturated heterocycles containing two condensed heterocyclic rings and a carbo(bi)cyclic ring have been prepared by the reaction of 4‐oxopentanoic acid (1) with (bi)cyclic amino alcohols. 5H‐Pyrrolo[1,2‐a][3,1]benzoxazin‐1(2H)‐ones 2−5 were formed in the reaction of 1 with trans‐ or cis‐2‐(hydroxymethyl)cyclohexylamines or ‐cyclohexenylamines. With di‐endo‐ or di‐exo‐3‐aminobicyclo[2.2.1]hept‐2‐yl‐ or ‐hept‐5‐en‐2‐ylmethanols, 1 yielded the corresponding derivatives 6−9 that are methylene‐bridged in the cyclohexane or cyclohexene rings. The stereoselectivity of the syntheses were high; only for 5, 7 and 9 were both C‐3a epimers produced in observable amounts. The structures were established by means of NMR spectroscopic methods by applying standard pulse techniques. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Synthesis of Nitrile Oligomers through Multiple Anion Capture Reactions of Allene Dianions
Authors: Langer Peter , Döring Manfred , Seyferth Dietmar , Görls Helmar
Published: May 2003

Domino reactions between 1,1‐dilithio‐3,3‐diphenylallene and nitriles resulted in the formation of products containing up to four nitrile molecules, representing the highest number to date of nitrile molecules involved in the formation of unambiguously characterized oligomers. The unusual domino process reported constitutes a new method for the synthesis of imidazoles. The solid‐state structures of the sterically encumbered products were studied by crystal structure analyses. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Efficient Large‐Scale Synthesis of Picolinic Acid‐Derived Nickel(II) Complexes of Glycine
Authors: Ueki Hisanori , Ellis Trevor K. , Martin Collin H. , Soloshonok Vadim A.
Published: May 2003

An efficient, large‐scale method for the preparation of 2‐[N‐(α‐picolyl)amino]acetophenone (PAAP) and 2‐[N‐(α‐picolyl)amino]benzophenone (PABP), the hitherto unknown 4‐methyl‐2‐[N‐(α‐picolyl)amino]benzophenone (4‐Me‐PABP) and 4‐nitro‐2‐[N‐(α‐picolyl)amino]benzophenone (4‐NO2‐PABP), and their corresponding NiII complexes with glycine is described. The key step of the method is the formation of the mixed anhydrides derived from o‐picolinic acid and ethyl chloroformate or p‐toluenesulfonyl chloride. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Di‐ and Trispirocyclopropanated Tetrahydropyridinones
Authors: Gensini Martina , Kozhushkov Sergei I. , Frank Daniel , Vidović Denis , Brandi Alberto , Meijere Armin de
Published: May 2003

A variety of spirocyclopropane‐annelated tetrahydropyridinones of types 14/15 and 18/19 have been prepared in good yields (68−80%) by means of 1,3‐dipolar cycloadditions between nitrones 25, 31, and 34 and cyclopropylidenespiropentane (7) and 7‐cyclopropylidenedispiro[2.0.2.1]heptane (8), with subsequent thermal rearrangement. While the overall reactions of nitrones 25 and 31 with 7‐cyclopropylidenedispiro[2.0.2.1]heptane (8) occurred with the commonly observed regioselectivity (i.e., the initially formed cycloadducts of type 12/13 rearranged to give compounds 29, 30, and 33 as major products), the reactions of 31 and 34 with cyclopropylidenespiropentane (7) and of 34 with 7‐cyclopropylidenedispiro[2.0.2.1]heptane (8) showed an opposite trend. Thermal rearrangement of compound 27 gave a mixture of pyridinone 29 and ring‐opened product 30 (19 and 58% yields, respectively). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
A New and Expedient Diastereoselective Synthesis of α‐(Hydroxyamino)phosphonates and α‐Aminophosphonates by Silyl Triflate Promoted Diethyl Phosphite Addition to Chiral N‐Benzyl Nitrones
Authors: De Risi Carmela , Perrone Daniela , Dondoni Alessandro , Pollini Gian Piero , Bertolasi Valerio
Published: May 2003

An efficient methodology for the synthesis of α‐aminophosphonates has been developed taking advantage of the tert‐butyldimethylsilyl triflate activated addition of diethyl phosphite to N‐benzyl nitrones derived from chiral α‐alkoxy and α‐(Boc‐amino) aldehydes. The stereoselective carbon− phosphorus bond‐forming reaction proceeded smoothly to give α‐(hydroxyamino)phosphonate intermediates as the primary adducts, which were subsequently converted into the corresponding polyhydroxylated α‐amino‐ and α,β‐diaminophosphonates by conventional reductive processes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Conjugate Addition of Phenols to 2‐Nitrogalactal − Synthesis of O‐(2‐Acetamido‐2‐deoxygalactosyl)tyrosine
Authors: Khodair Ahmed I. , Winterfeld Gottfried A. , Schmidt Richard R.
Published: May 2003

2‐Nitrogalactal derivative 1 afforded 2‐deoxy‐2‐nitrogalactopyranosides on treatment with phenol and substituted derivatives under base catalysis. Transformation of the nitro group into the amino and the acetamido groups and O‐deprotection could readily be performed, thus providing aryl 2‐acetamido‐2‐deoxygalactopyranosides 5 and 6 in high yields and with good stereoselectivities. The same reaction sequence could also be successfully applied to N‐Boc‐protected tyrosine methyl ester, to afford the O‐galactopyranonsyl tyrosine derivative 10. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Photochromic Properties of Perhydro‐ and Perfluorodithienylcyclopentene Molecular Switches
Authors: Jong Jaap J. D. de , Lucas Linda N. , Hania Ralph , Pugzlys Audrius , Kellogg Richard M. , Feringa Ben L. , Duppen Koos , Esch Jan H. van
Published: May 2003

Various substituted phenylthienyl perhydro‐ and perfluorocyclopentenes have been synthesized in order to compare their spectroscopic and photochromic properties. The difference in the electron densities of the central cyclopentene moieties in the perhydrocyclopentene and perfluorocyclopentene molecular switches has only a small effect on the absorption maxima of the electronic spectra, but causes some subtle changes in substituent and solvatochromic effects. The photochromic behaviour is remarkably similar, and both type of switches combine excellent quantum yields (0.6) with high degrees of photoconversion (> 0.85). The main difference is the lower photochemical and thermal stability of the perhydrocyclopentene molecular switches. It is concluded that in most studies the perhydrocyclopentenes are an excellent alternative for the perfluorocyclopentenes, while the perfluorocyclopentenes might be better suited for applications such as data storage, which depend critically on fatigue resistance and thermal stability. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Cycloaddition Behavior of 1,2‐Thiaphospholes: Reactions with Diazocumulenes and with Cyclopentadiene
Authors: Kerth Jochen , Jikyo Tamaki , Maas Gerhard
Published: May 2003

1,2‐Thiaphospholes 3a,b react with (1‐diazo‐2‐oxoalkyl)silanes 1a−c to form [1,2]thiaphospholo[2′,3′:3,4][1,3]diphospholo[1,5‐b][1,2]thiaphosphole systems 4 with cis‐anti‐cis configuration of the tricyclic framework. They are accompanied by small amounts of compounds 5 that are presumably the cis‐syn‐cis isomers of 4, and 6‐alkylidene‐1‐phospha‐2‐thiabicyclo[3.1.0]hex‐3‐enes 6. It is likely that these reactions proceed by [3+2] cycloaddition of diazocumulenes, which coexist with diazo compounds as minor equilibrium components, at the P=C bond of the heterophospholes, followed by N2 elimination and formation of short‐lived 2‐alkylidene‐1,2(λ5)thiaphospholes. The latter can either add to excess thiaphosphole to form the tricyclic products or undergo electrocyclization to form bicyclic alkylidenephosphiranes. Thiaphosphole 3a does not seem to react directly with cyclopentadiene in a [4+2] or [2+4] cycloaddition. Reaction with excess cyclopentadiene at 120 °C yields the polycyclic compounds 15 and 16, which are likely to arise from a Diels−Alder reaction of 3a, reacting as a heterodiene, with the cyclopentadiene dimer. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
The First, General, Highly Efficient Method for Preparing Tetrasubstituted Epoxides Using HOF·CH3CN
Authors: Rozen Shlomo , Golan Elizabeth
Published: May 2003

Tetrasubstituted epoxides, and especially electron‐depleted ones, generally are difficult to prepare. HOF·CH3CN complex, probably the best oxygen transfer agent known today, epoxidizes tetrasubstituted alkenes at 0 °C in a matter of minutes or less in excellent yields. HOF·CH3CN complex is very easy to prepare by bubbling diluted fluorine (commercial) through aqueous acetonitrile. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Cover Picture: Substrates for Investigation of DNA Polymerase Function: Synthesis and Properties of 4′‐C‐Alkylated Oligonucleotides (Eur. J. Org. Chem. 10/2003)
Authors: Detmer Ilka , Summerer Daniel , Marx Andreas
Published: May 2003

The cover picture shows the design and structures of 4′‐C‐alkylated thymidines. These modified nucleosides were synthesized and subsequently incorporated into oligonucleotides to probe inherent properties of the DNA double helix (left‐hand) side) and DNA polymerases in their interplay with their DNA substrates (right‐hand side). Details are discussed in the article by I. Detmer, D. Summerer and A. Marx on p. 1837 ff.
Voltametric and Flow Injection Determination of Oxytetracycline Residues in Food Samples Using Carbon Fiber Microelectrodes
Authors: Agüí L. , Guzman A. , Pedrero M. , Yáñez‐Sedeño P. , Pingarrón J. M.
Published: May 2003

A voltammetric method for the determination of the antibiotic oxytetracycline (OTC) in food samples is reported. Carbon fiber microelectrodes (CFMEs), which allow voltammetric measurements to be performed in a small volume (1 mL) of the analyte extract from the samples, are employed. Repeatable electroanalytical responses were obtained with no need of applying cleaning treatments to the CFME. Under the optimized square‐wave conditions, a linear calibration plot for OTC was obtained in the 1.0×10−6–1.0×10−4 mol L−1 range, with a detection limit of 2.9×10−7 mol L−1 (150 ng mL−1) OTC. The determination of OTC by a flow‐injection method with amperometric detection using a homemade flow cell specially designed to work with CFMEs, was also evaluated using pure acetonitrile as the carrier. The SW voltammetric method was applied to the determination of OTC in spiked milk and eggs samples, at 100 ng mL−1 and 200 ng g−1 levels, respectively. The procedure involved the extraction of the analyte in ethyl acetate, evaporation of the solvent and reconstitution of the residue in acetonitrile −5.0×10−4 mol L−1 tetrabutylammonium perchlorate medium. Recoveries of 96±8 and 91±8% were obtained for milk and eggs, respectively, by applying the standard additions method.
Electrochemical Biosensor for the Detection of Interaction Between Arsenic Trioxide and DNA Based on Guanine Signal
Authors: Ozsoz Mehmet , Erdem Arzum , Kara Pinar , Kerman Kagan , Ozkan Dilsat
Published: May 2003

The interaction of arsenic trioxide (As2O3) with calf thymus double‐stranded DNA (dsDNA), calf thymus single‐stranded DNA (ssDNA) and also 17‐mer short oligonucleotide (Probe A) was studied electrochemically by using differential pulse voltammetry (DPV) with carbon paste electrode (CPE) at the surface and also in solution. Potentiometric stripping analysis (PSA) was employed to monitor the interaction of As2O3 with dsDNA in solution phase by using a renewable pencil graphite electrode (PGE). The changes in the experimental parameters such as the concentration of As2O3, and the accumulation time of As2O3 were studied by using DPV; in addition, the reproducibility data for the interaction between DNA and As2O3 was determined by using both electrochemical techniques. After the interaction of As2O3 with dsDNA, the DPV signal of guanine was found to be decreasing when the accumulation time and the concentration of As2O3 were increased. Similar DPV results were also found with ssDNA and oligonucleotide. PSA results observed at a low DNA concentration such as 1 ppm and a different working electrode such as PGE showed that there could be damage to guanine bases. The partition coefficients of As2O3 after interaction with dsDNA and ssDNA in solution by using CPE were calculated. Similarly, the partition coefficients (PC) of As2O3 after interaction with dsDNA in solution was also calculated by PSA at PGE. The features of this proposed method for the detection of DNA damage by As2O3 are discussed and compared with those methods previously reported for the other type of DNA targeted agents in the literature.
Sphere‐Cap Mercury Microelectrodes for Scanning Electrochemical Microscopy Above an Insulating Substrate
Authors: Daniele Salvatore , Bragato Carlo , Ciani Ilenia , Baldo M. Antonietta
Published: May 2003

Sphere‐cap mercury microelectrodes, fabricated onto platinum microdisks 1 and 10 μm radius, were employed as tips in scanning electrochemical microscopy (SECM). Experimental current vs distance curves were acquired above an insulating substrate with a series of sphere caps whose aspect ratio h/a (h is the height of mercury deposit, a is the disk basal radius) varied between 0.28 and 2.14. It was found that the hindered diffusion effect of the insulating surface was the less pronounced the higher was the h/a parameter of the sphere cap. Comparison of experimental and theoretical approach curves displayed a fairly good agreement for subhemisphere caps (ha) caps. Preliminary coupled anodic stripping voltammetry and SECM measurements were also performed for the investigation on local chemical equilibria involving heavy metals at sediment/water interfaces.
Biosorption of Environmentally Relevant Heavy Metals on Selected Biomaterials for Wastewater Treatment
Authors: Ondruschka J. , Bley T.
Published: May 2003

Biosorbents offer a realistic alternative to established processes for the elimination of heavy metals from wastewaters as well as for the recovery of valuable materials. This paper describes and compares the use of different biosorbents occurring as waste products from fermentation processes with regard to their suitability for the purification of metal‐containing wastewaters. Besides the type and concentration of the metals the influence of the oxidation state of the cations and of the pH value of the system on the sorption capacity of the microorganisms are investigated.
Treatment of Rinsing Water from Bottle Washing Machines by Membrane Filtration with the Objective of Reuse
Authors: Rögener F. , Mavrov V. , Chmiel H.
Published: May 2003

This paper presents the processes tested for the pretreatment of rinsing water from bottle washing machines, the objective of which is to retain suspended and colloidal organic and inorganic matter in order to prevent membrane scaling and fouling in the downstream reverse osmosis stage. Microfiltration and ultrafiltration as well as two‐layer anthracite/sand filtration proved to be suitable pretreatment processes. The selection of membranes suitable for producing drinking water from rinsing water and the results from the operation of a demonstration plant in a brewery are also dealt with.
Modeling of PAH Elimination by Adiabatic Steam Stripping and Intraparticle Desorption
Authors: Frishfelds V. , Niemeyer B. , Hoehne J. , Jakovics A.
Published: May 2003

The decontamination process of solids loaded with PAH in a pilot plant is modeled. This process is separated into two main stages: fast steam stripping at the entrance of the separation tube and the subsequent slow desorption of PAH from the interior of the soil particles. The stripping process also occurs in two stages: fast diffusion controlled saturation of the partial pressures followed by the heat transfer controlled evaporation. The phase diagram of PAH/water is constructed using both the microscopic model and empirical relationships for systems with wide miscibility gaps. The numerical basis for the calculations describing desorption from the soil particles is discussed. The model for multiple PAH components is based on Langmuir type isotherms which include surface diffusion terms. The obtained results are contrasted with analytical data for systems displaying linear isotherms by dispersive approximation.
Minimizing Life Cycle Costs of Wastewater Pumps
Authors: Ackermann K.
Published: May 2003

Protecting natural resources often involves new technological challenges. For instance, the decrease per capita in water consumption (including industrial consumption) results in a reduction of the total quantity of wastewater. The resulting higher solid content of wastewater leads to oversized sewers silting up faster, stagnant wastewater, and an increase in its hydrogen sulfide content. Further challenges arise from the economic pressure on disposal plants. The target is to minimize the life cycle cost of wastewater pumps.
Theoretical Characterization of Slurry Fermentation
Authors: Glover K. , Kunz B.
Published: May 2003

This is an extensive study of the three classical fermentation systems (emerged, submerged and solid‐state fermentations), thus uncovering, a system that is an intrinsically concomitant overlap of submerged and solid‐state fermentations – slurry fermentation. It is a convenient method of fermentation with hardly any theoretical characterization. This paper details the specifics of this system and its potential fields of application.
Virtual reality in eating disorders
Authors: Perpiñá C. , Botella C. , Baños R. M.
Published: May 2003

Virtual Reality (VR) is widely used as a therapeutic tool in the field of neuropsychology and also in the treatment of anxiety disorders. In contrast, VR is much less well‐known in the area of the eating disorders. The objective of this paper is to draw attention to possible applications of this technology in the treatment of eating disorders and describe pilot work in the area of body image disturbance and binge eating using VR technology. Copyright © 2003 John Wiley & Sons, Ltd and Eating Disorders Association.
Internet‐based prevention of eating disorders
Authors: Zabinski Marion F. , Celio Angela A. , Jacobs M. Joy , Manwaring Jamie , Wilfley Denise E.
Published: May 2003

Internet technology has greatly influenced communication and information transfer worldwide and has also provided novel avenues for psychological research and treatment delivery. Preliminary research with computerized interventions have been promising and several studies have shown support for electronically delivered programmes related to eating disorder prevention among college‐aged women. Acceptability and efficacy findings for two Internet‐based eating disorders prevention programmes, Student Bodies, an asynchronous intervention, and a synchronous chatroom study, are presented. Initial findings indicate that computerized programmes are promising and future directions of research in this emerging field are discussed. Copyright © 2003 John Wiley & Sons, Ltd and Eating Disorders Association.
Mutational events in LMP1 gene of Epstein‐Barr virus in salivary gland lymphoepithelial carcinomas
Authors: Jen Kai Yu , Cheng Jun , Li Jian , Wu Lanyan , Li Yingfang , Yu Shifeng , Lin Hanliang , Chen Zhilong , Gurtsevitch Vladimir , Saku Takashi
Published: May 2003

It is still unknown what kinds of roles Epstein‐Barr virus (EBV) infection that are highly specific to salivary gland lymphoepithelial carcinomas (LECs) play in their tumorigenesis. To clarify the significance of EBV in LECs, we paid particular attention to the LMP1 gene, which is responsible for triggering several pathways for activating transcription factors. Sixty‐one cases of EBV positive LECs confirmed by PCR and in‐situ hybridization were collected from various areas of the world and studied immunohistochemically for latent membrane protein‐1. Furthermore, PCR for the LMP1 carboxyl (C)‐terminus region was performed, and the PCR products were sequenced for detection of other mutational events. LMP1 gene products were immunohistochemically demonstrated in 51% of the cases, while PCR amplification of the LMP1 gene was successful in 41 cases (67%). Among them, a 30 bp deletion in the C‐terminus of the LMP1 gene, which had been shown to be characteristic to EBV in Chinese nasopharyngeal carcinomas, was found in 20 cases (32%). Most of them were from Guangzhou, Chengdu and Taiwan, while most of the cases from Shanghai and other areas exhibited no 30 bp deletion. In addition, several point mutations including codon 338 of LMP1 were commonly shared by the cases with or without the 30 bp deletion. These results indicate that there are 2 major genomic variations of EBV infecting salivary gland LECs. The frequent mutational events in the C‐terminus in addition to the 30 bp deletion also seem to be critical for the pathogenesis because such mutational events may possibly promote cellular proliferation. © 2003 Wiley‐Liss, Inc.
Antisense treatment against Ki‐67 mRNA inhibits proliferation and tumor growth in vitro and in vivo
Authors: Kausch Ingo , Lingnau Anja , Endl Elmar , Sellmann Kirsten , Deinert Irina , Ratliff Timothy L. , Jocham Dieter , Sczakiel Georg , Gerdes Johannes , Böhle Andreas
Published: May 2003

The Ki‐67 protein is tightly regulated and depends on the proliferative status of a cell. It is present in the nuclei of proliferating cells but absent in resting cells. Since transformation of malignant cells is frequently associated with high cell proliferation and since proliferation is tightly associated with the Ki‐67 protein labeling index, this antigen may represent a potential target for cancer therapy. In the present study we determined the ability of a phosphorothioate antisense oligodeoxyribonucleotide (ODN) targeted against Ki‐67 mRNA to inhibit tumor cell proliferation specifically in cell culture, in multicellular 3‐dimensional spheroids (MCS) and in subcutaneous murine tumor models. Antisense treatment of 1 myeloid and different epithelial tumor cell lines in suspension and monolayer culture, respectively, resulted in specific reduction of Ki‐67 mRNA and protein, inhibition of proliferation and increased apoptotic cell death. Multicellular human bladder carcinoma spheroids lost their 3‐dimensional structure and underwent cell death after incubation with antisense oligonucleotides. The growth of subcutaneous syngeneic prostatic (p = 0.05) and transitional cell tumors (p = 0.001) in immunocompetent mice was significantly inhibited in antisense‐treated animals. From these findings we conclude that antisense inhibition of Ki‐67 protein expression may be a rational approach in anticancer therapy. © 2003 Wiley‐Liss, Inc.
Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men
Authors: Znaor Ariana , Brennan Paul , Gajalakshmi Vendhan , Mathew Aleyamma , Shanta Viswanathan , Varghese Cherian , Boffetta Paolo
Published: May 2003

Oral, pharyngeal and esophageal cancers are 3 of the 5 most common cancer sites in Indian men. To assess the effect of different patterns of smoking, chewing and alcohol drinking in the development of the above 3 neoplasms and to determine the interaction among these habits, we conducted a case‐control study in Chennai and Trivandrum, South India. The cases included 1,563 oral, 636 pharyngeal and 566 esophageal male cancer patients who were compared with 1,711 male disease controls from the 2 centers as well as 1,927 male healthy hospital visitors from Chennai. We observed a significant dose‐response relationship for duration and amount of consumption of the 3 habits with the development of the 3 neoplasms. Tobacco chewing emerged as the strongest risk factor for oral cancer, with the highest odds ratio (OR) for chewing products containing tobacco of 5.05 [95% confidence internal (CI) 4.26–5.97]. The strongest risk factor for pharyngeal and esophageal cancers was tobacco smoking, with ORs of 4.00 (95% CI 3.07–5.22) and 2.83 (95% CI 2.18–3.66) in current smokers, respectively. An independent increase in risk was observed for each habit in the absence of the other 2. For example, the OR of oral cancers for alcohol drinking in never smokers and never chewers was 2.56 (95% CI 1.42–4.64) and that of esophageal cancers was 3.41 (95% CI 1.46–7.99). Furthermore, significant decreases in risks for all 3 cancer sites were observed in subjects who quit smoking even among those who had quit smoking 2–4 years before the interview. © 2003 Wiley‐Liss, Inc.
KLF6, a putative tumor suppressor gene, is mutated in astrocytic gliomas
Authors: Jeng Yung‐Ming , Hsu Hey‐Chi
Published: May 2003

Gliomas are the most common tumors of the central nervous system and have a grave prognosis. Deletion of chromosome 10p15 is one of the most common chromosomal alterations in gliomas. Recently, a candidate tumor suppressor gene, KLF6, which is mapped to chromosome 10p, was found to be frequently mutated in prostate cancer. KLF6 is a zinc finger transcription factor and transactivates p21/WAF1/CIP expression. To elucidate the role of genetic alterations of KLF6 in gliomas, we analyzed the 4 exons of the gene by direct DNA sequencing in 155 gliomas. Of these, mutations of KLF6 were found in 9 of 76 (11.8%) glioblastomas multiforme, 2 of 28 (7.1%) anaplastic astrocytomas, 2 of 36 (5.5%) low‐grade diffuse astrocytomas and in none of the 15 oligodendrogliomas. All 13 mutations were located in the transactivation domain and most of them affected either serine residues or codons next to serine residues. Of the 13 cases with KLF6 mutation, loss of heterozygosity (LOH) at the KLF6 locus was inferred from the LOH displayed by the flanking microsatellite markers in 11 cases. We conclude that mutations of the KLF6 gene play a role in the pathogenesis of astrocytic gliomas. © 2003 Wiley‐Liss, Inc.
EBV‐encoded EBNA‐5 associates with P14ARF in extranucleolar inclusions and prolongs the survival of P14ARF‐expressing cells
Authors: Kashuba Elena , Mattsson Karin , Pokrovskaja Katja , Kiss Csaba , Protopopova Marina , Ehlin‐Henriksson Barbro , Klein George , Szekely Laszlo
Published: May 2003

Epstein‐Barr virus (EBV) carrying lymphoblastoid cells of normal origin express the full program of all 9 virus‐encoded, growth transformation associated proteins. They have an intact p53 pathway as a rule. This raises the question of whether any of the viral proteins impair the pathway functionally. Using a yeast 2‐hybrid system, we have shown that EBNA‐5 but not the other EBNAs interacts with the p14ARF protein, a regulator of the p53 pathway. The interaction was confirmed in vitro using a GST pull‐down assay. Moreover, expression of EBNA‐5 increased the survival of p14ARF‐transfected cells. EBV infection of resting B cells induced the expression of p14ARF mRNA without increased level of the protein. A fraction of the p14ARF localized to the nucleoli but the bulk of the protein accumulated in nuclear but extranucleolar inclusions. Formation of the extranucleolar inclusions led to complete relocalization of EBNA‐5 from nucleoplasm to these structures. The inclusions also contained p53 and HDM2, and were surrounded by PML bodies and proteasomes, which suggests that these inclusions could be targets for proteasome dependent protein degradation. © 2003 Wiley‐Liss, Inc.
Oligogenic segregation analysis of hereditary prostate cancer pedigrees: Evidence for multiple loci affecting age at onset
Authors: Conlon Erin M. , Goode Ellen L. , Gibbs Mark , Stanford Janet L. , Badzioch Michael , Janer Marta , Kolb Suzanne , Hood Lee , Ostrander Elain A. , Jarvik Gail P. , Wijsman Ellen M.
Published: May 2003

Previous studies have suggested strong evidence for a hereditary component to prostate cancer (PC) susceptibility. Here, we analyze 3,796 individuals in 263 PC families recruited as part of the ongoing Prostate Cancer Genetic Research Study (PROGRESS). We use Markov chain Monte Carlo (MCMC) oligogenic segregation analysis to estimate the number of quantitative trait loci (QTLs) and their contribution to the variance in age at onset of hereditary PC (HPC). We estimate 2 covariate effects: diagnosis of PC before and after prostate‐specific antigen (PSA) test availability, and presence/absence of at least 1 blood relative with primary neuroepithelial brain cancer (BC). We find evidence that 2 to 3 QTLs contribute to the variance in age at onset of HPC. The 2 QTLs with the largest contribution to the total variance are both effectively dominant loci. We find that the covariate for diagnosis before and after PSA test availability is important. Our findings for the number of QTLs contributing to HPC and the variance contribution of these QTLs will be instructive in mapping and identifying these genes. © 2003 Wiley‐Liss, Inc.
EBV specific antibody‐based and DNA‐based assays in serologic diagnosis of nasopharyngeal carcinoma
Authors: Chan Kwok H , Gu Yao L , Ng Fai , Ng Park SP , Seto Wing H , Sham Jonathan ST , Chua Daniel , Wei William , Chen Yue L , Luk Winsie , Zong Yong S , Ng Mun H
Published: May 2003

We assessed 5 EBV specific assays for their capacity to effect serologic diagnosis of suspected NPC. The assays were the immunofluorescent assays, VCA IgA and EA IgA, the enzyme‐linked immunosorbent assays specific for EBNA 1 IgA or zta IgG and an EBV DNA assay. Serum samples were taken from 218 symptomatic NPC patients presenting consecutively at a public hospital in Hong Kong, 51 of whom were subsequently diagnosed as having NPC; 4 had EBV‐associated lung cancer with similar serology as NPC. The remaining patients included 23 who had other cancers and 140 who had other diseases. Objectives of serodiagnosis under such clinical settings, therefore, are to both exclude and predict a diagnosis of NPC. None of the assays individually can meet both requirements adequately, however. The difficulty was best overcome by combining EBNA 1 IgA and zta IgG. It was shown that 68.3% of the patients gave a confirmed test results, negative or positive, by both tests. A confirmed negative result was associated with a negative predictive value of 99.1%, providing a clear indication to exclude a diagnosis of NPC; a confirmed positive result was associated with a positive predictive value of 86.8%, providing a clear indication to proceed with diagnostic work‐up of NPC. The remaining patients gave equivocal test results, being positive for one or the other test, which were associated with a positive predictive value of 43.3% and 24.2%, respectively. © 2003 Wiley‐Liss, Inc.
Differential prognostic impact of the cyclins E and B in premenopausal and postmenopausal women with lymph node‐negative breast cancer
Authors: Rudolph Pierre , Kühling Heidi , Alm Per , Fernö Mårten , Baldetorp Bo , Olsson Håkan , Parwaresch Reza
Published: May 2003

Searching for new prognostic factors, we investigated the influence of cyclin expression on breast cancer prognosis. A total of 273 archival tumor specimens from patients with pT1/pT2 N0 breast cancers treated by surgery and local irradiation were immunostained for cyclins E, A and B. Outcome was evaluated as metastasis‐free (MFS) and disease‐specific survival (DSS) over a median observation period of 99 months. In postmenopausal women, DSS was significantly predicted by cyclin E, and in premenopausal patients by cyclin B. No statistical significance was found for cyclin A. When the prognostic impact of cyclins was compared to that of standard prognostic indicators in a multivariate analysis, both cyclin E and cyclin B were selected as independent predictors of survival in postmenopausal and premenopausal patients, respectively. After inclusion of Ki‐67 in the model, cyclin E lost its significance, whereas cyclin B remained the only independent prognostic factor with a hazard ratio of 4.5 (p = 0.026) for tumor‐related death. Assessment of cyclin expression may, therefore, refine current prognostic models if considered in relation to menopausal status. The prognostic relevance of cyclins is likely attributable to an influence on proliferation, cell survival and genetic instability. Awareness of the molecular mechanisms leading to deregulated cyclin expression may guide decisions for risk‐adapted therapy regimens. © 2003 Wiley‐Liss, Inc.