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Selected AbstractsCorrection: IL-10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoniEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2003C. H. Sadler Vol. 33(4) 2003, pp 880-888 Pages 882 (Fig. 2) and 883 (Fig. 5) The x-axis label in Fig. 2 should have the same sampling times post-infection as Fig. 1. The legend to Fig. 5 should be amended to read: blue nuclei, red collagen and yellow connective tissue or hepatic parenchyma. [source] Timing primate evolution: Lessons from the discordance between molecular and paleontological estimatesEVOLUTIONARY ANTHROPOLOGY, Issue 4 2008M. E. Steiper Abstract The molecular clock has become an increasingly important tool in evolutionary biology and biological anthropology. Nevertheless, a source of contention with respect to this method is the frequent discordance with fossil-based estimates of divergence times. The primate radiation is a case in point: Numerous studies have dated the major primate nodes (reviewed in Steiper and Young,1, 2) and there are many instances where molecular and fossil-based estimates of divergence times differ (Fig. 1). Some investigators have recently focused on phenomena such as stratigraphic dating, the stochastic nature of molecular time estimates, and other sources as potential biases in molecular clock estimates.3, 4 In this paper we do not focus on accuracy or statistical error; rather, we argue that discordance is a predictable phenomenon that provides valuable information about the tempo and mode of primate molecular and morphological evolution. Using this perspective, we reexamine the principal theoretical and methodological factors that lead to discordance between molecular and fossil estimates of the origins of taxa and discuss how a better understanding of these factors can help to improve our understanding of primate evolution. [source] Evolutionary transformation of the hominin shoulderEVOLUTIONARY ANTHROPOLOGY, Issue 5 2007Susan G. Larson Despite the fact that the shoulder is one of the most extensively studied regions in comparative primate and human anatomy, two recent fossil hominin discoveries have revealed quite unexpected morphology. The first is a humerus of the diminutive fossil hominin from the island of Flores, Homo floresiensis (LB1/50), which displays a very low degree of humeral torsion1, 2 (Fig. 1; see Box 1). Modern humans have a high degree of torsion and, since this is commonly viewed as a derived feature shared with hominoids,3,6 one would expect all fossil hominins to display high humeral torsion. The second is the recently discovered Australopithecus afarensis juvenile scapula DIK-1-1 from Dikika, Ethiopia, which seems to most closely resemble those of gorillas.7 This specimen is the first nearly complete scapula known for an early hominin and, given the close phylogenetic relationship between humans and chimpanzees suggested by molecular studies,8,13 one would have expected more similarity to chimpanzees among extant hominoids. [source] Evolution and development of the primate limb skeletonEVOLUTIONARY ANTHROPOLOGY, Issue 3 2002Chi-Hua Chiu Abstract The order Primates is composed of many closely related lineages, each having a relatively well established phylogeny supported by both the fossil record and molecular data.1 Primate evolution is characterized by a series of adaptive radiations beginning early in the Cenozoic era. Studies of these radiations have uncovered two major trends. One is that substantial amounts of morphological diversity have been produced over short periods of evolutionary time.2 The other is that consistent and repeated patterns (variational tendencies3) are detected. Taxa within clades, such as the strepsirrhines of Madagascar and the platyrrhines of the Neotropics, have diversified in body size, substrate preference, and diet.2, 4,6 The diversification of adaptive strategies within such clades is accompanied by repeated patterns of change in cheiridial proportions7, 8 (Fig. 1) and tooth-cusp morphology.9 There are obvious adaptive, natural-selection based explanations for these patterns. The hands and feet are in direct contact with a substrate, so their form would be expected to reflect substrate preference, whereas tooth shape is related directly to the functional demands of masticating foods having different mechanical properties. What remains unclear, however, is the role of developmental and genetic processes that underlie the evolutionary diversity of the primate body plan. Are variational tendencies a signature of constraints in developmental pathways? What is the genetic basis for similar morphological transformations among closely related species? These are a sampling of the types of questions we believe can be addressed by future research integrating evidence from paleontology, comparative morphology, and developmental genetics. [source] Notes on South American Valerianaceae IIFEDDES REPERTORIUM, Issue 5-6 2004F. Weberling Professor em. Entre ValerianapotopensisBriq., descripta para Bolivia, y Valeriana humahuacensisBorsini, descripta para Jujuy, la provincia contigua de la Argentina, no se han encontrado características morfológicas para distinguir ambas especies, por eso éstas estarían unidas bajo del nombre ValerianapotopensisBriq. Por otra parte Valeriana bolivianaBritton y Valeriana bangianaGraebn., serían según Graebner (1906) dos especies distintas, pero no dió caracteres seguros para diferen-ciarlas. En este trabajo se observa que la forma de los frutos de los materiales tomados como tipo y paratipos es diferente, frutos ovados, como descripto para V. boliviana, se observan en unos paratipos, también se ven frutos ancho-ovados con un margen grueso, pero los del lectotipo V. boliviana (Rusby 871 NY) tienen un contorno casi circular como una lenteja, con un margen tenue, casi membranoso como los del lectotipo de V. bangiana (Bang 2415 G). Ni los caracteres vegetativos ni los caracteres de los frutos serían suficientes para poder distinguir V. bangianaGraebn. 1906 de V. bolivianaBritton 1891 como especies separadas. Se observa también que Valeriana variabilisGraebn. sería una forma de Valeriana warburgiiGraebn. La primera especie solo se distinguiría por caracteres poco manifiestos como el indumento de los frutos y los pelos frecuentemente se pierden durante de la maduración de los mismos, estos caracteres no serían suficientes para separar las dos especies. Por lo tanto se considera una nueva combinación, Valeriana warburgiiGraebn. subsp. variabilis(Graebn.) Weberling stat. nov. (© 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) ValerianapotopensisBriq., described from Bolivia, and Valeriana humahuacensisBorsini, described from Jujuy, the neighbouring province of Argentina, cannot be distinguished by reliable distinctive characters. This applies especially to the indument of the fruits, since the fruits of Valeriana often become increasingly glabrescent in advanced stages of development, with the mature fruits being completely bald. Therefore both species should be united under the older name ValerianapotopensisBriq. According to Graebner (1906) Valeriana bangianaGraebn., is to be regarded as separate species, differing from Valeriana bolivianaBritton by its vigorous densely foliated stem, a character cer-tainly insufficient for a reliable identification. The fruits of V. boliviana are described as "ovatis", which is confirmed by the para-type material of the Mandon collections. In the paratypes the fruits were found to be lanceolate-ovate (Rusby872) or broadly ovate with prominent nerves and a thickened solid margin (Rusby875). However, the fruits of the holotype Rusby 871 (Fig. 12a, b) present a different shape: compressed fruits of nearly circular outline, with a broad flattened some-what membraneous marginal ring. The same form of fruits, although considerably larger, was found in the type material of Valeriana bangiana. Because of the overlapping of the vegetative characters as well as the forms of the fruits V. bangianaGraebn. 1906 cannot be clearly separated from V. bolivianaBritton 1891, and is included into this species. Valeriana warburgiiGraebn. and V. variabilisGraebn. too cannot be separated at species level because of over-lapping characters. Again the indumentum of the fruits is apparently according to several authors the best key character, but is not at all reliable. However, the outline of the fruits shows some differences. Therefore V. variabilis is included into V. warburgii as follows: V. warburgiiGraebn. subsp. variabilis(Graebn.) Weberling stat. nov. [source] M25 roadworks reveal earliest UK Neanderthal occupation at DartfordGEOLOGY TODAY, Issue 5 2010Francis Wenban-Smith As anyone travelling on the roads of southeast England between 2006 and 2008 has probably been aware, major improvements have recently been made at the junction of the M25 and A2 motorways, south of the main Dartford crossing of the River Thames (Fig. 1). The roadworks, funded by the UK Highways Agency, with the main contractors Jacobs Babtie and Costain, were accompanied by archaeological investigations carried out by Oxford Archaeology between 2003 and 2006. The archaeological programme had a major Palaeolithic/Pleistocene element under my direction (Fig. 2) that has produced evidence of Neanderthal occupation early in the last glaciation (the Devensian, which lasted from 115 000 to 10 000 bp), during a period when Britain had until now, been thought to have been entirely deserted. Figure 1. Site location and areas of investigation. Figure 2. The author examines flint artefacts. [source] From clergymen to computers,the advent of virtual palaeontologyGEOLOGY TODAY, Issue 3 2010Russell J. Garwood Palaeontology was established as a science in the Victorian era, yet has roots that stretch deeper into the recesses of history. More than 2000 years ago, the Greek philosopher Aristotle deduced that fossil sea shells were once living organisms, and around 500 ad Xenophanes used fossils to argue that many areas of land must have previously been submarine. In 1027, the Persian scholar Avicenna suggested that organisms were fossilized by petrifying fluids; this theory was accepted by most natural philosophers up until the eighteenth century Enlightenment, and even beyond. The late 1700s were notable for the work of Georges Cuvier who established the reality of extinction. This, coupled with advances in the recognition of faunal successions made by the canal engineer William Smith, laid the framework for the discipline that would become known as palaeontology. As the nineteenth century progressed, the scientific community became increasingly well organized. Most fossil workers were gentleman scientists and members of the clergy, who self-funded their studies in a new and exciting field. Many of the techniques used to study fossils today were developed during this ,classical' period. Perhaps the most fundamental of these is to expose a fossil by splitting the rock housing it, and then conduct investigations based upon the exposed surface (Fig. 1). This approach has served the science well in the last two centuries, having been pivotal to innumerable advances in our understanding of the history of life. Nevertheless, there are many cases where splitting a rock in this way results in incomplete data recovery; those where the fossils are not flattened, but are preserved in three-dimensions. Even the ephemeral soft-tissues of organisms are occasionally preserved in a three-dimensional state, for example in the Herefordshire, La Voulte Sûr Rhone and Orsten ,Fossil Lagerstätten' (sites of exceptional fossil preservation). These rare and precious deposits provide a wealth of information about the history of life on Earth, and are perhaps our most important resource in the quest to understand the palaeobiology of extinct organisms. With the aid of twenty-first century technology, we can now make the most of these opportunities through the field of ,virtual palaeontology',computer-aided visualization of fossils. Figure 1. A split nodule showing the fossil within, in this case a cockroachoid insect. Fossil 4 cm long (From Garwood & Sutton, in press). [source] The Haiti Earthquake: a salutary lesson in (non) earthquake engineeringGEOLOGY TODAY, Issue 2 2010Peter Styles A devastating earthquake of magnitude 7 struck very close and almost beneath Port au Prince the capital of Haiti, the western half of the island of Hispaniola, early in the morning of Tuesday, 12 January 2010 (Fig. 1). While in absolute terms this was by no means the largest earthquake recorded this year globally, the death toll is around 230 000, making it one of the world's worst earthquakes in terms of casualties in recorded history, with almost uncountable economic loss to one of the poorest countries in the world. Figure 1. Intensity map of 2010 Haiti earthquake (Image: USGS). [source] The Swedish Deep Drilling Program: the quest for the Earth's inner secretsGEOLOGY TODAY, Issue 6 2009Henning Lorenz The Swedish Deep Drilling Program (SDDP) has been initiated to study fundamental problems of the dynamic Earth system, its natural history and evolution. Many key scientific questions can be addressed through in situ investigations only, requiring deep continental drilling. Some are unique to Scandinavia, most are of international interest and significance. At present, five core projects (Fig. 1) with international teams are integrating scientific problems with societal and industrial applications. If SDDP succeeds to attract the funding required, Sweden will have a number of world-class boreholes at key locations by 2020. Figure 1. Locations of SDDP drilling project proposals. PFDP,Postglacial Fault Drilling Project; PaMVAS,Palaeoproterozoic mineralized volcanic arc systems: the Skellefte District; COSC,Collisional Orogeny in the Scandinavian Caledonides; DRL,The Dellen Impact Crater, a geoscientific deep rock laboratory; SELHO,Svecofennian accretion, an example of the early structural evolution in a large hot orogen; CISP,Concentric Impact Structures in the Palaeozoic: the Lockne and Siljan craters. Background and inset image from Blue Marble Next Generation data set (NASA Earth Observatory, http://earthobservatory.nasa.gov/Features/BlueMarble/). [source] Domiciliary application of CryoCuff in severe haemophilia: qualitative questionnaire and clinical auditHAEMOPHILIA, Issue 4 2008A. I. D'YOUNG Abstract., The acute management of haemophilic bleeding episodesin the home setting is based on the concept of immediate factor replacement therapy and the PRICE regime , an acronym representing the concepts of Protection, Rest, Ice, Compression and Elevation [1,2]. Integral to this regime is the application of cold therapy, and yet little is known regarding the safe periods of application, or the relative safety of cryotherapy devices such as the CryoCuffÔ when used in the home setting by patients suffering from severe haemophilia and related bleeding disorders. This study examines the subjective patient response to the application of the CryoCuffÔ device in the home setting in terms of the effect on pain, joint swelling and the return to ,pre-bleed status' of the knee, ankle or elbow in patients with severe haemophilia A/B or type III von Willebrand's disease (VWD) immediately following haemarthrosis, and any potential adverse effects related to the device or recommended duration of application as stated in the PRICE guideline (Fig. 1). Twelve patients, either with severe haemophilia A/B or with VWD were recruited and asked to use the CryoCuffÔ device as part of the PRICE regime immediately following the onset of knee-, ankle- or elbow bleeds for the next one year. Each subject was then sent a qualitative questionnaire to determine subjective responses to the device. All patients reported that the application protocol was easy to follow, they were able to apply the device as per the PRICE regime and they were able to tolerate it for the recommended period. Whereas, all the patients felt that the device had a significant impact on alleviation of pain and return to pre-bleed status, 78% of the patients felt that the device led to a significant reduction in swelling around the affected joint. There was no conclusive evidence that the device resulted in any reduction in the amount of factor used to treat the acute bleeding episode, however, no patients reported any perceived delay in achieving haemostasis or required extra factor replacement therapy consequent to the usage of the device. No other adverse effects were reported by participants in this study. Figure 1. ,The qualitative participant questionnaire, given following 1 year of unsupervised use in the home setting immediately following the onset of the symptoms of haemarthroses. [source] Brain Imaging in Migraine ResearchHEADACHE, Issue 9 2010David Borsook MD Understanding the pathophysiology and pharmacology of migraine has been driven by astute clinical observations, elegant experimental medicine studies, and importantly by studying highly effective anti-migraine agents in the laboratory and the clinic. Significant progress has been made in the use of functional brain imaging to compliment observational studies of migraine phenotypes by highlighting pathways within the brain that may be involved in predisposition to migraine, modulating migraine pain or that could be sensitive to pharmacological or behavioral therapeutic intervention (Fig. 1). In drug discovery, molecular imaging approaches compliment functional neuroimaging by visualizing migraine drug targets within the brain. Molecular imaging enables the selection and evaluation of drug candidates by confirming that they engage their targets sufficiently at well tolerated doses to test our therapeutic hypotheses. Figure 1.,. Imaging and defining the migraine brain disease state: from anatomy to chemical entities (targets) to functional systems (function and pathways) (from Borsook et al31 with permission, Nature Publishing Group). Migraine is a progressive disorder. Developing our knowledge of where drugs act in the brain and of how the brain is altered in both episodic migraine (interictal state and ictal state) and chronic migraine are important steps to understanding why there is such differential responsiveness to therapeutics among migraine patients and to improving how they are evaluated and treated. [source] Stereochemical Models for Discussing Additions to ,,, -Unsaturated Aldehydes Organocatalyzed by Diarylprolinol or Imidazolidinone Derivatives , Is There an ,(E)/(Z)-Dilemma'?HELVETICA CHIMICA ACTA, Issue 4 2010Dieter Seebach Abstract The structures of iminium salts formed from diarylprolinol or imidazolidinone derivatives and ,,, -unsaturated aldehydes have been studied by X-ray powder diffraction (Fig.,1), single-crystal X-ray analyses (Table,1), NMR spectroscopy (Tables,2 and 3, Figs.,2,7), and DFT calculations (Helv. Chim. Acta2009, 92, 1, 1225, 2010, 93, 1; Angew. Chem., Int. Ed.2009, 48, 3065). Almost all iminium salts of this type exist in solution as diastereoisomeric mixtures with (E)- and (Z)-configured +NC bond geometries. In this study, (E)/(Z) ratios ranging from 88,:,12 up to 98,:,2 (Tables,2 and 3) and (E)/(Z) interconversions (Figs.,2,7) were observed. Furthermore, the relative rates, at which the (E)- and (Z)-isomers are formed from ammonium salts and ,,, -unsaturated aldehydes, were found to differ from the (E)/(Z) equilibrium ratio in at least two cases (Figs.,4 and 5,,a, and Fig.,6,,a); more (Z)-isomer is formed kinetically than corresponding to its equilibrium fraction. Given that the enantiomeric product ratios observed in reactions mediated by organocatalysts of this type are often ,99,:,1, the (E)-iminium-ion intermediates are proposed to react with nucleophiles faster than the (Z)-isomers (Scheme,5 and Fig.,8). Possible reasons for the higher reactivity of (E)-iminium ions (Figs.,8 and 9) and for the kinetic preference of (Z)-iminium-ion formation are discussed (Scheme,4). The results of related density functional theory (DFT) calculations are also reported (Figs.,10,13 and Table,4). [source] Structures of the Reactive Intermediates in Organocatalysis with Diarylprolinol EthersHELVETICA CHIMICA ACTA, Issue 7 2009Abstract Structures of the reactive intermediates (enamines and iminium ions) of organocatalysis with diarylprolinol derivatives have been determined. To this end, diarylprolinol methyl and silyl ethers, 1, and aldehydes, PhCH2CHO, tBuCH2CHO, PhCH=CHCHO, are condensed to the corresponding enamines, A and 3 (Scheme,2), and cinnamoylidene iminium salts, B and 4 (Scheme,3). These are isolated and fully characterized by melting/decomposition points, [,]D, elemental analysis, IR and NMR spectroscopy, and high-resolution mass spectrometry (HR-MS). Salts with BF4, PF6, SbF6, and the weakly coordinating Al[OC(CF3)3]4 anion were prepared. X-Ray crystal structures of an enamine and of six iminium salts have been obtained and are described herein (Figs.,2 and 4,8, and Tables,2 and 7) and in a previous preliminary communication (Helv. Chim. Acta2008, 91, 1999). According to the NMR spectra (in CDCl3, (D6)DMSO, (D6)acetone, or CD3OD; Table,1), the major isomers 4 of the iminium salts have (E)-configuration of the exocyclic NC(1,) bond, but there are up to 11% of the (Z)-isomer present in these solutions (Fig.,1). In all crystal structures, the iminium ions have (E)-configuration, and the conformation around the exocyclic N-CC-O bond is synclinal-exo (cf.C and L), with one of the phenyl groups over the pyrrolidine ring, and the RO group over the , -system. One of the meta -substituents (Me in 4b, CF3 in 4c and 4e) on a 3,5-disubstituted phenyl group is also located in the space above the , -system. DFT Calculations at various levels of theory (Tables,3,6) confirm that the experimentally determined structures (cf. Fig.,10) are by far (up to 8.3,kcal/mol) the most stable ones. Implications of the results with respect to the mechanism of organocatalysis by diarylprolinol derivatives are discussed. [source] 5-Benzyl-3-methylimidazolidin-4-one-Derived Reactive Intermediates of Organocatalysis , A Comforting Resemblance of X-Ray, NMR, and DFT Solid-Phase, Liquid-Phase, and Gas-Phase StructuresHELVETICA CHIMICA ACTA, Issue 1 2009Abstract The X-ray crystal structures of three (E)-1-cinnamoylidene iminium PF6 salts of 5-benzyl-3-methylimidazolidin-4-ones (2,2-dimethyl-, cis -2-(tert -butyl)-, and cis -2-styryl-substituted; 2,4, resp.) are reported (Figs.,3,5). In the 2,2-dimethyl and in the cis -2-styryl derivative, 2 and 4, respectively, a CH bond of the cis -substituent in 2-position points to the center of the benzene ring of the benzyl group above the five-membered ring (Fig.,6,,a and b). NMR Measurements (Fig.,8) provide evidence that the same structure is present in solution, and that a fourth derivative of this type, 5 (Scheme), has (Z)- instead of (E)-configuration around the CN bond. In the cis -2-(tert -butyl) derivative 3, the benzyl group is located over the iminium , -system (Figs.,4 and 6,,c). Overlays with DFT-calculated crotonylidene analogs, A and B, show that the theoretical and experimental structures are almost superimposable (Fig.,9 and Table). The structures are discussed in view of their role as reactive intermediates in organocatalysis and in view of the help synthetic organic chemists may experience from theory. [source] Isolation and X-Ray Structures of Reactive Intermediates of Organocatalysis with Diphenylprolinol Ethers and with ImidazolidinonesHELVETICA CHIMICA ACTA, Issue 11 20085-Repulsion, A Survey, Comparison with Computed Structures, the Geminal-Diaryl Effect at Work, with 1-Acyl-imidazolidinones: The Abstract Reaction of 2-phenylacetaldehyde with the Me3Si ether of diphenyl-prolinol, with removal of H2O, gives a crystalline enamine (1). The HBF4 salts of the MePh2Si ether of diphenyl-prolinol and of 2-(tert -butyl)-3-methyl- and 5-benzyl-2,2,3-trimethyl-1,3-imidazolidin-4-one react with cinnamaldehyde to give crystalline iminium salts 2, 3, and 4. Single crystals of the enamine and of two iminium salts, 2 and 3, were subjected to X-ray structure analysis (Figs.,1, 2, and 6), and a 2D-NMR spectrum of the third iminium salt was recorded (Fig.,7). The crystal and NMR structures confirm the commonly accepted, general structures of the two types of reactive intermediates in organocatalysis with the five-membered heterocycles, i.e., D, E (Scheme,2). Fine details of the crystal structures are discussed in view of the observed stereoselectivities of the corresponding reactions with electrophiles and nucleophiles. The structures 1 and 2 are compared with those of other diphenyl-prolinol derivatives (from the Cambridge File CSD; Table,1) and discussed in connection with other reagents and ligands, containing geminal diaryl groups and being used in enantioselective synthesis (Fig.,4). The iminium ions 3 and 4 are compared with N -acylated imidazolidinones F and G (Figs.,9, 12, and 13, and Table,3), and common structural aspects such as minimalization of 1,5-repulsion (the ,A1,3 -effect'), are discussed. The crystal structures of the simple diphenyl-prolinol,HBF4 salt (Fig.,3) and of Boc- and benzoyl-(tert -butyl)methyl-imidazolidinone (Boc-BMI and Bz-BMI, resp.; Figs.,10 and 11) are also reported. Finally, the crystal structures are compared with previously published theoretical structures, which were obtained from high-level-of-theory DFT calculations (Figs.,5 and 8, and Table,2). Delicate details including pyramidalization of trigonal N-atoms, distortions around iminium CN bonds, shielding of diastereotopic faces, and the , -interaction between a benzene ring and a Me group match so well with, and were actually predicting the experimental results that the question may seem appropriate, whether one will soon start considering to carry out such calculations before going to the laboratory for experimental optimizations. [source] NMR-Solution Structures of Fluoro-Substituted , -Peptides: A 314 -Helix and a Hairpin Turn.HELVETICA CHIMICA ACTA, Issue 12 2007-Fluoro-Amide Group, The First Case of a 90° OCCF Dihedral Angle in an Abstract To further study the preference of the antiperiplanar (ap) conformation in , -fluoro-amide groups, two , -peptides, 1 and 2, containing a (2-F)- ,3hAla and a (2-F)- ,2hPhe residue, have been synthesized. Their NMR-solution structures in CD3OH were determined and compared with those of non-F-substituted analogs, 3 and 4a. While we have found in a previous investigation (Helv. Chim. Acta2005, 88, 266) that a stereospecifically introduced F-substituent in the central position of a , - heptapeptide is capable of ,breaking' the 314 -helical structure by enforcing the FCCO ap -conformation, we could now demonstrate that the same procedure leads to a structure with the unfavorable ca. 90° FCCO dihedral angle, enforced by the 314 -helical folding in a , - tridecapeptide (cf.1; Fig.,4). This is interpreted as a consequence of cooperative folding in the longer , -peptide. A F-substituent placed in the turn section of a , -peptidic hairpin turn was shown to be in an ap -arrangement with respect to the neighboring CO bond (cf.2; Fig.,7). Analysis of the non-F-substituted , -tetrapeptides (with helix-preventing configurations of the two central ,2/,3 -amino acid residues) provides unusually tight hairpin structural clusters (cf.3 and 4a; Figs.,8 and 9). The skeleton of the , -tetrapeptide H-(R),3hVal-(R),2hVal-(R),3hAla-(S),3hPhe-OH (4a) is proposed as a novel, very simple backbone structure for mimicking , -peptidic hairpin turns. [source] A Joint Theoretical and Experimental Insight into the Electronic Structure of Chromophores Derived from 6H,12H -5,11-Methanodibenzo[b,f][1,5]diazocineHELVETICA CHIMICA ACTA, Issue 11 2007Vincent Lemaur Abstract We report on the synthesis and electronic spectra of the chiral, donor-acceptor (push-pull) chromophores (±)- 4 and (±)- 5 with a 6H,12H -5,11-methanodibenzo[b,f][1,5]diazocine scaffold (Scheme,1 and Fig.,2). The electronic structures of these compounds were investigated at a quantum-chemical level (Figs.,2 and 3). The chemical reactivity of 6H,12H -5,11-methanodibenzo[b,f][1,5]diazocine ((±)- 11) towards aromatic electrophilic substitution (Scheme,2 and Table) provided additional information about its electronic structure and confirmed nonnegligible delocalization of the lone pair of the bridge-head N-atoms in this heterocyclic system. [source] Structure,Activity Relationship in the Domain of Odorants Having Marine NotesHELVETICA CHIMICA ACTA, Issue 7 2007Jean-Marc Gaudin Abstract We synthesized or re-synthesized a large series of 2H -1,5-benzodioxepin-3(4H)-ones 9 (Scheme,1), 4,5-dihydro-1-benzoxepin-3(2H)-ones 10 (Schemes 3 and 4) and 5,6,8,9-tetrahydro-7H -benzocyclohepten-7-ones 11 (Schemes 5 and 6), since the lead compound for the olfactory note of perfumes based on marine accords is a well-known benzodioxepinone named Calone 1951® (9b). We meticulously described the odor profile of each synthesized compound and discussed relevant structure,odor relationships (Tables,1,3). In particular, we revealed a correlation between the conformation of the seven-membered ring and the activities of these compounds (Table,4 and Fig.,3). We also clarified the effect of the position and the size of the alkyl substituent at the aromatic ring. [source] A Novel Atisane Diterpenoid from Spiraea japonica var. acutaHELVETICA CHIMICA ACTA, Issue 7 2007Hai-Yang Liu Abstract A novel ent -atisane lactone, spiramilactone E (1), was isolated from Spiraea japonica var. acutaYu. Its structure was elucidated by extensive spectroscopic analyses, and unequivocally confirmed by single-crystal X-ray diffraction (Fig.,2). Compound 1 contains a , -lactone moiety between the 6-OH function and C(20), and ,- configuration for the 7-OH group, in contrast to known related diterpenes previously isolated from the S. japonica complex. [source] Structure-Based Design and Synthesis of the First Weak Non-Phosphate Inhibitors for IspF, an Enzyme in the Non-Mevalonate Pathway of Isoprenoid BiosynthesisHELVETICA CHIMICA ACTA, Issue 6 2007Corinne Baumgartner Abstract In this paper, we describe the structure-based design, synthesis, and biological evaluation of cytosine derivatives and analogues that inhibit IspF, an enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. This pathway is responsible for the biosynthesis of the C5 precursors to isoprenoids, isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2; Scheme,1). The non-mevalonate pathway is the sole source for 1 and 2 in the protozoan Plasmodium parasites. Since mammals exclusively utilize the alternative mevalonate pathway, the enzymes of the non-mevalonate pathway have been identified as attractive new drug targets in the fight against malaria. Based on computer modeling (cf. Figs.,2 and 3), new cytosine derivatives and analogues (Fig.,1) were selected as potential drug-like inhibitors of IspF protein, and synthesized (Schemes,2,5). Determination of the enzyme activity by 13C-NMR spectroscopy in the presence of the new ligands showed inhibitory activities for some of the prepared cytosine and pyridine-2,5-diamine derivatives in the upper micromolar range (IC50 values; Table). The data suggest that it is possible to inhibit IspF protein without binding to the polar diphosphate binding site and the side chain of Asp56,, which interacts with the ribose moiety of the substrate and substrate analogues. Furthermore, a new spacious sub-pocket was discovered which accommodates aromatic spacers between cytosine derivatives or analogues (binding to ,Pocket III') and rings that occupy the flexible hydrophobic region of ,Pocket II'. The proposed binding mode remains to be further validated by X-ray crystallography. [source] Benzo[a]heptalenes from Heptaleno[1,2- c]furans.HELVETICA CHIMICA ACTA, Issue 4 2007Abstract It is shown in this ,Part 2' that heptaleno[1,2- c]furans 1 react thermally in a Diels,Alder -type [4+2] cycloaddition at the furan ring with vinylene carbonate (VC), phenylsulfonylallene (PSA), , -(acetyloxy)acrylonitrile (AAN), and (1Z)-1,2-bis(phenylsulfonyl)ethene (ZSE) to yield the corresponding 1,4-epoxybenzo[d]heptalenes (cf. Schemes,1, 5, 6, and 8). The thermal reaction of 1a and 1b with VC at 130° and 150°, respectively, leads mainly to the 2,3- endo -cyclocarbonates 2,3- endo - 2a and - 2b and in minor amounts to the 2,3- exo -cyclocarbonates 2,3- exo - 2a and - 2b. In some cases, the (P*)- and (M*)-configured epimers were isolated and characterized (Scheme,1). Base-catalyzed cleavage of 2,3- endo - 2 gave the corresponding 2,3-diols 3, which were further transformed via reductive cleavage of their dimesylates 4 into the benzo[a]heptalenes 5a and 5b, respectively (Scheme,2). In another reaction sequence, the 2,3-diols 3 were converted into their cyclic carbonothioates 6, which on treatment with (EtO)3P gave the deoxygenated 1,4-dihydro-1,4-epoxybenzo[d]heptalenes 7. These were rearranged by acid catalysis into the benzo[a]heptalen-4-ols 8a and 8b, respectively (Scheme,2). Cyclocarbonate 2,3- endo - 2b reacted with lithium diisopropylamide (LDA) at ,70° under regioselective ring opening to the 3-hydroxy-substituted benzo[d]heptalen-2-yl carbamate 2,3- endo - 9b (Scheme,3). The latter was O -methylated to 2,3- endo -(P*)- 10b. The further way, to get finally the benzo[a]heptalene 13b with MeO groups in 1,2,3-position, could not be realized due to the fact that we found no way to cleave the carbamate group of 2,3- endo -(P*)- 10b without touching its 1,4-epoxy bridge (Scheme,3). The reaction of 1a with PSA in toluene at 120° was successful, in a way that we found regioisomeric as well as epimeric cycloadducts (Scheme,5). Unfortunately, the attempts to rearrange the products under strong-base catalysis as it had been shown successfully with other furan,PSA adducts were unsuccessful (Scheme,4). The thermal cycloaddition reaction of 1a and 1b with AAN yielded again regioisomeric and epimeric adducts, which could easily be transformed into the corresponding 2- and 3-oxo products (Scheme,6). Only the latter ones could be rearranged with Ac2O/H2SO4 into the corresponding benzo[a]heptalene-3,4-diol diacetates 20a and 20b, respectively, or with trimethylsilyl trifluoromethanesulfonate (TfOSiMe3/Et3N), followed by treatment with NH4Cl/H2O, into the corresponding benzo[a]heptalen-3,4-diols 21a and 21b (Scheme,7). The thermal cycloaddition reaction of 1 with ZSE in toluene gave the cycloadducts 2,3- exo - 22a and - 22b as well as 2- exo,3- endo - 22c in high yields (Scheme,8). All three adducts eliminated, by treatment with base, benzenesulfinic acid and yielded the corresponding 3-(phenylsulfonyl)-1,4-epoxybenzo[d]heptalenes 25. The latter turned out to be excellent Michael acceptors for H2O2 in basic media (Scheme,9). The Michael adducts lost H2O on treatment with Ac2O in pyridine and gave the 3-(phenylsulfonyl)benzo[d]heptalen-2-ones 28a and 3- exo - 28b, respectively. Rearrangement of these compounds in the presence of Ac2O/AcONa lead to the formation of the corresponding 3-(phenylsulfonyl)benzo[a]heptalene-1,2-diol diacetates 30a and 30b, which on treatment with MeONa/MeI gave the corresponding MeO-substituted compounds 31a and 31b. The reductive elimination of the PhSO2 group led finally to the 1,2-dimethoxybenzo[a]heptalenes 32a and 32b. Deprotonation experiments of 32a with t -BuLi/N,N,N,,N,-tetramethylethane-1,2-diamine (tmeda) and quenching with D2O showed that the most acid CH bond is HC(3) (Scheme,9). Some of the new structures were established by X-ray crystal-diffraction analyses (cf. Figs.,1, 3, 4, and 5). Moreover, nine of the new benzo[a]heptalenes were resolved on an anal. Chiralcel OD-H column, and their CD spectra were measured (cf. Figs.,8 and 9). As a result, the 1,2-dimethoxybenzo[a]heptalenes 32a and 32b showed unexpectedly new Cotton -effect bands just below 300,nm, which were assigned to chiral exciton coupling between the heptalene and benzo part of the structurally highly twisted compounds. The PhSO2 -substituted benzo[a]heptalenes 30b and 31b showed, in addition, a further pair of Cotton -effect bands in the range of 275,245,nm, due to chiral exciton coupling of the benzo[a]heptalene chromophore and the phenylsulfonyl chromophore (cf. Fig.,10). [source] A Novel Synthesis of Highly Substituted Perhydropyrrolizines, Perhydroindolizines, and Pyrrolidines: Inhibition of the Peptidyl-Prolyl cis/trans Isomerase (PPIase) Pin1HELVETICA CHIMICA ACTA, Issue 2 2007Romain Siegrist Abstract In this paper, we describe the synthesis and biological evaluation of highly substituted perhydropyrrolizines that inhibit the peptidyl-prolyl cis/trans isomerase (PPIase) Pin1, an oncogenic target. The enzyme selectively catalyzes the cis/trans isomerization of peptide bonds between a phosphorylated serine or threonine, and proline, thereby inducing a conformational change. Such structural modifications play an important role in many cellular events, such as cell-cycle progression, transcriptional regulation, RNA processing, as well as cell proliferation and differentiation. Based on computer modeling (Fig.,2), the new perhydropyrrolizinone derivatives (,)- 1a,b, decorated with two substituents, were selected and synthesized (Schemes,1,3). While enzymatic assays showed no biological activity, 15N,1H-HSQC-NMR spectroscopy revealed that (,)- 1a,b bind to the WW recognition domain of Pin1, apparently in a mode that does not inhibit PPIase activity. To enforce complexation into the larger active site rather than into the tighter WW domain of Pin1 and to enhance the overall binding affinity, we designed a perhydropyrrolizine scaffold substituted with additional aromatic residues (Fig.,5). A novel, straightforward synthesis towards this class of compounds was developed (Schemes,4 and 5), and the racemic compounds (±)- 22a,22d were found to inhibit Pin1 with Ki values (Ki,=,inhibition constant) in the micromolar range (Table,2). To further enhance the potency of these inhibitors, the optically pure ligands (+)- 22a and (+)- 33b,c were prepared (Schemes,6 and 7) and shown to inhibit Pin1 with Ki values down to the single-digit micromolar range. According to 15N,1H-HSQC-NMR spectroscopy and enzymatic activity assays, binding occurs at both the WW domain and the active site of Pin1. Furthermore, the new synthetic protocol towards perhydropyrrolizines was extended to the preparation of highly substituted perhydroindolizine ((±)- 43; Scheme,8) and pyrrolidine ((±)- 48a,b; Scheme,9) derivatives, illustrating a new, potentially general access to these highly substituted heterocycles. [source] A Pair of New Nortriterpene Saponin Epimers from the Roots of Gypsophila oldhamianaHELVETICA CHIMICA ACTA, Issue 5 2006Jian-Guang Luo Abstract A pair of new oleanane-type nortriterpene saponin epimers, neogypsoside,A (1) and B (2) (Fig.,1) with neogypsogenin,A (3) and neogypsogenin,B (4) as the two new aglycons, as well as the two known triterpene saponins 5 and 6(Fig.,1), were isolated from the roots of Gypsophila oldhamiana. Their structures were determined by analysis of their NMR data. A possible biogenetic pathway to the nortriterpene saponins 1 and 2 is proposed (Scheme,2). [source] Uncommon Sesquiterpenoids and New Triterpenoids from Jatropha neopauciflora (Euphorbiaceae)HELVETICA CHIMICA ACTA, Issue 1 2006Abraham García Abstract Eight new terpenoids (1,8) were isolated from the bark of Jatropha neopauciflora, together with eight known compounds. The new isolates include the sesquiterpenoids (1R,2R)-diacetoxycycloax-4(15)-ene (1); (1R,2R)-dihydroxycycloax-4(15)-ene (2), (2R)- , -cadin-4-ene-2,10-diol (3), (2R)- , -cadina-4,9-dien-2-ol (4), (1R,2R)-dihydroxyisodauc-4-en-14-ol (5) and its acetonide 6 (artifact), as well as the two triterpenoids (3,,16,)-16-hydroxylup-20(29)-en-3-yl (E)-3-(4-hydroxyphenyl)prop-2-enoate (7) and (3,,16,)-16-hydroxyolean-18-en-3-yl (E)-3-(4-hydroxyphenyl)prop-2-enoate (8). The structures of these compounds were established by extensive 1D- and 2D-NMR spectroscopic methods, and their absolute configurations were determined by circular-dichroism (CD) experiments, and by X-ray crystallographic analysis (compound 7; Fig.,3). A plausible biosynthesis of the sesquiterpenoids 1,5 is proposed (Scheme), starting from (,)-germacrene D as the common biogenetic precursor. [source] Squadinorlignoside: A Novel 7,9,-Dinorlignan from the Stems of Annona squamosaHELVETICA CHIMICA ACTA, Issue 10 2005Yu-Liang Yang Two new polar lignans, i.e., squadinorlignoside (=,4-[(1E)-1-(hydroxymethyl)-3-(4-hydroxyphenyl)prop-1-en-1-yl]phenyl , - D -glucopyranoside; 1) and (6R,7R,8S)-7a-[(, - D -glucopyranosyl)oxy]-1-methoxyisolariciresinol (2) were isolated from the stems of Annona squamosa, together with eight known lignans and five known neolignans (compounds 3,15; Fig.,1). All of these constituents are reported for the first time from the genus Annona. The structures, absolute configurations, and selected conformational aspects of the new compounds were elucidated spectroscopically. Compound 1 is the first example of a 7,9,-dinorlignan natural product. [source] Synthesis and Characterization of Copper Complexes Containing the Tripodal N7 Ligand Tris{2-[(pyridin-2-ylmethyl)amino]ethyl}amine (=N,-(Pyridin-2-ylmethyl)- N,N -bis{2-[(pyridin-2-ylmethyl)amino]ethyl}ethane-1,2-diamine): Equilibrium, Spectroscopic Data, and Crystal Structures of Mono- and Trinuclear Copper(II) ComplexesHELVETICA CHIMICA ACTA, Issue 9 2005Christian Gérard The stability constants of the CuII chelates with the tripodal heptadentate ligand tris{2-[(2-pyridylmethyl)amino]ethyl}amine (=N,-(pyridin-2-ylmethyl)- N,N -bis{2-[(pyridin-2-ylmethyl)amino]ethyl}ethane-1,2-diamine; tpaa), determined by potentiometry and UV spectrometry, show the formation of [Cu(tpaaH)]3+ and [Cu(tpaa)]2+ species. In the solid state, two mononuclear CuII compounds, [Cu(tpaa)](PF6)2 (1) and [Cu(tpaaH)](ClO4)3,H2O (2), and one trinuclear [Cu3(tpaa)2(ClO4)2](ClO4)4,2,H2O (3) complex were isolated and characterized by IR, UV/VIS, and EPR spectroscopy. An X-ray structure of the mononuclear protonated complex 2 shows that the Cu2+ ion has a distorted square-pyramidal geometry (,=0.21). and the proton is bound to the secondary-amine function of one uncoordinated arm of the tripod ligand (Fig.,4). The crystal lattice for 2 is stabilized by the H-bonds between the N-atom of the free pyridinyl group with the proton of the free secondary-amine function of the neighboring molecule. The linear trinuclear complex 3 consists of two entities of the pyramidal mononuclear complex 1 bound to the third central Cu2+ ion by the free unprotonated arms of the ligands in equatorial position (Fig.,5). The octahedral geometry of the third CuII atom is achieved by two perchlorate anions in the axial positions. The redox properties of 1,3 compounds was examined by cyclic voltammetry. [source] Binding Studies of Asymmetric Pentacoordinate Copper(II) Complexes Containing Phenanthroline and Ethane-1,2-diamine Ligands with Calf-Thymus DNAHELVETICA CHIMICA ACTA, Issue 9 2005Farukh Arjmand New chiral complexes of the composition [MLL,], where HL=1,2-bis(1H -benzimidazol-2-yl)ethane-1,2-diol=H2bimedol, M=CoII, NiII, CuII, and L,=1,10-phenanthroline (phen) or ethane-1,2-diamine (en), were synthesized and characterized. The ligand L exhibited a coordination mode involving the O-atom of only one OH group, the other one being directed away from the metal center. The complexes [Cu(Hbimedol)(en)]Cl (1), [Cu(Hbimedol)(phen)]Cl (2), [Co(Hbimedol)(phen)]Cl (3), [Ni(Hbimedol)(en)]Cl (4), and [Ni(Hbimedol)(phen)]Cl (5) were ionic in nature and stable at room temperature. The donor sets involved in coordination with the metal ions were the O-atom of one OH group and two N-atoms of the two benzimidazole moieties, besides the two N-atoms of phen or en (Fig.,1.). The proposed five-coordinate geometry of 1,5 was established by analysis of spectroscopic data; the ball-and-stick models supported the proposed structures of 1,5 since they showed apparently no strain on any bond and angle. The interaction of complexes 1 and 2 with calf-thymus DNA were carried out by UV/VIS titration, circular dichroism, electrochemical methods, and viscometry. The intrinsic binding constant Kb of 1 and 2 was determined as 1.57,104 and 1.51,104,M,1, respectively, suggesting that both complexes bind strongly to calf-thymus DNA. [source] Facile Synthesis of Diastereoisomerically and Optically Pure 2-Substituted Hexahydro-1H -pyrrolizin-3-onesHELVETICA CHIMICA ACTA, Issue 8 2005Romain Siegrist We report a short synthetic route that provides optically active 2-substituted hexahydro-1H -pyrrolizin-3-ones in four steps from commercially available Boc (tert -but(oxy)carbonyl))-protected proline. Diastereoisomers (,)- 11 and (,)- 12 were assembled from the proline-derived aldehyde (,)- 8 and ylide 9via a Wittig reaction and subsequent catalytic hydrogenation (Scheme,3). Cleavage of the Boc protecting group under acidic conditions, followed by intramolecular cyclization, afforded the desired hexahydro-1H -pyrrolizinones (,)- 1 and (+)- 13. Applying the same protocol to ylide 19 afforded hexahydro-1H -pyrrolizinones (,)- 25 and (,)- 26 (Scheme,5). The absolute configuration of the target compounds was determined by a combination of NMR studies (Figs.,1 and 2) and X-ray crystallographic analysis (Fig.,3). [source] A Novel Coupling 1,3-Dipolar Cycloaddition Sequence as a Three-Component Approach to Highly Fluorescent IndolizinesHELVETICA CHIMICA ACTA, Issue 7 2005Alexandru Indolizines 4 and biindolizines 6 can be synthesized in moderate yields in a consecutive one-pot three-component process by a coupling/1,3-dipolar cycloaddition sequence of a (hetero)arenecarbonyl chloride 1, a terminal alkyne 2, and a suitable 1-(2-oxoethyl) pyridinium bromide 3 or 5, respectively (Schemes,1 and 2). After the Sonogashira coupling, a [2+3] cycloaddition of the in situ formed pyridinium ylide, an allyl-type 1,3-dipole, furnishes a cycloadduct that is instantaneously oxidatively aromatized to give the highly fluorescent indolizine derivatives that were unambiguously characterized by an X-ray-structure analysis of compound 4d (Fig.,1). Additionally, fluorescence studies with pyridinyl-substituted representatives reveal not only that indolizines and biindolizines are highly interesting fluorescence dyes but that their fluorescence color can also be reversibly switched upon altering the pH of the medium. [source] Tris(perfluoroalkyl)silyl Entities as Unexpectedly Potent Tags for the Noncovalent Immobilization of Catalysts by Fluorous,Fluorous Interactions: Application to the Synthesis of Several Perfluoro-Tagged LigandsHELVETICA CHIMICA ACTA, Issue 5 2005Vasyl Andrushko Unexpectedly high retention times were obtained in HPLC investigations for compounds equipped with (C8F17CH2CH2)3Si tags on C8F17 -modified silica gel (Fig.,4). Hence, these tags have a high potential for the noncovalent immobilization of catalysts to be applied in organic solvents, allowing for an easy separation and re-use of the catalyst by filtration and reapplication. The tris(perfluoroalkyl)silyl tag could be incorporated in a straightforward manner into ligands as demonstrated by the synthesis of several prominent classes of ligands (Schemes,4,6). [source] | |||||||||||||||||||