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H M Hoffmann

Publications and source records attributed to H M Hoffmann.

17 recordsLinked to original sources
PubMed2001

The total synthesis of C-glycosides with completely resolved seven-carbon backbone polyol stereochemistry: stereochemical correlations and access to L-configured and other rare carbohydrates.

The de novo synthesis of a full set of hydroxymethyl C-glycosides from only two precursors is described. The seven-carbon target molecules contain five stereocentres and bridge the stereochemical gap between natural D-configured and non-natural L-configured series of hexoses. Key steps include hydroxylation, differential protection, stereoselective reduction and desymmetrization of 8-oxabicyclo[3.2.1]oct-6-enes. C-Terminus differentiation and C-terminus excision of the seven-carbon polyol backbone lead to hexoses, including those of the L-series. A stereochemical and genetic classification of C-glycosides is presented.

Carbohydrate Conformation↗
PubMed2001

Asymmetric synthesis of the northern half C1-C16 of the bryostatins.

Starting from 8-oxabicyclo[3.2.1]oct-6-en-3-one and racemic 2,2-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one, the C1-C16 segment of the bryostatins has been synthesized in 30 steps and 9% overall yield (17 steps longest linear sequence). Fragment coupling by dithiane strategy and protecting group manipulations provided an advanced chemodifferentiated northern half segment.

Antineoplastic Agents↗
PubMed2001

[Infant and child psychiatry in Denmark].

INTRODUCTION: A descriptive epidemiological study of children aged 0-36 months. METHODS: Diagnoses reported from the child psychiatric departments to The National Psychiatric Register were collected from a three-year period 1996, 1997, and 1998. The child psychiatric departments in Denmark filled in a questionnaire concerning referral, assessment, treatment, and consultant/liason functions. All the child psychiatric departments took part in the study. RESULTS: 529 children aged 0-3 years were reported to the National Psychiatric Register. In the period studied, there was a 30% increase in the number of children reported. Adjustment reactions were the commonest diagnosis in the youngest children, aged 0-12 months. Pervasive developmental disorders, particularly infantile autism, were commonest used in the age group 2-3 years. Twenty-four per cent of the children reported, especially the youngest children, had no specific psychiatric diagnosis. The increase in the number of children aged 0-1 year with adjustment reactions and non-specific diagnoses is discussed. Children aged 0-3 years are mainly treated as outpatients or by a consultant/liason child psychiatric service. The children referred to the child psychiatric departments in 1997 varied from fewer than 10 to about 100 children. Infant psychiatric units were established in two places in Denmark, in 1992 and 1997. DISCUSSION: The increasing number of children aged 0-3 years reported to the National Psychiatric Register in the period 1996-1998 reflects an increase in the children aged 2-3 years diagnosed with pervasive developmental disorders, and in the case of the youngest children, aged 0-1 year, a more extensive child psychiatric intervention in relation to populations at risk, such as infants with mentally ill mothers.

Child↗
PubMed2001

Versatile 8-oxabicyclo[3.2.1]oct-6-en-3-one: stereoselective methodology for generating C-glycosides, delta-valerolactones, and polyacetate segments.

[figure: see text] A new rearrangement of functionalized methoxy glycosides and a regioselective as well as stereoselective intramolecular Michael addition giving delta-valerolactones and C-glycosides are described. Applications to the synthesis of marine natural products are reported. Chemoselective deprotection of benzylated hydroxy groups is assumed to be facilitated by 6-endo-tet interaction with the 1,3-dithiane functionality.

Acetates↗
PubMed2000

Synthesis of enantiopure 3-quinuclidinone analogues with three stereogenic centers: (1S,2R,4S)- and (1S,2S, 4S)-2-(Hydroxymethyl)-1-azabicyclo[2.2.2]octan-5-one and stereocontrol of nucleophilic addition to the carbonyl group.

The pseudoenantiomeric title compounds have been prepared from quincorine (QCI) and quincoridine (QCD), respectively, in enantiopure form following an efficient six-step pathway. Nucleophilic attack at the carbonyl group proceeds preferentially from the supposedly more hindered endo pi-face, giving quinuclidinols with natural configuration at C5 (up to 97%). pi-Face selectivity is highest in the QCD series with bulky O-protecting groups, involving an unprecedented 1,7-stereoinduction.

Indicators and Reagents↗
PubMed2000

Synthesis of enantiopure 1-azabicyclo[3.2.2]nonanes via stereoselective capture of chiral carbocations.

[reaction: see text] A new class of doubly functionalized and enantiomerically pure 1-azabicyclo[3.2.2]nonanes derived from quincorine and quincoridine is described. 2,5-Disubstituted quinuclidines with a C9-mesyloxy group were easily transformed into the corresponding halides upon treatment with lithium salts. Subsequent silver salt-mediated ring expansion stereoselectively furnished the title azabicyclics. Chiral carbocations which are configurationally stable and nonplanar are postulated to account for the striking stereoselectivity of the capture of external nucleophile. 5-Ethynyl-2-iodomethylquinuclidines afford the alpha-benzoyloxy amines rather than alpha-methoxy amines, even in MeOH.

Amines↗
PubMed1997

Stage-specific expression of Dlx-5 during osteoblast differentiation: involvement in regulation of osteocalcin gene expression.

Two homeotic genes, Dlx and Msx, appear to regulate development of mineralized tissues, including bone, cartilage, and tooth. Expression of Msx-1 and Msx-2 has been studied during development of the osteoblast phenotype, but the role of Dlx in this context and in the regulation of bone-expressed genes is unknown. We used targeted differential display to isolate homeotic genes of the Dlx family that are expressed at defined stages of osteoblast differentiation. These studies were carried out with fetal rat calvarial cells that produce bone-like tissue in vitro. We observed a mineralization stage-specific mRNA and cloned the corresponding cDNA, which represents the rat homolog of Dlx-5. Northern blot analysis and competitive RT-PCR demonstrated that Dlx-5 and the bone-specific osteocalcin genes exhibit similar up-regulated expression during the mineralization period of osteoblast differentiation. This expression pattern differs from that of Msx-2, which is found predominantly in proliferating osteoblasts. Several approaches were pursued to determine functional consequences of Dlx-5 expression on osteocalcin transcription. Constitutive expression of Dlx-5 in ROS 17/2.8 cells decreased osteocalcin promoter activity in transient assays, and conditional expression of Dlx-5 in stable cell lines reduced endogenous mRNA levels. Consistent with this finding, antisense inhibition of Dlx-5 increased osteocalcin gene transcription. Osteocalcin promoter deletion analysis and binding of the in vitro translation product of Dlx-5 demonstrated that repressor activity was targeted to a single homeodomain-binding site, located in OC-Box I (-99 to -76). These findings demonstrate that Dlx-5 represses osteocalcin gene transcription. However, the coupling of increased Dlx-5 expression with progression of osteoblast differentiation suggests an important role in promoting expression of the mature bone cell phenotype.

Amino Acid Sequence↗
PubMed1996

Bone tissue-specific transcription of the osteocalcin gene: role of an activator osteoblast-specific complex and suppressor hox proteins that bind the OC box.

Bone-specific expression of the osteocalcin gene is transcriptionally controlled. Deletion analysis of osteocalcin promoter sequences by transient transfection of osseous (ROS 17/2.8) and nonosseous (R2 fibroblast) cells revealed that the most proximal 108 nucleotides are sufficient to confer tissue-specific expression. By gel mobility shift assays with wild-type and mutated oligonucleotides and nuclear extracts from several different cell lines we identified a novel transcription factor complex which exhibits sequence-specific interactions with the primary transcriptional element, the OC box (nt -99 to -76). This OC box binding protein (OCBP) is present only in osteoblast-like cells. Methylation interference demonstrated association of the factor with OC box sequences overlapping the Msx homeodomain consensus binding site. By assaying several mutations of the OC box, both in gel shift and transient transfection studies using ROS 17/2.8, we show the following. First, binding of OCBP correlates with osteocalcin promoter activity in ROS 17/2.8 cells. Increased binding leads to a 2-3-fold increase in transcription, while decreased binding results in transcription 30-40% of control. Second, homeodomain protein binding suppresses transcription. However, Msx expression is critical for full development of the bone phenotype as determined by antisense studies. Last, we show that one of the mutations of the OC box permits expression of osteocalcin in non-osseous cell lines. In summary, we demonstrate association of at least two classes of tissue-restricted transcription factors with the OC box element, the OCBP and Msx proteins, supporting the concept that these sequences contribute to defining tissue specificity.

Animals↗
PubMed1995

Intrinsic U2AF binding is modulated by exon enhancer signals in parallel with changes in splicing activity.

A functional analysis of exon replacement mutations was performed in parallel with RNA-protein binding assays to gain insight into the role of the exon in alternative and simple splicing events. These results show that constitutive exons from unrelated genes contain strong signals that promote splicing in multiple sequence contexts by enhancing 3' splice site activity. A clue to the nature of the relationship between the exon and adjacent 3' splice site is indicated by the binding properties of exon variant RNAs when tested with different biochemical preparations of the essential splicing protein, U2AF. In the context of a complete nuclear extract, U2AF binding to the 3' splice site is stimulated by the presence of an adjacent constitutive exon. In contrast, highly purified HeLa U2AF binds equivalently to the exon variants under conditions in which differential polypyrimidine tract binding is evident. These results provide support for an assisted binding model in which positive-acting signals within exons, exon enhancers, direct the binding of accessory factors, which in turn increase the intrinsic affinity of U2AF for the adjacent 3' splice site. Further support for an assisted binding model is indicated by biochemical complementation of U2AF binding and by the localization of a novel exon enhancer, which, when introduced into a weak exon, stimulates splicing activity in parallel with U2AF binding. Immunoprecipitation analysis identifies the splicing factor, SC35, as a constituent of the exon enhancer binding complex. These results are discussed in the context of current models for functional exon-bridging interactions.

Base Sequence↗
PubMed1994

Transcriptional control of the tissue-specific, developmentally regulated osteocalcin gene requires a binding motif for the Msx family of homeodomain proteins.

The OC box of the rat osteocalcin promoter (nt -99 to -76) is the principal proximal regulatory element contributing to both tissue-specific and developmental control of osteocalcin gene expression. The central motif of the OC box includes a perfect consensus DNA binding site for certain homeodomain proteins. Homeodomain proteins are transcription factors that direct proper development by regulating specific temporal and spatial patterns of gene expression. We therefore addressed the role of the homeodomain binding motif in the activity of the OC promoter. In this study, by the combined application of mutagenesis and site-specific protein recognition analysis, we examined interactions of ROS 17/2.8 osteosarcoma cell nuclear proteins and purified Msx-1 homeodomain protein with the OC box. We detected a series of related specific protein-DNA interactions, a subset of which were inhibited by antibodies directed against the Msx-1 homeodomain but which also recognize the Msx-2 homeodomain. Our results show that the sequence requirements for binding the Msx-1 or Msx-2 homeodomain closely parallel those necessary for osteocalcin gene promoter activity in vivo. This functional relationship was demonstrated by transient expression in ROS 17/2.8 osteosarcoma cells of a series of osteocalcin promoter (nt -1097 to +24)-reporter gene constructs containing mutations within and flanking the homeodomain binding site of the OC box. Northern blot analysis of several bone-related cell types showed that all of the cells expressed msx-1, whereas msx-2 expression was restricted to cells transcribing osteocalcin. Taken together, our results suggest a role for Msx-1 and -2 or related homeodomain proteins in transcription of the osteocalcin gene.

Animals↗
PubMed1990

A Sequential splicing mechanism promotes selection of an optimal exon by repositioning a downstream 5' splice site in preprotachykinin pre-mRNA.

To explore the structural basis of alternative splicing, we have analyzed the splicing of pre-mRNAs containing an optional exon, E4, from the preprotachykinin gene. This gene encodes substance P and related tachykinin peptides by alternative splicing of a common pre-mRNA. We have shown that alternative splicing of preprotachykinin pre-mRNA occurs by preferential skipping of optional E4. The competing mechanism that incorporates E4 into the final spliced RNA is constrained by an initial block to splicing of the immediate upstream intervening sequence (IVS), IVS3. This block is relieved by sequential splicing, in which the immediate downstream IVS4 is removed first. The structural change resulting from the first splicing event is directly responsible for activation of IVS3 splicing. This structural rearrangement replaces IVS4 sequences with E5 and its adjacent IVS5 sequences. To determine how this structural change promoted IVS3 splicing, we asked what structural change(s) would restore activity of IVS3 splicing-defective mutants. The most significant effect was observed by a 2-nucleotide substitution that converted the 5' splice site of E4 to an exact consensus match, GUAAGU. Exon 5 sequences alone were found not to promote splicing when present in one or multiple copies. However, when a 15-nucleotide segment of IVS5 containing GUAAGU was inserted into a splicing-defective mutant just downstream of the hybrid exon segment E4E5, splicing activity was recovered. Curiously, the 72-nucleotide L2 exon of adenovirus, without its associated 5' splice site, activates splicing when juxtaposed to E4. Models for the activation of splicing by an RNA structural change are discussed.

Base Sequence↗
PubMed1985

Microbial transformations of some monoterpenoids and sesquiterpenoids.

The absolute configurations of fragrances, flavours and drugs are often important for their special properties. The growing interest of organic chemists in chiral synthons has stimulated work on biotransformations, for which readily available and inexpensive compounds can be used as substrates. Microbial transformations of 1-menthenes like gamma-terpinene, alpha-terpinene, limonene and alpha-phellandrene give the corresponding 1,2-trans-diols with high stereospecificity. Because of the volatility and toxicity of these substrates, and their low solubility in aqueous solutions, a special fermentation technique has been developed in which the terpenes are fed continuously to extended cultures of Corynespora cassiicola or Diplodia gossypina. (4R)-Limonene is transformed by Gibberella cyanea to (1S,2S,4R)-p-menth-8-en-1,2-diol, but 3,3,5,5-tetramethyl-limonene yields a 6-monohydroxylated product and a 6,10-dihydroxylated product with a 6-hydroxy-8,10-epoxy structure as the main metabolite. Vicinal diols are also formed from aliphatic terpenes, by reaction at the terminal isoprenoid groups. Some oxirane structures are found as intermediates. Acyclic sesquiterpenes often form complex mixtures when they are metabolized further. The products of the transformation of trans-nerolidol by several fungi are given as examples. Cyclic sesquiterpenes, with less flexible structures, are oxidized more specifically. Whereas longifolene is a very poor substrate for Corynespora cassiicola, isolongifolene is always hydroxylated at one of the methyl groups attached to C-7. The 14- or 15-hydroxy compounds are further oxidized, very fast, in the 3 position or 4 position.

Bacteria↗
PubMed1983

Temperature dependence of ion permeation at the endplate channel.

The dependence of acetylcholine receptor mean single-channel conductance on temperature was studied at garter snake twitch-muscle endplates using fluctuation analysis. In normal saline under conditions where most of the endplate current was carried by Na+, the channel conductance increased continuously from near 0 degrees C to approximately 23 degrees C with a Q10 of 1.97 +/- 0.14 (mean +/- SD). When 50% of the bath Na+ was replaced by either Li+, Rb+, or Cs+, the Q10 did not change significantly; however, at any temperature the channel conductance was greatest in Cs-saline and decreased with the ion sequence Cs greater than Rb greater than Na greater than Li. The results were fit by an Eyring-type model consisting of one free-energy well on the extracellular side of a single energy barrier. Ion selectivity appeared to result from ion-specific differences in the well and not in the barrier of this model. With a constant barrier enthalpy for different ions, well free-energy depth was greatest for Cs+ and graded identical to the permeability sequence. The correlation between increased well depth (i.e., ion binding) and increased channel conductance can be accounted for by the Boltzmann distribution of thermal energy.

Animals↗
PubMed1980

[Headache associated with underlying internal diseases].

The vascular system of the head is of great importance in most types of headache because of the sympathetic efferents supplying the vessels. From neuroanatomic data it is to be assumed that vascular diseases of different genesis and cardiovascular diseases may give rise to headaches. The connection between headache and hypertensin is discussed at length with reference to pathophysiology. Further, headache is presented as a symptom with reference to observations of our own cases of inflammatory diseases of the vessels, sinus thrombosis, vessel deformities, accidents in anticoagulant therapy with subdural and intraspinal haemorrhages, cerebrospinal lues and endocrinopathies. Tables and illustrations supplement the text.

Aortic Valve Stenosis↗
PubMed1969

Allylfurans.

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Chemical Phenomena↗