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At least 577 records · Page 32Linked to original sources

PubMed1996

Non-peptide cholecystokinin-B/gastrin receptor antagonists based on bicyclic, heteroaromatic skeletons.

A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic, heteroaromatic frameworks, such as a 5,6-disubstituted indole or benzimidazole. These new ligands maintain the affinity and selectivity profile of the previous compounds in vitro but show a much more consistent behavior pattern in vivo. Representative examples of this class of compound have been shown to inhibit pentagastrin-stimulated acid secretion when administered intravenously at doses of 0.1 mumol kg-1 or less.

Animals↗

PubMed2000

The cumbiasins, structurally novel diterpenes possessing intricate carbocyclic skeletons from the West Indian sea whip Pseudopterogorgia elisabethae (Bayer).

From the hexane extract of the West Indian gorgonian Pseudopterogorgia elisabethae, two diterpenes, cumbiasins A (1) and B (2), having a novel tetracyclic carbon skeleton named cumbiane, have been isolated. In addition, we have isolated cumbiasin C (3), a ring cleavage product of cumbiasin B that possesses an unusual carbocyclic framework named seco-cumbiane. The structures and relative configurations of metabolites 1-3 were elucidated by interpretation of overall spectral data, which included 2D NMR correlation methods, IR, UV, and accurate mass measurements (HREI-MS and HRFAB-MS). The carbocyclic skeletons of the cumbiasins are unprecedented and represent new classes of C20 rearranged diterpenes. Cumbiasins A and B display mild in vitro anti-tuberculosis activity.

Animals↗

PubMed2006

A general route toward the synthesis of the cladiellin skeleton utilizing a SmI2-mediated cyclization.

An efficient synthesis of the cladiellin skeleton is reported utilizing methods that were previously developed in this laboratory. The approach is based on a SmI(2)-mediated cyclization reaction for the construction of the oxacyclononane unit. A [4 + 3] annulation strategy was used to create the octahydroisobenzofuran moiety. This route provides the cladiellin skeleton in only 14 steps without the use of protecting groups. The present approach also enabled the synthesis of the 3,7-diastereomer of the natural product polyanthellin A.

Alkenes↗

PubMed1997

Total Synthesis of (+)-Aspicilin. The Naked Carbon Skeleton Strategy vs the Bioorganic Approach.

The advantages of the "naked carbon skeleton" strategy in the total synthesis of polyoxygenated natural products are demonstrated in the total synthesis of the 18-membered macrolide (+)-aspicilin, 1. This approach employs the easily prepared, nonfunctionalized carbon skeleton of the target molecule, hexadeca-1,3,15-triene, 2. All the required stereogenic carbinol centers are then introduced onto this partially unsaturated hydrocarbon chain using the Sharpless asymmetric dihydroxylation (AD) reaction. Thus, asymmetric synthesis of 1 is achieved in 14 steps and 11% overall yield. Three stereogenic carbinol centers are introduced with very high regio- and enantioselectivity (epimeric excess of 96% at positions 3, 4, and 86% at position 15) by using AD-mix-beta while the fourth is obtained using AD-mix-alpha. This approach is compared with an alternative synthesis of 1 (19 steps and 4.3% overall yield) using chiral building blocks derived from D-arabinose and from the enzymatic reduction of oct-7-yn-2-one, 34, with Thermoanaerobium brockii alcoholdehydrogenase (TBADH).

Journal Article↗

PubMed2003

Chemical transformations on botryane skeleton. Effect on the cytotoxic activity.

Eighteen compounds with a botryane skeleton have been obtained through chemical transformations of various toxins from the fungus Botrytis cinerea. During the course of these transformations, the C-10 carbon of the botryane skeleton was found to exhibit an interesting high regioselectivity to oxidizing and reducing agents. In addition, the cytotoxicity of 27 botryane derivatives was determined in vitro against Hs578T, MDA-MB-231, HT-1080, U87-MG, IMR-90, and HUVEC cell lines. The results of this study confirm that the cytotoxicity of botrydial (1) and its derivatives is related to the presence of a 1,5-dialdehyde functionality.

Aldehydes↗

PubMed2005

Skeletal diversity via a folding pathway: synthesis of indole alkaloid-like skeletons.

Inspired by the skeletal diversity of naturally occurring indole alkaloids and the rich potential of chemistry developed by Padwa and co-workers, we conceived a pathway entailing six modes of intramolecular reactions leading to indole alkaloid-like skeletons. In this context, an efficient folding pathway via a rhodium-catalyzed tandem cyclization-cycloaddition involving three of the modes has been developed (two of which are shown above) that affords densely functionalized compounds with three distinct skeletons in a stereocontrolled manner.

Cyclization↗

PubMed2005

Synthesis of the carbocyclic skeleton of abyssomicins C and D.

[reaction: see text] Intramolecular Diels-Alder substrate trienyl methylenebutenolide 5 was prepared in six steps by coupling 3-methoxy-4-methylenebutenolide (6) with trienone keto aldehyde 7. Heating 5 in CHCl(3) for 2 d at 70 degrees C afforded 80% of a single Diels-Alder adduct 4 with the complete carbon skeleton of abyssomicin C. Addition of thiophenoxide to the enone double bond of 4 followed by an intramolecular Michael addition afforded 15 with the abyssomicin D carbon skeleton.

Acids, Carbocyclic↗

PubMed2003

The skeleton as a unique environment for breast cancer cells.

Bone is a favored location for several cancer metastases especially breast, prostate and myeloma. This review evaluates various properties of the skeleton that contribute to its successful colonization by breast cancer cells. The first consideration is the unique aspects of the vasculature of metaphyseal bone, which may account for the initial lodging of breast cancer cells in specific regions of the skeleton. Metasphyseal bone, found at the ends of long bone, in ribs and in vertebrae, is comprised of trabecular bone interspersed with marrow and a rich vasculature. The chemotactic factors that arise from bone marrow and bone cells are discussed in terms of cancer cell migration out of the vasculature and entry of cancer cells into the marrow cavity. Once the breast cancer cells have migrated into the metaphysis, they interact both directly and indirectly with bone cells and other cells in the marrow. As tumor growth progresses, functional bone cells are lost, most likely through apoptosis.

Animals↗

PubMed2001

The quantitative and qualitative analysis of the craniofacial skeleton of mice lacking the IGF-I gene.

Insulin-like growth factors are mediators of growth hormone and are believed to also stimulate growth independently. Insulin-like growth factor I (IGF-I) null mutant mice exhibit a lower rate of skeletal growth compared with their wild-type (control) littermates. Although their general body dimensions seem proportionate, their heads appear shortened with a blunt nose compared with the controls. The aim of this project was threefold: 1) to investigate whether differences in shape/form exist between the craniofacial skeleton of the IGF-I null mutant mice and their control littermates by using three techniques; 2) to determine whether the three techniques yield similar, different, or complementary information regarding the size and shape of specimens; and 3) to investigate whether the histological sections obtained from the craniofacial skeleton exhibit any differences between the two groups. Thirty adult male mice, 12 mutant and 18 wild type, obtained from 11 litters were examined. Lateral and superio-inferior radiographs of their head were analyzed by the procrustes, the macroelement, and the traditional cephalometric techniques. Later, the animals were processed for routine histological examination. The IGF null mutant mice demonstrated a generalized decrease of craniofacial size (43-64% of the normal adult size) and a non-allometric change of shape when compared with their wild-type littermates. While the mandible did not exhibit any shape changes, the facial and cranial areas demonstrated prominent changes. Examination of histological sections did not reveal any structural difference between the two groups at the adult stage. Furthermore, procrustes and macroelement techniques offer a more complete, detailed, and comprehensive description of the specimens compared.

Journal Article↗

PubMed1999

Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11.

The bones that comprise the axial skeleton have distinct morphological features characteristic of their positions along the anterior/posterior axis. We previously described a novel TGF-beta family member, myostatin (encoded by the gene Mstn, formerly Gdf8), that has an essential role in regulating skeletal muscle mass. We also identified a gene related to Mstn by low-stringency screening. While the work described here was being completed, the cloning of this gene, designated Gdf11 (also called Bmp11), was also reported by other groups. Here we show that Gdf11, a new transforming growth factor beta(TGFbeta) superfamily member, has an important role in establishing this skeletal pattern. During early mouse embryogenesis, Gdf11 is expressed in the primitive streak and tail bud regions, which are sites where new mesodermal cells are generated. Homozygous mutant mice carrying a targeted deletion of Gdf11 exhibit anteriorly directed homeotic transformations throughout the axial skeleton and posterior displacement of the hindlimbs. The effect of the mutation is dose dependent, as Gdf11+/- mice have a milder phenotype than Gdf11-/- mice. Mutant embryos show alterations in patterns of Hox gene expression, suggesting that Gdf11 acts upstream of the Hox genes. Our findings suggest that Gdf11 is a secreted signal that acts globally to specify positional identity along the anterior/posterior axis.

Animals↗

PubMed1999

Patterning the zebrafish axial skeleton requires early chordin function.

Members of the bone morphogenetic protein (BMP) family actively promote ventral cell fates, such as epidermis and blood, in the vertebrate gastrula. More dorsally, the organizer region counteracts BMP signalling through secretion of BMP-binding antagonists chordin and noggin, allowing dorsally derived tissues such as neurectoderm and somitic muscle to develop. BMPs also function in skeletal development and regeneration of bone following injury. Noggin antagonism is thought to prevent osteogenesis at sites of joint formation, whereas chordin has not yet been implicated in skeletogenesis. Analyses of zebrafish mutants have confirmed the action of chordin (chd) in opposing ventralizing signals at gastrulation. Some ventralized mutants recover and develop into fertile adults, thereby revealing a requirement for chd function for the later processes of fin and caudal skeletal patterning. We observe in mutants the misexpression of genes encoding BMPs and putative downstream genes, and ectopic sclerotomal cells. Through injections of chd mRNA into the early embryo, we restored wild-type gene expression patterns, and the resultant fish, although genotypically mutant, developed normal axial skeletons and fins. Our results demonstrate that chordin function during gastrulation is important for the correct morphogenesis of the adult zebrafish skeleton.

Animals↗

PubMed1996

Targeted disruption of the murine erythroid band 3 gene results in spherocytosis and severe haemolytic anaemia despite a normal membrane skeleton.

Band 3 is the most abundant integral protein of the red blood cell membrane. It performs two critical biological functions: maintaining ionic homeostasis, by transporting Cl- and HCO3-ions, and providing mechanical stability to the erythroid membrane. Erythroid band 3 (AE1) is one of three anion exchangers that are encoded by separate genes. The AE1 gene is transcribed by two promoters: the upstream promoter produces erythroid band 3, whereas the downstream promoter initiates transcription of the band 3 isoform in kidney. To assess the biological consequences of band 3 deficiency, we have selectively inactivated erythroid but not kidney band 3 by gene targeting in mice. Although no death in utero occurred, the majority of homozygous mice die within two weeks after birth. The erythroid band 3 null mice show retarded growth, spherocytic red blood cell morphology and severe haemolytic anaemia. Remarkably, the band 3-/- red blood cells assembled normal membrane skeleton thus challenging the notion that the presence of band 3 is required for the stable biogenesis of membrane skeleton. The availability of band 3-/- mice offers a unique opportunity to investigate the role of erythroid band 3 in the regulation of membrane-skeletal interactions, anion transport and the invasion and growth of malaria parasite into red blood cells.

Alleles↗

PubMed2001

Reversible erythrocyte skeleton destabilization is modulated by beta-spectrin phosphorylation in childhood leukemia.

The erythrocyte skeleton plays an essential role in determining the shape and deformability of the red cell. Disruption of the interaction between components of the red cell membrane skeleton may cause loss of structural and functional integrity of the membrane. Several observations based on studies in vitro strongly suggest that phosphorylation may modify interactions between proteins, leading to a reduced affinity. In particular, increased phosphorylation of beta-spectrin decreases membrane mechanical stability. In order to investigate the presence of membrane protein defects we investigated the erythrocyte membrane protein composition and phosphorylation in 22 children with leukemia at diagnosis and during the remission phase. Sixteen children had acute lymphoblastic leukemia (ALL), three had chronic myeloid leukemia (CML) and three had acute myeloid leukemia (AML). Ten patients (eight ALL and two CML) displayed elliptocytosis and poikilocytosis, an increase of spectrin dimers (41.8 +/- 15.6) and an enhanced phosphorylation of beta-spectrin (108 +/- 15%) at diagnosis. These alterations disappeared during the remission phase. This is the first demonstration of a reversible erythrocyte membrane alteration in leukemia. Since the beta-spectrin phosphate sites are located near the C-terminal region and close to the head of the beta-chain that is involved in dimer-dimer interaction, we supposed that the beta-chain phosphorylation has an effect upon the interactions between spectrin dimers, ie the tetramerization process. The weakening of this process should be responsible for the presence of elliptocytes and poikilocytes as reported in hereditary elliptocytosis and pyropoikilocytosis.

Acute Disease↗

PubMed1999

A technique for three-dimensional cephalometric analysis as an aid in evaluating changes in the craniofacial skeleton.

A technique is presented for creating a standardized view for use in three-dimensional cephalometry. Three-dimensional cephalometric analysis has become a valuable tool in the assessment of skeletal remodeling, contour changes, and changes in proportion that occur with aging. Computer-assisted tomographic data can be used in either coronal or axial sections; the present study was performed with axially acquired data that was processed in several steps to achieve a standardized position of the facial skeleton for further evaluation. This technique may be a useful adjunct to standard cephalometrics to evaluate the craniofacial skeleton.

Anatomy, Cross-Sectional↗

PubMed2000

[Construction principles in the forepaw and hindpaw of the domestic cat (Felis catus). 1: Skeleton].

The differences in the skeleton of the forepaw and hindpaw of the domestic cat are an expression of a highly specialized, functional adaption: The mesaxonic forepaw with abducable first digit is used for running as well as for catching and climbing. The paraxonic hindpaw becomes, particularly through the arched construction of the metacarpus, a long and strong caulking tool both in sprinting and climbing up. The discussion focuses on evolutionary considerations. Moreover, common points and differences in the skeleton of the forepaw and hindpaw of the domestic cat and their importance are summarized and briefly compared with the situation in the dog.

Animals↗

PubMed1999

Development of the skeleton in Japanese quail embryos.

In the research fields of experimental embryology, teratological testing, and developmental engineering in avian species, a knowledge of normal embryonic development is necessary so that research may be performed efficiently and precisely. A series of normal stages based on external appearance has been established in both chicken and quail embryos. Those based on skeletal features, however, have not been elucidated. The present study newly established a series of normal stages for the development of the Japanese quail embryo skeleton. This series is composed of 15 stages determined by observing the timing of chondrification and calcification of the skeleton every 24 h, from 3 to 17 days of incubation. Cartilage and ossified bones were stained blue and red with Alcian blue 8GX and alizarin red S, respectively. These skeletogenous stages of the Japanese quail embryo will be useful as a normal control not only in studies of experimental embryology, teratological testing, and developmental engineering, but also in the analysis of mutant embryos with skeletal abnormalities.

Animals↗

PubMed2000

Regulative specification of ectoderm in skeleton disrupted sea urchin embryos treated with monoclonal antibody to Pl-nectin.

Pl-nectin is a glycoprotein first discovered in the extracellular matrix (ECM) of Paracentrotus lividus sea urchin embryo, apically located on ectoderm and endoderm cells. The molecule has been described as functioning as an adhesive substrate for embryonic cells and its contact to ectoderm cells is essential for correct skeletogenesis. The present study was undertaken to elucidate the biochemical characteristics of Pl-nectin and to extend knowledge on its in vivo biological function. Here it is shown that the binding of mesenchyme blastula cells to Pl-nectin-coated substrates was calcium dependent, and reached its optimum at 10 mM Ca2+. Perturbation studies using monoclonal antibody (McAb) to Pl-nectin, which prevent ectoderm cell-Pl-nectin contact, show that dorsoventral axis formation and ectoderm differentiation were retarded. At later stages, embryos recovered and, even if growth and patterning of the skeleton was greatly affected, the establishment of dorsoventral asymmetry was reached. Similarly, the expression of specific ectoderm and endoderm territorial markers was achieved, although occurring with some delay. Endoderm differentiation and patterning was not obviously affected. These results suggest that both endoderm and ectoderm cells have regulative capacities and differentiation of territories is restored after a lag period. On the contrary, failure of inductive differentiation of the skeleton cannot be rescued, even though the ectoderm has recovered.

Animals↗

PubMed1997

Ultrasonographic and radiologic visualization of the developing embryonic skeleton.

We investigated the development of the skeleton in the embryonic and early fetal period both with ultrasonography and radiology. Eight normal embryos/fetuses were studied weekly with real-time transvaginal sonography between 8 and 16 weeks of gestation to establish the ultrasonographic characteristics of normal ossification. Additionally, ossification was studied in radiographs obtained from five embryos/fetuses between 9 and 14 weeks of gestation. Ossification centers, visualized as increased echogenicity of the bone, were recognized with ultrasonography from 9 weeks onwards. The appearance of primary ossification centers as observed by transvaginal ultrasonography was at the same gestational age or at most 1 week later than when obtained with radiography or whole-specimen staining techniques. Transvaginal ultrasonography enables early visualization of ossification centers in the embryo and fetus. Detailed knowledge of the development of ossification of the skeleton may contribute to early prenatal diagnosis of skeletal dysplasias.

Bone Development↗