Targeting alphavbeta3 integrin: design and applications of mono- and multifunctional RGD-based peptides and semipeptides.

The outstanding physio-pathological role played by integrin receptors in living subjects motivates the enormous interest shown by scientists worldwide for this topic. More than twenty years of research has spanned across the structural and functional elucidation of these proteins and over their antagonism-based biomedical applications. The proof-of concept stage, aimed at identifying potent inhibitors, covered a decade of studies, and paved the way for a more advanced era of research where these antagonist molecules were thrown into the deep end of applicative studies. This review intends to summarize the major efforts conducted thus far and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing alpha(v)beta(3) integrin antagonists, in both their small and macromolecular formats. In particular, Chapters 1 and 2 offer a comprehensive outlook on the rational basis for the design of integrin inhibitors, Chapter 3 chronicles the biological and medical applications of monofunctional RGD integrin ligands both in their monomeric and multimeric asset, and Chapter 4 illustrates the potential of RGD-based multifunctional systems in molecular medicine.

Variable strategy toward carbasugars and relatives. 2. Diversity-based synthesis of beta-D-xylo, beta-D-ribo, beta-L-arabino, and beta-L-lyxo 4a-carbafuranoses and (4a-carbafuranosyl)thiols.

The silyloxy diene-based construction of carbasugars, previously exploited for the synthesis of four carbocyclic furanose and pyranose analogues, has been investigated further. By introducing a novel silylative cycloaldolization protocol and by adjusting a couple of minor transformations, the efficiency of this synthetic sequence was greatly improved. Through a series of lactone/thiolactone aldehyde cyclization precursors, four carbafuranoses (4a-carba-beta-D-xylofuranose, 4a-carba-beta-D-ribofuranose, 4a-carba-beta-L-arabinofuranose, and 4a-carba-beta-L-lyxofuranose) and four (carbafuranosyl)thiols [(4a-carba-beta-D-xylofuranosyl)thiol, (4a-carba-beta-D-ribofuranosyl)thiol, (4a-carba-beta-L-arabinofuranosyl)thiol, and (4a-carba-beta-L-lyxofuranosyl)thiol] were assembled. From this study, it was shown that these constructions tolerate a variety of precursors, and in many instances, they are suitable for scaling-up.

Variable strategy toward carbasugars and relatives. 1. Stereocontrolled synthesis of pseudo-beta-D-gulopyranose, pseudo-beta-D-xylofuranose, (pseudo-beta-D-gulopyranosyl)amine, and (pseudo-beta-D-xylofuranosyl)amine.

Four novel, chiral nonracemic carbasugars have been synthesized from 1,2-O-isopropylidene-D-glyceraldehyde. Furan- and pyrrole-based 2-silyloxy dienes--mimics of the alpha,gamma-dianions of gamma-hydroxy- and gamma-aminobutanoic acid, respectively--nicely served to complete the syntheses of two all-oxygen compounds, pseudo-beta-D-gulopyranose and pseudo-beta-D-xylofuranose, and two "anomeric" amino derivatives, (pseudo-beta-D-gulopyranosyl)amine (1,2,4-tri-epi-validamine) and (pseudo-beta-D-xylofuranosyl)amine. Two sequential, highly diastereoselective carbon-carbon bond-forming maneuvers, i.e., a vinylogous crossed aldol addition and an intramolecular aldolization, proved central to these constructions. The fact that readily available heterocyclic diene scaffolds can be employed in the assembly of a varied repertoire of carbasugars and analogues widens the prospects of dienoxy silane chemistry.

The utility of furan-, pyrrole-, and thiophene-based 2-silyloxy dienes as demonstrated by modular synthesis of annonaceous acetogenin core units and their pyrrolidine and thiolane analogues.

We report a modular strategy for obtaining the core units of annonaceous acetogenins and their nitrogen and sulfur analogues, which generates great structural diversity. This synthesis is based on the application of a reiterative vinylogous addition protocol involving a unique triad of silyloxy diene modules, 2-[(tert-butyldimethylsilyl)oxy]furan (TBSOF), N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy]pyrrole (TBSOP), and 2-[(tert-butyldimethylsilyl)oxy]thiophene (TBSOT) and suitable heteroatom-stabilized carbenium ions. By combining TBSOF, TBSOP, and TBSOT nucleophilic synthons with certain tetrahydrofuran, pyrrolidine, and thiolane acceptors, the construction of varied, adjacently linked oligo-heterocyclic motifs related to the core segments of the annonaceous acetogenins is assured. At first, the reliability of the pivotal coupling maneuver was certified, by assembling a collection of 18 model constructs, covering all oxygen, nitrogen, and sulfur heteroatom combinations (i.e., compounds 7-9, 13-15, and 19-21). This uniformed protocol was then suited to forge advanced bis-tetrahydrofuran, bis-pyrrolidine, and bis-thiolane scaffolds encompassing the heterocyclic core portion of various binuclear annonaceous acetogenins and relatives. The utility of this synthesis was demonstrated by the preparation of a repertoire of eight isomeric bis-tetrahydrofuran units, 41-48, two bis-pyrrolidine units, 62 and 63, and four bis-thiolane units, 78-81.

Porcine-derived surfactant treatment of severe bronchiolitis.

BACKGROUND: It is hypothesized that surfactant treatment helps to improve severe bronchiolitis by restoring surfactant system activity. This study aims to assess the effect of surfactant on gas exchange, peak inspiratory pressure and duration of mechanical ventilation and intensive care unit (ICU) stay in children with severe bronchiolitis. METHODS: Twenty children with bronchiolitis requiring mechanical ventilation were randomly assigned to one of two groups (10 patients each). Group A was treated with continuous positive pressure ventilation (CPPV) plus surfactant. Group B was treated with CPPV only. Porcine-derived surfactant, 50 mg/kg body weight, was instilled into the trachea. Arterial tension of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio, arterial tension of carbon dioxide (PaCO2), and peak inspiratory pressure (PIP) were assessed. Heart rate and non-invasive arterial blood pressure were monitored. The duration of CPPV and the length of ICU stay were also recorded. Finally, the incidence of complications and the survival rate were assessed. RESULTS: In group A, the PaO2/FiO2 ratio significantly improved from 1 h and a reduction in PaCO2 was noted from 12 h. A reduction of PIP was observed from 3 h. The duration of CPPV and the length of ICU stay were reduced in group A. No complications were reported in either group and all children survived. CONCLUSIONS: Surfactant treatment of severe bronchiolitis appeared to improve gas exchange, reduce PIP and shorten CPPV and ICU stay. However, these initial results must be confirmed by a larger and more rigorously controlled study.

Expeditious syntheses of sugar-modified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophene-based siloxy dienes.

A series of individual sugar-modified pyrimidine nucleosides including enantiomerically enriched 2',3'-dideoxynucleosides 14a-c (alpha and beta anomers of L- and D-series), 2',3'-dideoxy-4'-thionucleosides 21a-c (alpha and beta anomers of L- and D-series), and 2',3'-dideoxy-4'-azanucleosides 28a-c (beta anomers of L- and D-series) were synthesized, with uniform chemistry and high stereochemical efficiency, exploiting a triad of versatile heterocyclic siloxy dienes, namely, 2-(tert-butyldimethylsiloxy)furan (TBSOF), 2-(tert-butyldimethylsiloxy)thiophene (TBSOT), and N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)pyrrole (TBSOP). The synthetic procedure advantageously used both enantiomers of glyceraldehyde acetonide (D-1 and L-1) as sources of chirality and as synthetic equivalents of the formyl cation. The outlined chemistry also allowed for the rapid assemblage of a 30-member collection of racemic nucleosides (D,L-L) as well as one 15-member ensemble of chiral analogues (L-L), along with some related sublibraries.

[The effects of administering surfactant to two adolescents with leukemia suffering from respiratory distress]. / Effets d'un apport de surfactant chez deux adolescents leucémiques atteints de détresse respiratoire.

Two adolescents (12 years old, suffering from acute lymphoid leukaemia (LLA) and 16 years old with acute myeloid leukaemia (LMA)) were treated with porcine surfactant (Curosurf). The indication for this treatment was a severe Respiratory Distress Syndrome (RDS) which appeared during leukaemia treatment. Pulmonary thrombo-embolism was suspected. The surfactant administered improved ventilation and oxygenation, enabling confirmation of the diagnosis which would otherwise have been impossible due to the seriousness of their condition.

Follow-up on infants treated with porcine surfactant replacement for severe neonatal and infant respiratory distress syndrome: antigenic reactivity evaluation.

A follow-up was carried out on twenty-two children (thirteen of whom were newborn) who had been treated with porcine surfactant (Curosurf) for respiratory distress syndrome. All the infants were enrolled in the follow-up at different times after surfactant replacement to evaluate the clinical status and the incidence (if any) of respiratory disease, adverse drug effects and allergic conditions. Twelve of the twenty-two children treated completed the follow-up. Seven prematurely-born children died of endocranial haemorrhage; two children died of malignant development of the basal pathology (leukaemia). Treatment with pig surfactant appears to cause no allergic side effects. Skin and laboratory tests performed were negative.