Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling

Abstract: Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)₂-DAS-(Lys)₂ ( 2 , SK&F 107647 ) were investigated. A convergent approach (‘3 + 2’-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2 . Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)₂-DAS-(Lys(Z)-OBn)₂ ( 6 , DAS=2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH ( 26 ). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1, 2, 3-benzotriazin-3-yl-1, 1, 3, 3-tetramethyluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.     

Ultraschallkontrastmittel — physikalische Grundlagen

Zusammenfassung Das Wirkungsprinzip von Ultraschallkontrastmitteln (US-KM, US Ultraschall) beruht auf den speziellen physikalischen und akustischen Eigenschaften der gasgefüllten Mikrobläschen. Abhängig vom Druck der eingestrahlten US-Welle treten neben einer Erhöhung der Rückstreuung, die wesentlich zur Verbesserung der Bildqualität beiträgt, nichtlineare Effekte auf, die von der Erzeugung harmonischer Frequenzanteile bis hin zur Zerstörung der Bläschen durch die Schallwelle reichen. Speziell die nichtlinearen Effekte bilden die Grundlage für neu entwickelte kontrastmittelspezifische Bildgebungstechniken wie harmonic oder intermittent imaging.Dieser Artikel gibt eine Übersicht über die physikalischen Eigenschaften der Mikrobläschen, ihr akustisches Verhalten im Ultraschallfeld sowie die Ausnutzung der auftretenden Effekte für die Bildgebung. Auf neue Entwicklungen in Richtung gewebespezifischer Kontrastmittel und sich daraus ergebende therapeutische Anwendungsmöglichkeiten wird ebenso wie auf die potenziellen Gefahren durch kontrastmittelinduzierte Bioeffekte und daraus resultierenden Richtlinien für die klinische Anwendung der Kontrastmittel (KM) eingegangen.Ein Erratum zu diesem Beitrag können Sie unter finden.     

The nature of diversity and diversification at the ABO locus

In this study we analyzed the complete genomic sequences, except intron 1, and 2 regulatory regions of 6 common (ABO*A101, ABO*A201, ABO*B101, ABO*O01, ABO*O02, and ABO*O03) and 18 rare ABO alleles, 3 of which were new. This was done by phylogenetic analysis and correlating sequence data with the ABO phenotypes. The study revealed multiple polymorphisms in noncoding regions. The intron-based phylogenetic analysis revealed 5 main lineages: ABO*A, ABO*B, ABO*O01, ABO*O02, and ABO*O03. The genomic sequences of most rare ABO alleles differed slightly from those of the common alleles. Singular mutations or hybrid alleles were most common, but a few exhibited mosaic sequence pattern containing multiple exon and/or intron motifs from other ABO lineages. Thus, both an accumulation of mutations as well as an assortment of the mutations by recombination seems to be responsible for the ABO gene diversity. The prevalence of replacement mutations indicates positive selection for allelic diversity. Phenotype-genotype correlation showed that sequence variations within the complete coding sequence can affect A- and B-antigen expression. All variant ABO*A/B alleles and one new ABO*O03-like allele were associated with weak ABO phenotypes. These findings are suggestive of the requirement of a comprehensive coding sequence database for sequence-based phenotype prediction.     

Evaluation of a miniature electromagnetic position tracker

The advent of miniaturized electromagnetic digitizers opens a variety of potential clinical applications for computer aided interventions using flexible instruments; endoscopes or catheters can easily be tracked within the body. With respect to the new applications, the systematic distortions induced by various materials such as closed metallic loops, wire guides, catheters, and ultrasound scan heads were systematically evaluated in this paper for a new commercial tracking system. We employed the electromagnetic tracking system Aurora (Mednetix/CH, NDI/Can); data were acquired using the serial port of a PC running SuSE Linux 7.1 (SuSE, Gmbh, Nürnberg). Objects introduced into the digitizer volume included wire loops of different diameters, wire guides, optical tracking tools, an ultrasonic (US) scan head, an endoscope with radial ultrasound scan head and various other objects used in operating rooms and interventional suites. Beyond this, we determined the influence of a C-arm fluoroscopy unit. To quantify the reliability of the system, the miniaturized sensor was mounted on a nonmetallic measurement rack while the transmitter was fixed at three different distances within the digitizer range. The tracker was shown to be more sensitive to distortions caused by materials close to the emitter (average distortion error 13.6 mm +/- 16.6 mm for wire loops positioned at a distance between 100 mm and 200 mm from the emitter). Distortions caused by materials near the sensor (distances smaller than 100 mm) are small (typical error 2.2 mm +/- 1.9 mm). The C-arm fluoroscopy unit caused considerable distortions and limits the reliability of the tracker (distortion error 18.6 mm +/- 24.9 mm). Distortions resulting from the US scan head are high at distances smaller than about 100 mm from the emitter. The distortions also increase when the scan head is positioned horizontally and close to the sensor (average error 4.1 mm +/- 1.5 mm when the scan head is positioned within a distance of 100 mm from the sensor). The distortions are slightly higher when the ultrasound machine is switched on. We also evaluated the influence of common medical instruments on distance measurements. For these measurements the average deviation from the known distance of 200 mm amounted to 3.0 mm +/- 1.5 mm (undistorted distance measurement 1.5 mm +/- 0.3 mm). The deviations also depend on the relative orientation between emitter and sensor. The results demonstrate that the miniature tracking system opens up new perspectives with regard to surgery applications where a flexible instrument is to be tracked within the body. Significant distortions caused by metallic objects only occur in the worst cases, for example, in the presence of a closed, unisiolated wire loop or a C-arm fluorescence unit close to the emitter and which can be avoided by suitable usage.     

Thiophene as a structural element of physiologically active substances. 11. Substituted thieno[2,3-d]imidazoles as potential antiviral agents

Thiophene as a Structural Element of Physiologically Active Compounds, XI: Substituted Thieno[2,3-d]imidazoles as Potentially Antiviral Compounds A novel synthesis of thieno[2,3-d]imidazole is described. In the key reaction sequence a nitrothiophene derivative is reacted with disodium cyanamide. The resulting sodium salt is subjected to ring closure after a catalytic hydrogenation step. Compound 1 , prepared by this procedure, has a substitution pattern equal to that of the benzene analogue enviroxime (B) , which is highly active against picorna virus and rhino virus in particular. However, the thienoimidazole 1 was found to be less active against these viruses than the benzimidazole.     

Hyperprostaglandin E syndrome in a nine-year-old child

The authors describe the history of a nine year old girl, with a disease that seemed to be hyperprostaglandin-E syndrome. They give a survey of the literature about the pathophysiological cause of the disease, the clinical and laboratory findings and the effect of indomethacin, which can inhibit the synthesis of prostaglandins. Prolonged treatment with indomethacin can decrease the urinary excretion of prostaglandine, polyuria and hypercalciuria and it can moderate the growth retardation. They found the same but milder clinical and laboratory features at the four year old brother of the patient too.