Syntheses of furanocembranoid macrocycles with emphasis on the total sof providencin

Furanocembranoide Diterpene sind eine riesige, stets wachsende Klasse mariner Naturstoffe. Sowohl ihre interessanten biologischen Eigenschaften und ihre komplexen molekularen Architekturen, als auch ihre begrenzte Verfügbarkeit, machen sie zu herausfordernden synthetischen Zielen. Die Mehrheit der Vertreter dieser Klasse lässt sich in drei Hauptgruppen unterteilen, die sich im Wesentlichen durch ihre umgelagerten Kohlenstoffgerüste unterscheiden: Pseudopterane, Gersolane und Furanocembranoide. Innerhalb dieser drei Klassen unterscheiden sich deren Vertreter hauptsächlich durch ihren Oxidationsgrad und ihr Oxidationsmuster. Providencin (1) ist ein bekannter Vertreter der Furanocembranoide. Es wurde im Jahr 2003 von Rodriguez et al. isoliert und charakterisiert und besitzt einige seltene Strukturmotive, wie sein, bisher literatur-unbekanntes, hoch oxigeniertes Bicyclo[12.2.0]hexadecan-Skelett. Des Weiteren besitzt Providencin (1) neun stereogene Zentren und eine vierfach substituierte Cyclobutan-Einheit. Wegen der hohen Ringspannung, die das Molekül aufweist, weichen Furan und Butenolid Untereinheit in eine zueinander orthogonale Position aus, welche die Totalsynthese von Providencin (1) erschweren. Bis heute ist keine Totalsynthese literaturbekannt. Im Folgenden werden mehrere Zugänge präsentiert, welche die Ringspannung des Moleküls sukzessive herabsetzen. Die schrittweise Öffnung rigider Strukturmotive ermöglicht eine höhere Flexibilität und deshalb eine Erleichterung der schwierigen Makrozyklisierung. Dazu werden vier gut etablierte Makrozyklisierungsmethoden in zwei Syntheseserien (Cyclobutan- und Isopropenyl-Serie) verwendet: Ringschlussmetathese, Horner-Wadsworth-Emmons Bedingungen, Makro-laktonisierung und (Übergangs-)metall vermittelte Kohlenstoff-Kohlenstoff-Bindungs-knüpfung. Die Fragmente der einzelnen Ansätze wurden stereoselektiv synthetisiert. Ausgangsmaterial für die Cyclobutan-Serie war (±)-cis-Bicyclo[3.2.0]hept-2-en-6-on (180), welches den gewünschten viergliedrigen Ring bereits besitzt. Für die Isopropenyl-Serie wurde (R)-(-)-Carvon (359) als optimales Startmaterial gewählt. Sowohl in der Cyclobutan-, als auch in der Isopropenyl-Serie erwies sich der Metathese Zugang als zielführend. Dadurch konnten hoch funktionalisierte, weit fortgeschrittene Zwischenstufen synthetisiert werden, wie zum Beispiel Verbindung 213 in einer 21-Stufen Sequenz oder Verbindung 369 in einer 14-Stufen Sequenz. Da Providencin (1) unter den furanocembranoiden Diterpenen der einzige Vertreter ist, der eine Cyclobutan-Untereinheit an dieser Position aufweist, ermöglicht die Cyclobutan-Serie lediglich die maßgeschneiderte Synthese von (1). Der Isopropenyl-Ansatz ermöglicht jedoch die Synthese zahlreicher weiterer Vertreter dieser Naturstoffklasse, wie zum Beispiel Iopholide (57), Iophodiol A/B und Bipinnatin E (58).The class of furanocembranoid diterpenes is a huge, still growing family of marine natural products. Their interesting biological activities and complex molecular architectures, accompanied by their limited availability make them challenging synthetic targets. The vast majority of the family’s constituents can be divided in three different classes, depending on their rearranged carbon-skeletons: pseudopteranes, gersolanes and furanocembranoids. Among each other, they mainly differ in their degrees of oxygenation and oxygenation patterns. A well known member of the latter family is Providencin (1). It was first isolated and subsequently structure elucidated in 2003 by Rodriguez et al. The cyclic diterpene has some very interesting structural features. Its highly oxygenated hexacyclic structure is based on a previously undescribed bicyclo[12.2.0]hexadecane ring system. It bears nine stereogenic centers and its cyclobutanol subunit is four-fold substituted. Due to the highly strained ring system, the butenolide moiety is in a perpendicular orientation to the furan moiety, which makes the total synthesis of this molecule considerably difficult. To this day, no total synthesis has been published. Herein several approaches with decreasing the molecule’s ring strain are reported. The stepwise opening of rigid motifs should facilitate the crucial step of the macrocyclization. Four different, well established macrocyclization techniques were tested in two different synthetic series (cyclobutane- and isopropenyl-series): Ring closing metathesis, Horner-Wadsworth-Emmons conditions, macrolactonization, and (transition) metal mediated carbon-carbon-bond forming reactions. The fragments of each approach were synthesized in a stereoselective and convergent manner. The cyclobutane series exhibits this structural motif already in the starting material (±-cis-bicyclo[3.2.0]hept-2-en-6-one; 180), whereas in the isopropenyl series (R)-(-)-Carvone (359) was used. The latter one is a chiral pool starting material and therefore, allows the total synthesis of diterpenes starting with a cyclic monoterpene. The metathesis approaches in the cyclobutane, as well as in the isopropenyl series gave the most promising results and yielded highly advanced intermediates in the synthesis of Providencin (1). Since Providencin (1) is the only depicted member of the cembranoid family bearing a cyclobutane moiety in this position, the cyclobutane series is perfect for the synthesis of (1). In contrast, the isopropenyl series offers a flexible approach to the carbon-skeleton of numerous members of this family. Overall, most promising key intermediate 213 was synthesized in a 21-linear-steps sequence and provided access to a possible total synthesis of Providencin (1). Furthermore, the 14-step-synthesis of key intermediate 369 disclosed the biomimetic synthesis of Providencin (1) en route with numerous other natural products, such as Iopholide (57), Iophodiol A/B and Bipinnatin E (58)

Grounding systems for power supply facilities

This study aims to define some recommendations for choice of grounding system type for power supply facility. Operating modes of 0.4 kV networks approved by International Electrotechnical Commission (IEC) were considered and their advantages and disadvantages were identified. The comparison criteria were based on the conditions of human safety from electric shock in the breakdown of insulation on the body of electrical equipment, possibilities of expanding the network and uninterruptible power supply. The real application of the neutral modes and the possibility of installing protective devices were also taken into account. All the recommendations made is planned to apply for the modernization of the urban networks and the calculation of the earthing arrangement by using special software

Four-day antithrombin therapy does not seem to attenuate hypercoagulability in patients suffering from sepsis

INTRODUCTION: Sepsis activates the coagulation system and frequently causes hypercoagulability, which is not detected by routine coagulation tests. A reliable method to evaluate hypercoagulability is thromboelastography (TEG), but this has not so far been used to investigate sepsis-induced hypercoagulability. Antithrombin (AT) in plasma of septic patients is decreased, and administration of AT may therefore reduce the acquired hypercoagulability. Not clear, however, is to what extent supraphysiologic plasma levels of AT decrease the acute hypercoagulability in septic patients. The present study investigates the coagulation profile of septic patients before and during four day high-dose AT therapy. METHODS: Patients with severe sepsis were randomly assigned to receive either 6,000 IU AT as a bolus infusion followed by a maintenance dose of 250 IU/hour over four days (n = 17) or placebo (n = 16). TEG, platelet count, plasma fibrinogen levels, prothrombin time and activated partial thromboplastin time were assessed at baseline and daily during AT therapy. RESULTS: TEG showed a hypercoagulability in both groups at baseline, which was neither reversed by bolus or by maintenance doses of AT. The hypercoagulability was mainly caused by increased plasma fibrinogen, and to a lesser extent by platelets. Plasmatic coagulation as assessed by the prothrombin time and activated partial thromboplastin time was similar in both groups, and did not change during the study period. CONCLUSION: The current study shows a distinct hypercoagulability in patients suffering from severe sepsis, which was not reversed by high-dose AT treatment over four days. This finding supports recent data showing that modulation of coagulatory activation in septic patients by AT does not occur before one week of therapy. Trial registration: Current Control Trials ISRCTN2293102

Endobronchial intubation detected by insertion depth of endotracheal tube, bilateral auscultation, or observation of chest movements: randomised trial

Objective To determine which bedside method of detecting inadvertent endobronchial intubation in adults has the highest sensitivity and specificity

The effect of exercise on vastus medialis oblique muscle architecture: An ultrasound investigation.

The vastus medialis oblique (VMO) is thought to be implicated in patellofemoral pain (PFP), and weakness in this portion of the vastus medialis muscle may lead to PFP. Management includes physiotherapy to strengthen the VMO. Although this intervention has been shown to be effective, the effects on the architecture of the muscle have not been investigated. This study aims to determine the changes in VMO architecture following a program of strengthening exercises. Twenty-one male participants underwent an initial ultrasound scan to measure the fiber angle and the insertion level of the VMO on the patella. Each subject then undertook a 6-week quadriceps femoris strengthening program; the scan and measurements were then repeated. A significant increase in VMO fiber angle and insertion length was observed. Average fiber angle increased by 5.24°; average insertion length increased by 2.7 mm. There was found to be a significant negative correlation between the initial values and the degree of change. Pearson's coefficient of correlation for measurements of patella length taken before and after exercise was 0.921, indicating a high degree of reliability. There was a significant positive correlation between fiber angle change and declared level of compliance (R2 = 0.796). The results reported here indicate that physiotherapy leads to a significant change in VMO morphology. Given the inverse correlation noted between initial architectural parameters and the degree of change, we suggest that patients who would benefit most from physiotherapy can be identified in clinic using a simple ultrasound technique

Shedding light on the variability of optical skin properties: finding a path towards more accurate prediction of light propagation in human cutaneous compartments

YesFinding a path towards a more accurate prediction of light propagation in human skin remains an aspiration of biomedical scientists working on cutaneous applications both for diagnostic and therapeutic reasons. The objective of this study was to investigate variability of the optical properties of human skin compartments reported in literature, to explore the underlying rational of this variability and to propose a dataset of values, to better represent an in vivo case and recommend a solution towards a more accurate prediction of light propagation through cutaneous compartments. To achieve this, we undertook a novel, logical yet simple approach. We first reviewed scientific articles published between 1981 and 2013 that reported on skin optical properties, to reveal the spread in the reported quantitative values. We found variations of up to 100-fold. Then we extracted the most trust-worthy datasets guided by a rule that the spectral properties should reflect the specific biochemical composition of each of the skin layers. This resulted in the narrowing of the spread in the calculated photon densities to 6-fold. We conclude with a recommendation to use the identified most robust datasets when estimating light propagation in human skin using Monte Carlo simulations. Alternatively, otherwise follow our proposed strategy to screen any new datasets to determine their biological relevance.European Marie-Curie Actions Programme, Grant agreement no. 60788

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules

Costs and effectiveness of a brief MRI examination of patients with acute knee injury

The aim of this study was to assess the costs and effectiveness of selective short magnetic resonance imaging (MRI) in patients with acute knee injury. A model was developed to evaluate the selective use of MRI in patients with acute knee injury and no fracture on radiography based on the results of a trial in which 208 patients were randomized between radiography only and radiography plus MRI. We analyzed medical (diagnostic and therapeutic) costs, quality of life, duration of diagnostic workup, number of additional diagnostic examinations, time absent from work, and time to convalescence during a 6-month follow-up period. Quality of life was lowest (EuroQol at 6 weeks 0.61 (95% CI 0.54–0.67)); duration of diagnostic workup, absence from work, and time to convalescence were longest; and the number of diagnostic examinations was largest with radiography only. These outcomes were more favorable for both MRI strategies (EuroQol at 6 weeks 0.72 (95% CI 0.67–0.77) for both). Mean total costs were 2,593 euros (95% CI 1,815–3,372) with radiography only, 2,116 euros (95% CI 1,488–2,743) with radiography plus MRI, and 1,973 euros (95% CI 1,401–2,543) with selective MRI. The results suggest that selective use of a short MRI examination saves costs and potentially increases effectiveness in patients with acute knee injury without a fracture on radiography

Photobiomodulation devices for hair regrowth and wound healing: a therapy full of promise but a literature full of confusion.

yesPhotobiomodulation is reported to positively influence hair regrowth, wound healing, skin rejuvenation, and psoriasis. Despite rapid translation of this science to commercial therapeutic solutions, significant gaps in our understanding of the underlying processes remain. The aim of this review was to seek greater clarity and rationality specifically for the selection of optical parameters for studies on hair regrowth and wound healing. Our investigation of 90 reports published between 1985-2015 revealed major inconsistencies in optical parameters selected for clinical applications. Moreover, poorly understood photoreceptors expressed in skin such as cytochrome c oxidase, cryptochromes, opsins, may trigger different molecular mechanisms. All this could explain the plethora of reported physiological effects of light. To derive parameters for optimal clinical efficacy of photobiomodulation, we recommend a more rational approach, underpinning clinical studies with research of molecular targets and pathways using well-defined biological model systems enabling easy translation of optical parameters from in vitro to in vivo. Furthermore, special attention needs to be paid when conducting studies for hair regrowth, aiming for double-blind, placebo-controlled randomized clinical trials as the gold standard for quantifying hair growth.European Marie-Curie Actions Programme, Grant agreement no.: 60788