Enantioselective Total Synthesis of (‐)‐Finerenone using Asymmetric Transfer Hydrogenation

(−)‐Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6‐step synthesis of (−)‐finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (−)‐finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.<br/

Evaluation of Transperineal Magnetic Resonance Imaging/Ultrasound-Fusion Biopsy Compared to Transrectal Systematic Biopsy in the Prediction of Tumour Aggressiveness in Patients with Previously Negative Biopsy

Objectives: We compared the transperineal MRI/ultrasoundfusion biopsy (fusPbx) to transrectal systematic biopsy (sys-Pbx) in patients with previously negative biopsy and investigated the prediction of tumour aggressiveness with regard to radical prostatectomy (RP) specimen. Material and Methods: A total of 710 patients underwent multiparametric magnetic resonance imaging (mpMRI), which was evaluated in accordance with Prostate Imaging Reporting and Data System (PI-RADS). The maximum PI-RADS (maxPI-RADS) was defined as the highest PI-RADS of all lesions detected in mpMRI. In case of proven prostate cancer (PCa) and performed RP, tumour grading of the biopsy specimen was compared to that of the RP. Significant PCa (csPCa) was defined according to Epstein criteria. Results: Overall, scPCa was detected in 40% of patients. The detection rate of scPCa was 33% for fusPbx and 25% for sysPbx alone (p < 0.005). Patients with a maxPI-RADS ≥3 and a prostate specific antigen (PSA)-density ≥0.2 ng/mL2 harboured more csPCa than those with a PSA-density < 0.2 ng/mL2 (41% [33/81] vs. 20% [48/248]; p < 0.001). Compared to the RP specimen (n = 140), the concordance of tumour grading was 48% (γ = 0.57), 36% (γ = 0.31) and 54% (γ = 0.6) in fusPbx, sysPbx and comPbx, respectively. Conclusions: The combination of fusPbx and sysPbx outperforms both biopsy modalities in patients with re-biopsy. Additionally, the PSA-density may represent a predictor for csPCa in patients with maxPI-RADS ≥3

Measuring thermoelectric transport properties of materials

In this review we discuss considerations regarding the common techniques used for measuring thermoelectric transport properties necessary for calculating the thermoelectric figure of merit, zT. Advice for improving the data quality in Seebeck coefficient, electrical resistivity, and thermal conductivity (from flash diffusivity and heat capacity) measurements are given together with methods for identifying possible erroneous data. Measurement of the Hall coefficient and calculation of the charge carrier concentration and mobility is also included due to its importance for understanding materials. It is not intended to be a complete record or comparison of all the different techniques employed in thermoelectrics. Rather, by providing an overview of common techniques and their inherent difficulties it is an aid to new researchers or students in the field. The focus is mainly on high temperature measurements but low temperature techniques are also briefly discussed

Quantitative computed tomography and magnetic resonance imaging of the human pineal gland

Deckblatt Inhaltsverzeichnis 1 Einleitung 4 1\. 1 Aufbau und Funktion der menschlichen Zirbeldrüse 4 1\. 2 Melatonin 6 1\. 3 Schlafstörungen und Melatonin 10 1\. 4 Zirbeldrüsenverkalkung und Melatonindefizit 11 1\. 5 Radiologische Untersuchungen der Gl.pinealis 13 2 Material und Methoden 19 2\. 1 Zirbeldrüsen 19 2\. 2 Antropomorphes Phantom 20 2\. 3 CT-Messungen und Auswertung 22 2\. 4 MRT-Messungen und Auswertung 25 3 Ergebnisse 28 3\. 1 CT-Messungen 28 3.2 MR-Messung 36 4 Diskussion 42 5 Zusammenfassung 49 6 Anhang 51 7 Danksagung 54 8 LiteraturverzeichnisStand der Forschung und Fragestellung Mit zunehmendem Alter finden sich beim Menschen immer häufiger Zirbeldrüsenkonkremente. Die Melatoninproduktion kann dadurch beeinträchtigt werden. Mit Hilfe der Computertomographie kann das Volumen des unverkalkten Zirbeldrüsengewebes (UCPT, uncalcified pineal tissue) quantifiziert werden. In dieser Arbeit wurde der Einfluß der benutzten Schichtdicke auf die Reproduzierbarkeit solcher Messungen untersucht. Außerdem wurde der Zusammenhang zwischen der Signalintensität der Zirbeldrüsen auf MR- Aufnahmen und der Drüsenverkalkung erforscht. Material und Methoden Untersucht wurden 22 postmortal entnommene menschliche Zirbeldrüsen. Die computertomographische Bestimmung des Volumens des unverkalkten Drüsengewebes (UCPT) erfolgte nach der Methode von Kunz et al. Die 1mm-, 2mm-, 4mm- und 8mm- CT-Messungen wurden jeweils zweimal durchgeführt. Als Maß für die Reproduzierbarkeit (repeatability) wurde die Wertepaarvarianz (within-subject- variance) benutzt. Zur statistischen Auswertung dienten der Friedman-Test und der multiple Vergleich nach Wilcoxon und Wilcox. Die MR-Untersuchung jeder Drüse wurde jeweils nur einmal mit Hilfe dreier MR-Sequenzen durchgeführt. Als Maß für die Signalintensität auf MR-Aufnahmen diente das dimensionslose signal intensity ratio (SIR). Der Pearson- Korrelationskoeffizient diente zur statistischen Auswertung des Zusammenhangs zwischen dem SIR-Werten und dem computertomographisch ermittelten mittleren Dichtewerten der Drüsen. Ergebnisse Die 1mm-CT-Methode zeigte die beste Reproduzierbarkeit sowohl für die Drüsenvolumenmessung als auch für die UCPT-Messung. Die within-subject variance der Volumenmessung war 41,5 mm6 und die der UCPT-Messung 44 VU2(VU=volume units). Die 1mm-Messung unterscheidet sich signifikant von der 4mm- und der 8mm-Messung nicht aber von der 2mm-Messung. Bei keiner der drei hier benutzten MR-Sequenzen konnte ein signifikanter Zusammenhang zwischen SIR (signal intensity ratio) und dem computertomographisch ermittelten mittleren Dichtewert der Drüse gefunden. Schlussfolgerung Die Ergebnisse zeigen, daß die 1mm-Methode den 4mm- und 8mm-Methoden hinsichtlich der Reproduzierbarkeit überlegen ist. Die von uns benutzten MR-Sequenzen waren nicht für die Beurteilung der Zirbeldrüsenverkalkung geeignet.Rationale and Objectives Increasing pineal calcification can cause a relative melatonin deficite. Computed tomography can be used for quantifying the uncalcified pineal tissue volume (UCPT). Earlier studies had shown that the UCPT is positively and significantly associated with the excretion of the melatonine metabolite aMT6s in urine. The main purpose of this study was to estimate the influence of slice thickness on the repeatability of such CT- assisted measurements. Another aim of the study was to examine the relationship between the signal intensity of pineal glands on MR images and their level of calcification. Methods We examined 22 human pineal glands obtained at autopsy. Total pineal volume and uncalcified pineal tissue volume(UCPT) were estimated using a CT-assisted method developed by Kunz et al. CT measurements were repeated twice with a slice thickness of 1, 2, 4 or 8 mm. The within-subject variance of these repeated measurements is an estimate of their repeatability. The Friedman test and the Wilcoxon-Wilcox test were used to compare the repeatability of the different methods. Magnetic resonance imaging was used to measure the SIR (signal intensity ratio) of the pineal glands. SIR is the quotient of the signal intensity of the gland and the signal intensity of water. Each examination included measurements with three different MR sequences (one T2 weighted and two T1 weighted). For each sequence the SIR was compared with the mean radiographic density of the respecive glands using Pearson�s correlation coefficient. The mean radiographic density was calculated using the CT data. Results The 1mm-slice method had the best repeatability. In this case the within-subject variance of the volume measurement was 41,5 mm6 and the within-subject variance of the UCPT measurement was 44 VU2 (VU=Volume Units). The 1mm-slice method has a significantly better repeatability in comparison to the 4mm- and 8mm-methods (p<0,05). For all three MR sequences there was no significant correlation between SIR and mean radiographic density. Conclusions The repeatability of CT-assisted UCPT measurements is greatly influenced by slice thickness. 1mm slices offer a significantly improved repeatability in comparison to 4 mm or 8mm slices. The MR sequences used in this study proved to be unsuitable for the evaluation of pineal calcification

Equilibria and formation kinetics of some cyclen derivative complexes of lanthanides

International audienceThe kinetics of the formation reactions between the lanthanide(III) ions Ce3+, Eu3+ and Yb3+ and four cyclen derivative ligands, DO3A-B, DO3A-ME, DO2A and DO2A-2B, were studied by spectrophotometry and a stopped-flow method at 25°C in 1.0 M KCl solutions. The reactions were found to be of first order, which was interpreted in terms of the formation of a diprotonated intermediate, Ln(H2L)+. The formation of products occurs via deprotonation and rearrangement of the intermediate, characterised by the rate constant, kr. The rate law obtained, kr=kOH[OH−], is similar to those obtained for the formation reactions of DOTA and DOTA derivative complexes. The rate constants, kOH, decrease with decrease in the number of charged carboxylate functional groups in the ligands; the lowest rates were found for the formation of the DO2A complexes. The formation rates increase significantly from Ce3+ to Yb3+. The direct proportionality between the formation rates and [H+]−1 was interpreted by assuming the equilibrium formation of a monoprotonated intermediate, Ln(HL), which undergoes deprotonation in a slow, rate-determining step. The validity of general base catalysis was detected in the formation reactions, which supports the assumption of the rate-controlling role of deprotonation of the monoprotonated intermediate. The protonation constants of the ligands DO3A-ME and DO2A-2B and the stability constants of their complexes were also determined. The ligand DO2A forms the usual complexes Ln(DO2A)+ and the unusual species Ln(DO2A)2 −. In the complexes Ln(DO2A)2 −, the two ligands exhibit different coordination modes which were demonstrated by 1H NMR spectroscopy