Access to Naphthoic Acid Derivatives through an Oxabenzonorbornadiene Rearrangement.

Herein, the synthesis of 1-hydroxy-2-naphthoic acid esters through an unexpected Lewis-acid-mediated 1,2-acyl shift of oxabenzonorbornadienes is reported. Using this methodology, novel substitution patterns for 1-hydroxy-2-naphtoic acid esters can be obtained. A mechanistic proposal and rationale for this transformation, the products of which had been previously incorrectly characterized, is given.

Electrocatalytic Activation of Donor-Acceptor Cyclopropanes and Cyclobutanes: An Alternative C(sp3 )-C(sp3 ) Cleavage Mode.

We describe the first electrochemical activation of D-A cyclopropanes and D-A cyclobutanes leading after C(sp3 )-C(sp3 ) cleavage to the formation of highly reactive radical cations. This concept is utilized to formally insert molecular oxygen after direct or DDQ-assisted anodic oxidation of the strained carbocycles, delivering ß- and γ-hydroxy ketones and 1,2-dioxanes electrocatalytically. Furthermore, insights into the mechanism of the oxidative process, obtained experimentally and by additional quantum-chemical calculations are presented. The synthetic potential of the reaction products is demonstrated by diverse derivatizations.

Regio- and Diastereoselective Dimerization of Diazo Carbonyls: A Cooperative Catalytic Approach to Complex Scaffolds with Four Contiguous Stereocenters.

Starting from readily available o-diazoacyl-substituted arene carboxylates, scaffolds with the 5,9-epoxycyclohepta[b]pyran-2(3H)-one core were obtained by cooperative RhII , Lewis and Brønsted acid catalysis. Four new bonds, three functional groups (lactone, ketal, and alcohol) and four contiguous stereocenters are formed during this regio- and diastereoselective process in a single synthetic step. Intensive optimization and mechanistic studies, including the trapping, isolation, and elucidation of reaction intermediates, led to a plausible mechanistic scenario. The reaction is proposed to involve carbonyl ylides but also transient species of the ketocarbene equilibrium that undergo a cascade of cycloaddition and skeletal rearrangements.

Palladium-Catalyzed Selective meta-C-H Deuteration of Arenes: Reaction Design and Applications.

Deuterium-labeled compounds find wide applications in kinetic studies, and within the pharmaceutical industry. An easily removable pyrimidine-based auxiliary has been employed for the meta-C-H deuteration of arenes. The scope of this Pd-catalyzed deuteration using commercially available [D1 ]- and [D4 ]-acetic acid has been demonstrated by its application in phenylacetic acid and phenylmethanesulfonate derivatives. A detailed mechanistic study led us to explore the reversibility of the non-rate determining C-H activation step. The present study of meta-deuterium incorporation illustrates the template morphology in terms of selectivity. The applicability of this method has been demonstrated by the selective deuterium incorporation into various pharmaceuticals.

(3+3)-Annulation of Carbonyl Ylides with Donor-Acceptor Cyclopropanes: Synergistic Dirhodium(II) and Lewis Acid Catalysis.

The first (3+3)-annulation process of donor-acceptor cyclopropanes using synergistic catalysis is reported. The Rh2 (OAc)4 -catalyzed decomposition of diazo carbonyl compounds generated carbonyl ylides in situ. These 1,3-dipoles were converted with donor-acceptor cyclopropanes, activated by Lewis acid catalysis, to afford multiply substituted pyran scaffolds in high yield and diastereoselectivity. Extensive optimization studies enabled access to 9-oxabicyclo[3.3.1]nonan-2-one and 10-oxabicyclo[4.3.1]decen-2-ol cores, exploiting solvent effects on intermediate reactivity.

A Three-Arm Randomized Trial of Different Renal Denervation Devices and Techniques in Patients With Resistant Hypertension (RADIOSOUND-HTN).

BACKGROUND: Both radiofrequency and ultrasound endovascular renal sympathetic denervation (RDN) have proven clinical efficacy for the treatment of hypertension. We performed a head-to-head comparison of these technologies. METHODS: Patients with resistant hypertension were randomly assigned in a 1:1:1 manner to receive either treatment with (1) radiofrequency RDN of the main renal arteries; (2) radiofrequency RDN of the main renal arteries, side branches, and accessories; or (3) an endovascular ultrasound-based RDN of the main renal artery. The primary end point was change in systolic daytime ambulatory blood pressure at 3 months. RESULTS: Between June 2015 and June 2018, 120 patients were enrolled (mean age, 64±9 years±SD; mean daytime blood pressure, 153/86±12/13 mm Hg). Of these, 39 were randomly assigned to radiofrequency main renal artery ablation, 39 to combined radiofrequency ablation of the main artery and branches, and 42 to ultrasound-based treatment. Baseline daytime blood pressure, clinical characteristics, and treatment were well balanced between the groups. At 3 months, systolic daytime ambulatory blood pressure decreased by 9.5±12.3 mm Hg ( P<0.001) in the whole cohort. Although blood pressure was significantly more reduced in the ultrasound ablation group than in the radiofrequency ablation group of the main renal artery (-13.2±13.7 versus -6.5±10.3 mm Hg; mean difference, -6.7 mm Hg; global P=0.038 by ANOVA, adjusted P=0.043), no significant difference was found between the radiofrequency ablation groups (-8.3±11.7 mm Hg for additional side branch ablation; mean difference, -1.8 mm Hg; adjusted P>0.99). Similarly, the blood pressure reduction was not found to be significantly different between the ultrasound and the side branch ablation groups. Frequencies of blood pressure response ≥5 mm Hg were not significantly different (global P=0.77). CONCLUSIONS: In patients with resistant hypertension, endovascular ultrasound-based RDN was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories, and side branches was not. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02920034.

Ultrasound-based renal sympathetic denervation for the treatment of therapy-resistant hypertension: a single-center experience.

INTRODUCTION: The effectiveness of renal sympathetic denervation (RDN) as a treatment for therapy-resistant hypertension has been doubted as the Simplicity-HTN-3 trial was unable to show any treatment benefit over sham procedure. This might partly be explained by a high procedural variability in treatment with radiofrequency-based catheters. Recently, newer systems for RDN, like ultrasound-based devices, have been introduced into practice. To date however, data on their effectiveness for the treatment of resistant hypertension are scarce. We sought to evaluate the safety and effectiveness of an ultrasound-based, balloon-irrigated RDN catheter in a larger single-center cohort. METHODS: Patients with therapy-resistant hypertension [average blood pressure (BP) >135 mmHg SBP or >90 mmHg DBP in ambulatory BP measurement despite at least three antihypertensive drugs, including at least one diuretic] underwent ultrasound-based RDN. Treatment effect was assessed by comparing BP values at baseline and 3 months after the procedure. Patients underwent renal artery duplex sonography or MRI before and after RDN to exclude renal artery stenosis. RESULTS: Fifty consecutive patients underwent ultrasound-based RDN, of which 25 had undergone an unsuccessful radiofrequency RDN before. Mean SBP change at 3 months was -9.7 ±â€Š12.6/-10.6 ±â€Š13.7/-8.2 ±â€Š15.2 mmHg (ambulatory 24-h mean/daytime/night, P < 0.001 for all) and DBP changed by -5.1 ±â€Š7.4/-5.8 ±â€Š7.8/-3.9 ±â€Š10.3 mmHg (P ≤ 0.001/<0.001/0.01). No new renal artery stenosis could be detected after RDN. CONCLUSION: Ultrasound-based RDN seems to be well tolerated and effective for the treatment of patients with therapy-resistant hypertension.

[3 + 3]-Cycloaddition of Donor-Acceptor Cyclopropanes with Nitrile Imines Generated in Situ: Access to Tetrahydropyridazines.

Donor-acceptor cyclopropanes are reacted under the influence of a Lewis acid with hydrazonyl chlorides to afford tetrahydropyridazines. Formally, this transformation can be regarded as a [3 + 3]-cycloaddition of three-membered rings and nitrile imines generated in situ. This efficient method provides fast access to a variety of structurally diverse pyridazine derivatives. The structure of a typical product was confirmed by X-ray crystallography.

Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension.

UNLABELLED: Few data are available with regard to the effectiveness of renal sympathetic denervation in patients with resistant hypertension yet only mildly elevated blood pressure (BP). Patients with resistant hypertension and slightly elevated BP (day-time systolic pressure, 135-149 and diastolic pressure, 90-94 mm Hg on 24-hour ambulatory measurement) were randomized in a 1:1 ratio to renal sympathetic denervation with the Symplicity Flex Catheter (Medtronic) or an invasive sham procedure. The primary efficacy end point was the change in 24-hour systolic BP at 6 months between groups in the intention to treat population. A total of 71 patients underwent randomization. Baseline day-time systolic BP was 144.4±4.8 mm Hg in patients assigned to denervation and 143.0±4.7 mm Hg in patients randomized to the sham procedure. The mean change in 24-hour systolic BP in the intention to treat cohort at 6 months was -7.0 mm Hg (95% confidence interval, -10.8 to -3.2) for patients undergoing denervation and -3.5 mm Hg (95% confidence interval, -6.7 to -0.2) in the sham group (P=0.15). In the per protocol population, the change in 24-hour systolic BP at 6 months was -8.3 mm Hg (95% confidence interval, -11.7 to -5.0) for patients undergoing denervation and -3.5 mm Hg (95% confidence interval, -6.8 to -0.2) in the sham group (P=0.042). In patients with mild resistant hypertension, renal sympathetic denervation failed to show a significant reduction in the primary end point of 24-hour systolic BP at 6 months between groups in the intention to treat analysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01656096.

Studies with an immobilized metal affinity chromatography cassette system involving binuclear triazacyclononane-derived ligands: automation of batch adsorption measurements with tagged recombinant proteins.

This study describes the determination of the adsorption isotherms and binding kinetics of tagged recombinant proteins using a recently developed IMAC cassette system and employing automated robotic liquid handling procedures for IMAC resin screening. These results confirm that these new IMAC resins, generated from a variety of different metal-charged binuclear 1,4,7-triaza-cyclononane (tacn) ligands, interact with recombinant proteins containing a novel N-terminal metal binding tag, NT1A, with static binding capacities similar to those obtained with conventional hexa-His tagged proteins, but with significantly increased association constants. In addition, higher kinetic binding rates were observed with these new IMAC systems, an attribute that can be positively exploited to increase process productivity. The results from this investigation demonstrate that enhancements in binding capacities and affinities were achieved with these new IMAC resins and chosen NT1A tagged protein. Further, differences in the binding performances of the bis(tacn) xylenyl-bridged ligands were consistent with the distance between the metal binding centres of the two tacn moieties, the flexibility of the ligand and the potential contribution from the aromatic ring of the xylenyl group to undergo π/π stacking interactions with the tagged proteins.

Effects of ionic strength and mobile phase pH on the binding orientation of lysozyme on different ion-exchange adsorbents.

Chromatography is the most widely used technique for the purification of biopharmaceuticals in the biotech industry. Surprisingly, process development is often still based on empirical studies or experience; recently high-throughput screening stations are employed to minimize development time and to improve screening quality. Still, experimental effort remains high and a more detailed understanding of adsorption mechanisms on a molecular level underlying chromatographic separation could help in the future to select and design chromatography steps in silico. In this study, we focused on the elucidation of protein orientation upon adsorption onto a chromatographic resin. We identified two characteristic binding sites of lysozyme on SP Sepharose Fast Flow and one multipoint interaction of lysozyme with SP Sepharose XL. Increasing ionic strength did not significantly influence the binding, whereas changes in the mobile phase pH led to a re-orientation on SP Sepharose FF. This phenomenon agrees well with theoretical considerations, including a detailed description of the surface charge distribution with changing pH and linear elution experiments, giving an idea why proteins are often retained on ion-exchange materials beyond their isoelectric point.