The acid mediated ortho-iodination of Weinreb amides using a readily available catalyst is described. The selective ortho-iodination of Weinreb amides, challenging substrates in directed C–H ...activations, and also of benzamides is achieved. The process works under mild conditions and tolerates air and moisture, having a great potential for industrial applications. The methodology can be applied under mechanochemical conditions maintaining the reaction outcome and selectivity.
The borylation of aryl and heteroaryl C–H bonds is valuable for the site-selective functionalization of C–H bonds in complex molecules. Iridium catalysts ligated by bipyridine ligands catalyze the ...borylation of the C–H bond that is most acidic and least sterically hindered in an arene, but predicting the site of borylation in molecules containing multiple arenes is difficult. To address this challenge, we report a hybrid computational model that predicts the Site of Borylation (SoBo) in complex molecules. The SoBo model combines density functional theory, semiempirical quantum mechanics, cheminformatics, linear regression, and machine learning to predict site selectivity and to extrapolate these predictions to new chemical space. Experimental validation of SoBo showed that the model predicts the major site of borylation of pharmaceutical intermediates with higher accuracy than prior machine-learning models or human experts, demonstrating that SoBo will be useful to guide experiments for the borylation of specific C(sp2)–H bonds during pharmaceutical development.
Reaching sub-millisecond 3D tracking of individual molecules in living cells would enable direct measurements of diffusion-limited macromolecular interactions under physiological conditions. Here, we ...present a 3D tracking principle that approaches the relevant regime. The method is based on the true excitation point spread function and cross-entropy minimization for position localization of moving fluorescent reporters. Tests on beads moving on a stage reaches 67 nm lateral and 109 nm axial precision with a time resolution of 0.84 ms at a photon count rate of 60 kHz; the measurements agree with the theoretical and simulated predictions. Our implementation also features a method for microsecond 3D PSF positioning and an estimator for diffusion analysis of tracking data. Finally, we successfully apply these methods to track the Trigger Factor protein in living bacterial cells. Overall, our results show that while it is possible to reach sub-millisecond live-cell single-molecule tracking, it is still hard to resolve state transitions based on diffusivity at this time scale.
Abstract
Reduced left ventricular ejection fraction (LVEF) is associated with increased mortality after acute myocardial infarction (AMI). However, the prognostic impact of elevated systolic ...pulmonary artery pressure (sPAP) in the very elderly patients after AMI is lacking. We aimed to study the impact of elevated sPAP on one- and five-year all-cause mortality after AMI in very elderly patients, 80 years of age and older. Of a total number of 353 patients (≥ 80 years) who were hospitalized with acute coronary syndrome, 162 patients presenting with AMI and with available data of sPAP on echocardiography were included and followed-up for 5 years. The survival analyses were performed using Cox-Regression models adjusted for conventional risk factors including LVEF. Altogether 66 of 162 patients (41%) had ST-segment elevation MI, and 121 (75%) of patients were treated with percutaneous coronary intervention in the acute phase. Echocardiography during the admission revealed that 78 patients (48%) had a LVEF ≤ 45% and 66 patients (41%) had a sPAP ≥ 40 mmHg. After one and five years of follow-up, 23% (n = 33) and 53% (n = 86) of patients died, respectively. A multivariable Cox-Regression analysis showed that the elevated sPAP (≥ 40 mmHg) was an independent predictor of increased mortality in both one and five years after AMI; HR of 2.63 (95%, CI 1.19–5.84,
P
0.017) and HR of 2.08 (95%, CI 1.25–3.44,
P
0.005) respectively, whereas LVEF ≤ 45% did not show any statistically significant impact, neither on one- nor on five-year mortality (HR 1.3, 95% CI 0.6–2.9,
p
= 0.469) and (HR 1.4, 95% CI 0.8–2.4,
p
= 0.158), respectively. Elevated sPAP was an independent risk factor for one- and five-year all-cause mortality after AMI in very elderly patients and sPAP seems to be a better prognostic predictor for all-cause mortality than LVEF. The risk of all-cause mortality after AMI increased with increasing sPAP.
Rapid and accurate translation of the genetic code into protein is fundamental to life. Yet due to lack of a suitable assay, little is known about the accuracy-determining parameters and their ...correlation with translational speed. Here, we develop such an assay, based on Mg2+ concentration changes, to determine maximal accuracy limits for a complete set of single-mismatch codon–anticodon interactions. We found a simple, linear trade-off between efficiency of cognate codon reading and accuracy of tRNA selection. The maximal accuracy was highest for the second codon position and lowest for the third. The results rationalize the existence of proofreading in code reading and have implications for the understanding of tRNA modifications, as well as of translation error-modulating ribosomal mutations and antibiotics. Finally, the results bridge the gap between in vivo and in vitro translation and allow us to calibrate our test tube conditions to represent the environment inside the living cell.
In the pursuit of improved compound identification and database search tasks, this study explores heteronuclear single quantum coherence (HSQC) spectra simulation and matching methodologies. HSQC ...spectra serve as unique molecular fingerprints, enabling a valuable balance of data collection time and information richness. We conducted a comprehensive evaluation of the following four HSQC simulation techniques: ACD/Labs (ACD), MestReNova (MNova), Gaussian NMR calculations (DFT), and a graph-based neural network (ML). For the latter two techniques, we developed a reconstruction logic to combine proton and carbon 1D spectra into HSQC spectra. The methodology involved the implementation of three peak-matching strategies (minimum-sum, Euclidean-distance, and Hungarian distance) combined with three padding strategies (zero-padding, peak-truncated, and nearest-neighbor double assignment). We found that coupling these strategies with a robust simulation technique facilitates the accurate identification of correct molecules from similar analogues (regio- and stereoisomers) and allows for fast and accurate large database searches. Furthermore, we demonstrated the efficacy of the best-performing methodology by rectifying the structures of a set of previously misidentified molecules. This research indicates that effective HSQC spectral simulation and matching methodologies significantly facilitate molecular structure elucidation. Furthermore, we offer a Google Colab notebook for researchers to use our methods on their own data (https://github.com/AstraZeneca/hsqc_structure_elucidation.git).
A triphenylphosphinegold(I)-catalyzed cyclopropanation of olefins using propargyl esters as gold(I)−carbene precursors is reported. This reaction provided the basis for the use of a DTBM-SEGPHOS ...gold(I) complex as a catalyst in the enantioselective (up to 94% ee) preparation of vinyl cyclopropanes with high cis-selectivity.
A protocol for the C–H activation/iodination of benzoic acids catalyzed by a simple iridium complex has been developed. The method described in this paper allows the ortho-selective iodination of a ...variety of benzoic acids under extraordinarily mild conditions in the absence of any additive or base in 1,1,1,3,3,3-hexafluoroisopropanol as the solvent. The iridium catalyst used tolerates air and moisture, and selectively gives ortho-iodobenzoic acids with high conversions. Mechanistic investigations revealed that an Ir(III)/Ir(V) catalytic cycle operates, and that the unique properties of HFIP enables the C–H iodination using the carboxylic moiety as a directing group.
Twelve antibiotic substances for human use, including trimethoprim and representatives of the fluoroquinolone (FQ), sulfonamide (SA), penicillin (PE), cephalosporin (CE), nitroimidazole (NI), ...tetracycline (TC), and macrolide (MA) groups, were subjected to a screening study at five Swedish sewage treatment plants (STPs) during one week in 2002 and one week in 2003. The analytes were extracted from raw sewage water, final effluent, and sludge by solid-phase extraction (SPE) or liquid−solid extraction (as appropriate) and then identified and quantified by liquid chromatography/tandem mass spectrometry. The most frequently detected antibiotics in the matrices considered in this study were norfloxacin, ofloxacin, ciprofloxacin, trimethoprim, sulfamethoxazole, and doxycycline. The other analytes were only detected in a few samples. Analysis of the weekly mass flows through each STP showed that FQs were partly eliminated from the water during sewage water treatment and the highest amounts of these substances were found in sludge. Sulfamethoxazole and trimethoprim were mainly found in raw sewage water and final effluent, but these substances had balancing mass flows, indicating that they too can withstand sewage water treatment. The mass flow patterns for doxycycline were more complex, with high amounts occurring in sludge in some cases, suggesting that the behavior of this analyte may be more strongly influenced by the treatment process and other variables at individual STPs. The environmental load (the sum of the amounts in the final effluent and sludge) normalized to the number of inhabitants in the catchment area of each investigated STP compared with theoretical predictions based on consumption data (in parentheses) showed good correlations: norfloxacin, 0.8 (0.9); ofloxacin, 0.3 (0.2); ciprofloxacin, 1.3 (3.5); sulfamethoxazole, 0.2 (0.4); trimethoprim, 1.1 (1.0); and doxycycline, 0.7 (0.4) mg per person per week. The results show that reasonably accurate predictions of environmental load of these antibiotics can be time-effectively derived from consumption data without additional measurements.
Radical hydrofunctionalizations of electronically unbiased dienes are challenging to render regioselective, because the products are nearly identical in energy. Here, we report two engineered ...FMN-dependent “ene”-reductases (EREDs) that catalyze regiodivergent hydroalkylations of cyclic and linear dienes. While previous studies focused exclusively on the stereoselectivity of alkene hydroalkylation, this work highlights that EREDs can control the regioselectivity of hydrogen atom transfer, providing a method for selectively preparing constitutional isomers that would be challenging to prepare using traditional synthetic methods. Engineering the ERED from Gluconabacter sp. (GluER) furnished a variant that favors the γ,δ-unsaturated ketone, while an engineered variant from a commercial ERED panel favors the δ,ε-unsaturated ketone. The effect of beneficial mutations has been investigated using substrate docking studies and the mechanism probed by isotope labeling experiments. A variety of α-bromo ketones can be coupled with cyclic and linear dienes. These interesting building blocks can also be further modified to generate difficult-to-access heterocyclic compounds.
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