A divergent synthesis of (-)-4-epi-shikimic acid was developed. This route features a one-pot zinc-mediated reductive ring opening of an arabinofuranose followed by a Barbier reaction and culminates in a ring-closing metathesis. Functionalization of (-)-4-epi-shikimic acid via conjugate addition of a thiol occurs in high diastereoselectivity to afford a product with the features of fucosylated glycans. 相似文献
Correction for ‘Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery’ by Christine N. Morrison et al., Chem. Sci., 2020, 11, 1216–1225, https://doi.org/10.1039/C9SC05586J.The authors regret that in the original article, inhibitory values reported for some metallofragments were incorrect. Unfortunately, DMSO stock solutions of reportedly active ferrocene-based metallofragments were found to decompose in the presence of light, which resulted in inaccurate inhibition values. The authors maintain that the core conclusions of the paper are accurate and the utility of three-dimensional metal complexes for fragment-based drug discovery has merit.In the original article, ‘class A’ metallofragments are comprised of ferrocene derivatives (Fig. 1). Some of these ferrocene fragments (specifically those containing carbonyl groups) are reported as broadly inhibiting several protein targets. It was noted in our original report that the ferrocene scaffold was likely promiscuous due to its lipophilicity and potential redox activity, but that it might still serve as a useful metallofragment for fragment-based drug discovery (FBDD) campaigns. However, re-evaluation of these compounds against the influenza endonuclease (PAN) failed to reproduce our original inhibition results for the class A metallofragments using freshly prepared stocks, indicating a problem with the materials used in the original study.Open in a separate windowFig. 1Chemical structures of class A metallofragments.Several compounds from class A were originally reported as having near complete (100%) inhibition against PAN endonuclease at an inhibitor concentration of 200 μM (and2).2). However, when re-evaluated under identical conditions, using freshly prepared DMSO stock solutions, inhibition was only observed with one fragment of this class (A22, Fig. 1), with the previously reported highly active fragments (A4, A7–A21,
Open in a separate windowReported and re-evaluated percent inhibition values of representative metallofragments against PAN endonuclease at 200 μM inhibitor concentration. Each compound was tested in triplicate from either two or three independent experimentsa
Open in a separate windowIn the original article, one representative member of each metallofragment class was assessed for stability by NMR. Compound A1 (ferrocene) proved stable in DMSO and class A metallofragments were stored as DMSO stocks at −80 °C, but were not consistently protected from light. As noted above, many of the derivatives in class A contain a ferrocenyl carbonyl motif. It has been previously reported that ferrocenyl ketones can undergo photoaquation (λ > 280 nm) in wet DMSO to produce a monocyclopentadienyliron cation, the anionic ligand, and free cyclopentadiene.1 Suspecting issues with photostability, we dissolved several of the ferrocenyl fragments in DMSO-d6, exposed them to ambient room light (fluorescent light bulb), and monitored stability by NMR. Indeed, photoinstability was confirmed by the observance of free cyclopentadienyl peaks appearing in the 1H NMR spectrum (Fig. 2). It should also be noted that while the fresh stock of A22 retained significant inhibition against PAN, it also exhibits sensitivity to light in DMSO.Open in a separate windowFig. 2Compound A7 in DMSO-d6 (left) and after exposure to ambient light for 24 h (right) demonstrating the photoinstability of this compound.Based on these findings, the authors regret that the inhibitory data associated with class A metallofragments are incorrect, likely because of photodecomposition of these ferrocene derivatives. To confirm if other classes of metallofragments were correctly reported, a representative member of each class was evaluated against PAN endonuclease at an inhibitor concentration of 200 μM using freshly prepared DMSO stocks. Each compound was tested in triplicate in two or three independent experiments, with the addition of 2,4-dioxo-4-phenylbutanoic acid (DPBA) as a positive control.2 Fortunately, these experiments largely reproduced our original findings. Although several fragments showed slightly greater activity upon re-evaluation (J1, L1, M1, Fig. 3), only one fragment initially identified as a hit (>50% inhibition) failed to show activity when re-examined (F1, Fig. 3). Other than compound F1, all selected compounds designated as ‘hits’ (>50% inhibition) retained a high level of inhibitory activity upon re-evaluation. Taken together, the authors believe the inaccuracies stemming from photostability issues are limited to class A compounds; however, these inaccuracies would include all other inhibition data reported for class A compounds, including assay data against other enzyme targets, IC50 values, and thermal shift assay (TSA) binding data. Furthermore, the hit rate against each target is likely lower than reported, with PAN having an adjusted hit rate of ∼28% (20/71).Open in a separate windowFig. 3Chemical structures of representative metallofragments from each class re-examined for inhibition activity against PAN endonuclease.The authors maintain that three-dimensional metallofragments represent a useful new line of inquiry for FBDD and our ongoing studies seek to further test this hypothesis. The core message of our original study – the ability of metallofragments to be useful scaffolds for FBDD that occupy hard-to-access three-dimensional chemical space – remains unchanged. However, as demonstrated by our error, the authors acknowledge that metallofragments may pose unique challenges that must be carefully considered and controlled for when using them in FBDD campaigns.The authors would like to take this opportunity to thank the readers who alerted them to the concerns regarding the inhibitory activities and allowed them to reinvestigate. Both the authors and the Royal Society of Chemistry appreciate their support.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.相似文献
Potential energy curves obtained through extensive ab initio configuration interaction calculations are reported for the states of HF below 14 eV as well as that for the ground state of HF+. Agreement with ultraviolet absorption data is obtained to within 0.2 eV. The disagreement between the reported UV absorption and electron scattering data is examined. 相似文献
The application of the elegant Fourier transform method of Smith et al.3,4 to measurements on ultrathin, “black” lipid membrane is described. A digital computer generates a waveform containing many frequencies, applies it to the measurement cell containing an artificial, ultrathin membrane, collects the resulting electrical response, extracts the cell admittance by a substitution method, and facilitates subsequent numerical data analysis. The performance of the instrument is illustrated. 相似文献
Functional connectivity measures based upon low-frequency blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) signal fluctuations have become a widely used tool for investigating spontaneous brain activity in humans. Still unknown, however, is the precise relationship between neural activity, the hemodynamic response and fluctuations in the MRI signal. Recent work from several groups had shown that correlated low-frequency fluctuations in the BOLD signal can be detected in the anesthetized rat — a first step toward elucidating this relationship. Building on this preliminary work, through this study, we demonstrate that functional connectivity observed in the rat depends strongly on the type of anesthesia used. Power spectra of spontaneous fluctuations and the cross-correlation-based connectivity maps from rats anesthetized with α-chloralose, medetomidine or isoflurane are presented using a high-temporal-resolution imaging sequence that ensures minimal contamination from physiological noise. The results show less localized correlation in rats anesthetized with isoflurane as compared with rats anesthetized with α-chloralose or medetomidine. These experiments highlight the utility of using different types of anesthesia to explore the fundamental physiological relationships of the BOLD signal and suggest that the mechanisms contributing to functional connectivity involve a complicated relationship between changes in neural activity, neurovascular coupling and vascular reactivity. 相似文献
The effectiveness of different concrete and pictorial models on students' understanding of the part-whole construct for fractions was investigated. Using interview data from fourth and fifth grade students from three different districts that adopted the Mathematics Trailblazers series, authors identified strengths and limitations of models used. Pattern blocks had limited value in aiding students' construction of mental images for the part-whole model as well as limited value in building meaning for adding and subtracting fractions. A paper fraction chart based on a paper folding model supported students' ability to order fractions with same numerators but was less useful in helping students on estimation tasks. The dot paper model and chips did not support fifth grade students' initial understanding of the algorithm. 相似文献
