Activity

The ring-closing reactions based on chemical bond metathesis enable the efficient construction of a wide variety of cyclic systems which receive broad interest from medicinal and organic communities. However, the analogous reaction with C-N bond metathesis as a strategic fundamental step remains an unanswered challenge. Herein, we report the design of a new fundamental metallic C-N bond metathesis reaction that enables the palladium-catalyzed ring-closing reaction of aminodienes with aminals. The reactions proceed efficiently under mild conditions and exhibit broad substrate generality and functional group compatibility, leading to a wide variety of 5- to 16-membered N-heterocycles bearing diverse frameworks and functional groups.Concentrations of 137Cs in seawater, seabed sediment, and pore water collected from the area around Fukushima were investigated from 2015 to 2018, and the potential of coastal sediments to supply radiocesium to the bottom environment was evaluated. The 137Cs concentration in the pore water ranged from 33 to 1934 mBq L-1 and was 10-40 times higher than that in the overlying water (seawater overlying within 30 cm on the seabed). At most stations, the 137Cs concentrations in the overlying water and the pore water were approximately proportional to those in the sediment. The conditional partition coefficient between pore water and sediment was [0.9-14] × 102 L kg-1, independent of the year of sampling. These results indicated that an equilibrium of 137Cs between pore water and sediment has been established in a relatively short period, and 137Cs in the pore water is gradually exported to seawater near the seabed. A simple box model estimation based on these results showed that 137Cs in the sediment decreased by about 6% per year by desorption/diffusion of 137Cs from the seabed.With the global outbreak of the coronavirus disease 2019 (COVID-19), the highly infective, highly pathogenic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has attracted great attention. Currently, a method to simultaneously diagnose the seven known types human coronaviruses remains lacking and is urgently needed. In this work, we successfully developed a portable microfluidic system for the rapid, accurate, and simultaneous detection of SARS-CoV, middle east respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2, and four other human coronaviruses (HCoVs) including HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. The disk-like microfluidic platform integrated with loop-mediated isothermal amplification provides highly accurate, sensitive, and specific results with a wide linear range within 40 min. The diagnostic tool achieved 100% consistency with the “gold standard” polymerase chain reaction in detecting 54 real clinical samples. The integrated system, with its simplicity, is urgently needed for the diagnosis of SARS-CoV-2 during the COVID-19 pandemic.Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the world. Studies report the presence of extracellular amyloid plaques consisting of β-amyloid peptide and intracellular tangles consisting of hyperphosphorylated tau proteins as the histopathological indicators of AD. The process of β-amyloid peptide generation by sequential cleavage of amyloid precursor protein by β-secretase (BACE1) and γ-secretase, followed by its aggregation to form amyloid plaques, is the mechanistic basis of the amyloid hypothesis. Other popular hypotheses related to the pathogenesis of AD include the tau hypothesis and the oxidative stress hypothesis. Various targets of the amyloid cascade are now in prime focus to develop drugs for AD. Revumenib MLL inhibitor Many BACE1 inhibitors, β-amyloid aggregation inhibitors, and Aβ clearance strategies using monoclonal antibodies are in various stages of clinical trials. This review provides an in-depth evaluation of the role of BACE1 in disease pathogenesis and also highlights the therapeutic approaches developed to find more potent but less toxic inhibitors for BACE1, particularly emphasizing the natural scaffold as a nontoxic lead for BACE1 inhibition. Cellular targets and signaling cascades involving BACE1 have been highlighted to understand the physiological role of BACE1. This knowledge is extremely crucial to understand the toxicity evaluations for BACE1-targeted therapy. We have particularly highlighted the scope of flavonoids as a new generation of nontoxic BACE1 inhibitory scaffolds. The structure-activity relationship of BACE1 inhibition for this group of compounds has been highlighted to provide a guideline to design more selective highly potent inhibitors. The review aims to provide a holistic overview of BACE1-targeted therapy for AD that paves the way for future drug development.Herein, we report the first calorimetric study of the protonation of planar and nonplanar free-base porphyrins H2OETPP (strongly saddled by its substituents), H2T(tBu)P (strongly ruffled by its substituents), and the nominally planar porphyrins (npPs) H2OEP, H2TPP, H2T(nPe)P, and H2T(iPr)P. The observed enthalpies of protonation in solution (ΔHprotsoln) for formation of the dications in 1,1,2,2-tetrachloroethane with 2% trifluoroacetic acid are -45 ± 1 kcal mol-1 for the npPs, -52.0 kcal mol-1 for H2T(tBu)P, and -70.9 kcal mol-1 for H2OETPP. The corresponding enthalpies of protonation (ΔHDFT) obtained from DFT calculations (-27 ± 5, -42, and -63 kcal mol-1, respectively) reproduce this trend. The much more negative enthalpy of protonation seen for H2OETPP is consistent with this molecule being pre-deformed into the saddle structure favored by porphyrin dications. Except for OETPP, the calculated enthalpies of the first protonations (ΔH1) are significantly more positive than the enthalpies of the second protonations (ΔH2). In addition, the structural strain energies for the first protonations (ΔEst(1)) are also significantly more positive than ΔEst(2). According to the calculations, the monocations thus have higher proton affinities than the corresponding free-base porphyrins due to a structural strain effect, which is consistent with the generally elusive nature of the porphyrin monocation. The recent observations of monocations for free-base porphyrins with a high degree of saddling can be rationalized in terms of ΔH1 and ΔH2 being similar; so, the monocation is no longer an unstable intermediate.