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Sullivan Cullen posted an update 7 months ago
An unprecedented and expeditious tandem bisannulation of polyfluoroalkylated tetralones with benzamidines to access various fluoroalkyl tetracyclic -diazepines through multiple C-N bond formation and C(sp3)-F bond cleavage is reported. The process features high regio-/chemoselectivities, broad substrate scope, good functional group tolerance, procedural simplicity, mild reaction conditions, and scale-up synthesis. Mechanistic studies showed that the distinctive fluorine effect of polyfluoroalkyl tetralone plays a vital role for the aza-tetracycle construction.Dynamic correlation plays an important role in the accurate calculation of chemical compounds such as the description of equilibrium structures in chemical systems. A model for the fast estimation of dynamic correlation energy is introduced in this work. This model is based on the idea of decomposition of the contribution of dynamic correlation energy calculated by nth order Møller-Plesset perturbation (MPn) theory with respect to atomic regions. Multiple levels of theory, including MP2, MP2.5, and MP4, are used as the reference, and the corresponding correlation energy densities are calculated. The proposed model is concise, fast, and promising for practical use, such as the prediction of reaction energies. It can also work as a baseline model or pretrained model for follow-up studies of machine learning.Specialized cellular networks of oxidoreductases coordinate the dithiol/disulfide-exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to μM concentrations), they must also be able to resist non-specific triggering by the ca. 50 mM background of non-catalytic cellular monothiols. However, no such selective reduction-sensing systems have yet been established. Here, we used rational structural design to independently vary thermodynamic and kinetic aspects of disulfide stability, creating a series of unusual disulfide reduction trigger units designed for stability to monothiols. We integrated the motifs into modular series of fluorogenic probes that release and activate an arbitrary chemical cargo upon reduction, and compared their performance to that of the literature-known disulfides. The probes were comprehensively screened for biological stability and selectivity against a range of redox effector proteins and enzymes. This design process delivered the first disulfide probes with excellent stability to monothiols yet high selectivity for the key redox-active protein effector, thioredoxin. We anticipate that further applications of these novel disulfide triggers will deliver unique probes targeting cellular thioredoxins. Senaparib price We also anticipate that further tuning following this design paradigm will enable redox probes for other important dithiol-manifold redox proteins, that will be useful in revealing the hitherto hidden dynamics of endogenous cellular redox systems.In the present paper, we report the quantitative evaluation of the electron density shift (EDS) maps within different complexes. Values associated with the total EDS maps exhibited good correlation with different quantities such as interaction energies, Eint, intermolecular distances, bond critical points, and LMOEDA energy decomposition terms. Besides, EDS maps at different cutoffs were also evaluated and related with the interaction energies values. Finally, EDS maps and their corresponding values are found to correlate with Eint within systems with cooperative effects. To our knowledge, this is the first time that the EDS has been quanitatively evaluated.A visible-light-promoted aerobic hydroxyazidation of indole derivatives with TMSN3 is described. The reaction proceeded under photocatalyst-free conditions to furnish trans-2-azidoindolin-3-ols with high regioselectivity and stereoselectivity. The protocol is operationally simple, and the starting materials (e.g., 1-(pyrimidin-2-yl) indoles, azidotrimethylsilane, and air) are readily available. The proposed mechanism in which substrates act as photocatalysts upon excitation using blue light-emitting diodes (LEDs) was supported by experimental studies.The chemisorption of an electrolyte species on electrode surfaces is ubiquitous and affects the dynamics and mechanism of various electrochemical reactions. Understanding of the chemical structure and property of the resulting electrical double layer is vital but limited. Herein, we operando probed the electrochemical interface between a gold electrode surface and a common electrolyte, phosphate buffer, using our newly developed in situ liquid secondary ion mass spectrometry. We surprisingly found that, on the positively charged gold electrode surface, sodium cations were anchored in the Stern layer in a partially dehydrated form by a formation of compact ion pairs with the accumulated phosphate anions. The resulting strong adsorption phase was further revealed to retard the electro-oxidation reaction of ascorbate. This finding addressed one major gap in the fundamental science of electrode-electrolyte interfaces, namely, where and how cations reside in the double layer to impose effects on electrochemical reactions, providing insights into the engineering of better electrochemical systems.A range of tablet excipients were evaluated for their influence on the physical form and chemical stability of levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O). LSP-excipient binary powder blends were stored under two conditions (a) in hermetically sealed containers at 40 °C and (b) at 40 °C/75% RH. By use of synchrotron X-ray diffractometry, the disappearance of LSP could be quantified and the appearance of crystalline levothyroxine (free acid) could be identified. Under hermetically sealed conditions (40 °C) hygroscopic excipients such as povidone induced partial dehydration of LSP to form levothyroxine sodium monohydrate. When stored at 40 °C/75% RH, acidic excipients induced measurable disproportionation of LSP resulting in the formation of levothyroxine (free acid). HPLC analyses of drug-excipient mixtures revealed that lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium caused pronounced chemical decomposition of LSP. On the other hand, magnesium stearate, sodium stearyl fumarate, and alkaline pH modifiers did not affect the physical and chemical stability of the API following storage at 40 °C/75% RH.
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