Активность

Experimental kinetics studies support the computations, showing that the seven-membered and acyclic hydrazide catalysts react 10 times faster than the six-membered catalyst. Unraveling the mechanism of this reaction is an important step in understanding other reactions catalyzed by hydrazides, and explaining the ring size effect is critical because cyclic catalysts provide a constrained scaffold, enabling the development of asymmetric variants of these reactions.Docking is one of the most important steps in virtual screening pipelines, and it is an established method for examining potential interactions between ligands and receptors. However, this method is computationally expensive, and it is often among the last steps of the process of compound libraries evaluation. In this work, we investigate the feasibility of learning a deep neural network to predict the docking output directly from a two-dimensional compound structure. The developed protocol is orders of magnitude faster than typical docking software, and it returns ligand-receptor complexes encoded in the form of the interaction fingerprint. Its speed and efficiency unlock the application possibilities, such as screening compound libraries of vast size on the basis of contact patterns or docking score (derived on the basis of predicted interaction schemes). We tested our approach on several G protein-coupled receptor targets and 4 CYP enzymes in retrospective virtual screening experiments, and a variant of graph convolutional network appeared to be most effective in emulating docking results. The method can be easily used by the community based on the code available in the Supporting Information.Rhodium(III)-catalyzed enantioselective oxidative C-H/C-H cross-coupling reaction between two arenes is disclosed. With the combination of a chiral CpRh(III) complex and a chiral carboxylic acid additive, the direct coupling reactions between 1-aryl isoquinoline derivatives and electron-rich heteroarenes such as thiophenes, furans, benzothiophenes, and benzofurans are realized via a double C-H functionalization process. A series of axially chiral compounds are obtained in excellent yields and enantioselectivities (up to 99% yield and 99% ee). Mechanistic studies suggest that both C-H bond cleavages may not be the turnover-limiting step.A density functional theory study is presented here to offer mechanistic insights and explications of experimentally intriguing observations in the Au(I)-catalyzed cyclization of cyclic and acyclic acetals of alkynylaldehydes that leads to indenone formation. The reactivity of catalytic cycles with and without methoxy migration is clearly defined when the alkyne terminus is phenylated. The reaction mechanism of indenone formation proceeds first with the coordination of Au(I) to alkyne to initiate the reaction with 1,5-H shift as a rate-determining step (RDS), and the fastest 1,5-H shift is achieved when one phenyl ring carries an electron-donating group and the other one is substituted with an electron-withdrawing group. Following the 1,5-H shift, the reaction undergoes feasible steps that are cyclization and 1,2-H shift before elimination to persist the iterative cycle, but the reactivity of both steps is highly affected by the existence of the phenyl group on the alkyne terminus. The unreactivity of the alkyne terminus not bearing a phenyl ring is because the cyclization is thermodynamically disfavorable, subsequently deactivating the 1,2-H shift kinetically and thermodynamically. The absence of a tether in the acetal unit considerably outpaces any 1,5-H shift and instead activates 1,5-methoxy migration, giving methoxy-migrated indenone, with the 1,2-OMe shift being an RDS.The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. see more In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5′-(α,β-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human cancer cells and CD8+ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the “selectivity” and “alkyl-induced” pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an “alkyl-induced” pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.Large volumes of per- and polyfluoroalkyl substances (PFAS)-contaminated wastewaters, such as municipal solid waste landfill leachates, pose a challenge for PFAS treatment technologies in practice today. In this study, the surfactant properties of PFAS were exploited to concentrate the compounds in foam produced via the bubble aeration of landfill leachate. The effectiveness of the foaming technique for concentrating PFAS varied by compound, with a mean removal percentage (the percent difference between PFAS in leachate before and after foam removal) of 69% and a median removal percentage of 92% among the 10 replicate foaming experiments. This technique appears to be similarly effective at sequestering sulfonates and carboxylate PFAS compounds and is less effective at concentrating the smallest and largest PFAS molecules. The results of this study suggest that for the pretreatment or preconcentration of landfill leachates, foaming to sequester PFAS may provide a practical approach that could be strategically coupled to high-energy PFAS-destructive treatment technologies.