Herein, we report the preparation of bridged tetrahydrobenzobazepines, which was accomplished through an aza‐Piancatelli cyclization/Michael addition sequence in a one‐pot fashion from readily ...available precursors. It is noteworthy that a general method to access these scaffolds was hitherto unprecedented. Additionally, the multifaceted aspects of this process have been exemplified through its application to the synthesis of 2‐azabicyclo3.2.1octanes and bridged tetrahydrobenzoboxepines, along with post‐derivatizations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Thieno3,2‐bpyrroles with N‐arylamino and 3‐thienoylpropyl functionalities are synthesized in up to 68 % yield from acylthiophenes, acetylene gas and hydrazines via the intermediate ...methylene‐6,8‐dioxabicyclo3.2.1octanes, which undergo multi‐position structural reorganization into the title compounds in the presence of hydrazines and TFA.
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Limited treatment options exist to combat infections caused by multidrug-resistant (MDR) Gram-negative bacteria possessing broad-spectrum β-lactamases. The design of novel β-lactamase inhibitors is ...of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1–3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D β-lactamases with unprecedented k 2/K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C β-lactamses rapidly but not the tested OXAs. Compounds 1–3 formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that 1–3 complexed with KPC-2 adopted a “chair conformation” with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR Acinetobacter baumannii. Compounds 1–3 are novel β-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted.
A readily prepared and functionalized vinylogous nucleophile has been explored and utilized to construct bridged bicyclic compounds. The corresponding cascade Michael/Henry reaction occurred with ...relatively high reactivity under catalyst‐free and mild conditions. A range of structurally distinct bicyclo3.2.1octanes were generated in 40–96% isolated yields with excellent diastereoselectivities (≥10:1 dr). Gram‐scale synthesis was also demonstrated.
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•1,5-Dimethylbicyclo3.2.1octan-8-one-oxime; a safety assessment based on RIFM's criteria.•A safety assessment based on 7 human health endpoints plus environmental.•All endpoints were cleared using ...target data, read-across, and/or TTC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Research Octane Number (RON) is a key quality parameter for gasoline, obtained offline through complex, time-consuming, and expensive standard methods. Measurements are usually only available a ...few times per week and after long delays, making process control very challenging. Therefore, alternative methods have been proposed to predict RON from readily available data. In this work, we report the development of inferential models for predicting RON from process data collected in a real catalytic reforming process. Data resolution and synchronization were explicitly considered during the modelling stage, where 20 predictive linear and non-linear machine learning models were assessed and compared using a robust Monte Carlo double cross-validation approach. The workflow also handles outliers, missing data, multirate and multiresolution observations, and processes dynamics, among other features. Low RMSE were obtained under testing conditions (close to 0.5), with the best methods belonging to the class of penalized regression methods and partial least squares. The developed models allow for improved management of the operational conditions necessary to achieve the target RON, including a more effective use of the heating utilities, which improves process efficiency while reducing costs and emissions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. ...The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of β-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of β-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO “critical priority pathogen” producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure–activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.
Prenylated indole alkaloids (PIAs) possess great structural diversity and show biological activities. Despite significant efforts in investigating the biosynthetic mechanism, the key step in the ...transformation of 2,5-diazabicyclo2.2.2octane-containing PIAs into a distinct class of pentacyclic compounds remains unknown. Here, using a combination of gene deletion, heterologous expression, and biochemical characterization, we show that a unique fungal P450 enzyme CtdY catalyzes the cleavage of the amide bond in the 2,5-diazabicyclo2.2.2octane system, followed by a decarboxylation step to form the 6/5/5/6/6 pentacyclic ring in 21
-citrinadin A. We also demonstrate the function of a subsequent cascade of stereospecific oxygenases to further modify the 6/5/5/6/6 pentacyclic intermediate
to the complete 21
-citrinadin A biosynthesis. Our findings reveal a key enzyme CtdY for the pathway divergence in the biosynthesis of PIAs and uncover the complex late-stage post-translational modifications in 21
-citrinadin A biosynthesis.
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IJS, KILJ, NUK, PNG, UL, UM
The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, ...we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo3.2.1octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model.
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•A series of 2-azabicyclo3.2.1octane derivatives was designed and synthesized.•Antitumor activities of these compounds were evaluated in six cancer cell lines.•Compound 14t induced G1/S cell cycle arrest and apoptosis in LoVo and SW620 cells.•Compound 14t significantly reduced the volumes and size of colon tumors in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An ideal stereoselective insertion of in situ generated benzynes into lawsones through domino formal 2+2‐cycloaddition followed by rearrangement is disclosed. The reaction allowed for the preparation ...of biologically important benzannulated bicyclo3.3.0octanes in good yields and with excellent selectivities by using simple substrates and conditions.
An ideal stereoselective insertion of in situ generated benzynes into lawsones through domino formal 2+2‐cycloaddition–rearrangement is disclosed. The method gave access to biologically important benzannulated bicyclo3.3.0octanes in good yields and with excellent selectivities.
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