ChemInform Abstract: Mechanistic Studies on the Thiation of Carbonyls by Lawesson′s Reagent: The Role of a 3-Coordinate Phosphorus(V) Species.

A weakly coordinating monodentate heteroaryl thioether directing group has been developed for use in Pd(II) catalysis to orchestrate key elementary steps in the catalytic cycle that require conformational flexibility in a manner that is difficult to accomplish with traditional strongly coordinating directing groups. This benzothiazole thioether, (BT)S, directing group can be used to promote oxidative Heck reactivity of internal alkenes providing a wide range of products in moderate to high yields. To demonstrate the broad applicability of this directing group, arene C–H olefination was also successfully developed. Reaction progress kinetic analysis provides insights into the role of the directing group in each reaction, which is supplemented with computational data for the oxidative Heck reaction. Furthermore, this (BT)S directing group can be transformed into a number of synthetically useful functional groups, including a sulfone for Julia olefination, allowing it to serve as a “masked olefin” directing group in synthetic planning. In order to demonstrate this synthetic utility, natural products (+)-salvianolic acid A and salvianolic acid F are formally synthesized using the (BT)S directed C–H olefination as the key step.

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Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells

Cell Death Discovery ◽

10.1038/s41420-021-00456-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ariadna Recasens ◽

Sean J. Humphrey ◽

Michael Ellis ◽

Monira Hoque ◽

Ramzi H. Abbassi ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Cyclin B ◽

Anaphase Promoting Complex ◽

Mechanistic Studies ◽

Glioblastoma Cells ◽

Cycle Arrest ◽

Dual Specificity ◽

Rb Pathway ◽

High Doses

AbstractBoth tumour suppressive and oncogenic functions have been reported for dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Herein, we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma. Our phosphoproteomic and mechanistic studies show that DYRK1A induces degradation of cyclin B by phosphorylating CDC23, which is necessary for the function of the anaphase-promoting complex, a ubiquitin ligase that degrades mitotic proteins. DYRK1A inhibition leads to the accumulation of cyclin B and activation of CDK1. Importantly, we established that the phenotypic response of glioblastoma cells to DYRK1A inhibition depends on both retinoblastoma (RB) expression and the degree of residual DYRK1A activity. Moderate DYRK1A inhibition leads to moderate cyclin B accumulation, CDK1 activation and increased proliferation in RB-deficient cells. In RB-proficient cells, cyclin B/CDK1 activation in response to DYRK1A inhibition is neutralized by the RB pathway, resulting in an unchanged proliferation rate. In contrast, complete DYRK1A inhibition with high doses of inhibitors results in massive cyclin B accumulation, saturation of CDK1 activity and cell cycle arrest, regardless of RB status. These findings provide new insights into the complexity of context-dependent DYRK1A signalling in cancer cells.

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The Fe(III)-catalyzed functionalization of saturated hydrocarbons by tert-butyl hydroperoxide: Mechanistic studies on the role of dioxygen

Tetrahedron Letters ◽

10.1016/s0040-4039(00)61120-6 ◽

1992 ◽

Vol 33 (38) ◽

pp. 5473-5476 ◽

Cited By ~ 22

Author(s):

Derek H.R. Barton ◽

Stéphane D. Bévière ◽

Warinthorn Chavasiri ◽

Darío Doller ◽

Bin Hu

Keyword(s):

Mechanistic Studies ◽

Saturated Hydrocarbons ◽

Butyl Hydroperoxide ◽

Tert Butyl ◽

Tert Butyl Hydroperoxide

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Mechanistic Studies in Organo-Metallic Electrochemistry. The Role of Computer Based Techniques & Simulation

Molecular Electrochemistry of Inorganic, Bioinorganic and Organometallic Compounds ◽

10.1007/978-94-011-1628-2_41 ◽

1993 ◽

pp. 437-452

Author(s):

N. Taylor ◽

T. Boddington ◽

P. Halford-Maw ◽

R. Luo ◽

D. Mills

Keyword(s):

Mechanistic Studies ◽

Computer Based

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TUFT1 promotes metastasis and chemoresistance in triple negative breast cancer through the TUFT1/Rab5/Rac1 pathway

Cancer Cell International ◽

10.1186/s12935-019-0961-4 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Weiguang Liu ◽

Jianjun Han ◽

Sufang Shi ◽

Yuna Dai ◽

Jianchao He

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Multivariate Analyses ◽

Tumor Model ◽

Rab Gtpase ◽

Xenograft Tumor ◽

Mechanistic Studies ◽

Xenograft Tumor Model

Abstract Background Triple negative breast cancer (TNBC) is a breast cancer (BC) subtype that is characterized by its strong invasion and a high risk of metastasis. However, the specific mechanisms underlying these phenotypes are unclear. TUFT1 plays an important role in BC and impacts the proliferation and survival of BC cells. Recent studies have shown that TUFT1 mediates intracellular lysosome localization and vesicle transport by regulating Rab GTPase, but the relevance of this activity in TNBC is unknown. Therefore, our aim was to systematically study the role of TUFT1 in the metastasis and chemoresistance of TNBC. Methods We measured TUFT1, Rab5-GTP, and Rac1-GTP expression levels in samples of human TNBC by immunohistochemistry (IHC) and conducted univariate and multivariate analyses. shRNA-mediated knockdown and overexpression, combined with transwell assays, co-immunoprecipitation, a nude mouse xenograft tumor model, and GTP activity assays were used for further mechanistic studies. Results TUFT1 expression was positively correlated with Rab5-GTP and Rac1-GTP in the TNBC samples, and co-expression of TUFT1 and Rab5-GTP predicted poor prognosis in TNBC patients who were treated with chemotherapy. Mechanism studies showed that TUFT1 could activate Rab5 by binding to p85α, leading to activation of Rac1 through recruitment of Tiam1, and concurrent down-regulation of the NF-κB pathway and proapoptotic factors, ultimately promoting metastasis and chemoresistance in TNBC cells. Conclusions Our findings suggest that the TUFT1/Rab5/Rac1 pathway may be a potential target for the effective treatment of TNBC.

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Palladium-catalyzed Suzuki-Miyaura coupling of thioureas or thioamides

Nature Communications ◽

10.1038/s41467-019-13701-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Shaoyu Mai ◽

Wendong Li ◽

Xue Li ◽

Yingwei Zhao ◽

Qiuling Song

Keyword(s):

Silver Salt ◽

Coupling Reaction ◽

Coupling Reactions ◽

Mechanistic Studies ◽

Aromatic Rings ◽

Cross Coupling Reactions ◽

Broad Array ◽

Palladium Catalyzed

AbstractCross-coupling reactions involving metal carbene intermediates play an increasingly important role in C–C bond formation. Expanding the carbene precursors to a broader range of starting materials and more diverse products is an ongoing challenge in synthetic organic chemistry. Herein, we report a Suzuki-Miyaura coupling reaction of in situ-generated Pd–carbene complexes via desulfurization of thioureas or thioamides. This strategy enables the preparation of a broad array of substituted amidinium salts and unsymmetrical diaryl ketones. The reaction is readily scalable, compatible with bromo groups on aromatic rings, tolerant to moisture and air and has a broad substrate scope. Furthermore, a single crystal structure of Pd-diaminocarbene complex is obtained and proven to be the key intermediate in both catalytic and stoichiometric reactions. Preliminary mechanistic studies demonstrate the dual role of the silver salt as a desulfurating reagent assisting the elimination of sulfur and as oxidant facilitating the PdII/Pd0/PdII catalytic cycle.

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