Differential mechanism of action of the CK1ε inhibitor GSD0054

In the current study, we explored for the first time, the mechanism of action of the new Casein kinase 1 ε (CK1ε) selective inhibitor GSD0054. Although GSD0054 behaved as a selective CK1ε inhibitor in enzymatic assays, we studied whether this inhibitory activity also occurred inside the cells. The effects of GSD0054 on β-catenin expression and disruption of cell cycle progression were studied in the human breast cancer cell lines MDA-MB-453 (β-catenin negative) and T-47D (β-catenin positive). We also performed molecular modeling studies using computational docking against CK1ε to explain and predict the mechanism of action of this compound. Moreover, the commercially available CK1ε inhibitor PF-4800567 and the CK1δ/ε inhibitors PF-670462 and IC261 were also studied for comparison purposes. GSD0054 showed anti-proliferative activity against MDA-MB-453 and T-47D cells despite the fact that MDA-MB-453 cells do not possess active β-catenin. However, selective cell killing occurred in the more resistant, β-catenin active, T-47D cells. CK1ε was confirmed as a cellular target, although other targets or alternative mechanisms of action could possibly explain the anti-proliferative activity in MDA-MB-453 cells.info:eu-repo/semantics/publishedVersio

Straightforward synthesis of enantiomerically pure 1, 2, 3-triazoles derived from amino esters

A practical and straightforward approach that enables for the first time, the synthesis of enantiomerically pure 1,4,5-trisubstituted, 1,5-disubstituted, and fused 1,2,3 triazole derivatives has been developed. The synthesis employs enantiomerically pure amino esters derived from amino acids and commercially available ketones under metal-free conditions.status: publishe

Development and characterization of BODIPY-derived tracers for fluorescent labeling of the endoplasmic reticulum

Visualization of the structure of the Endoplasmic Reticulum (ER) in living cells is important for the understanding of its function. Here we synthesized a library of 8-BODIPY labeled hydroxyquinoline derivatives and evaluated their spectroscopic properties, cytotoxicity, and intracellular localization. The compounds were easily obtained in 34–80% yield. Based on the spectral properties and low cytotoxicity, we selected the quinolin-8-yl pentanoate derivative 17 for in vivo labeling of the ER. Fluorescence staining of the ER was evaluated by comparison with a commercial ER tracker. The molecules here developed are smaller than the alternatives commercially available while still presenting a high specificity towards the ER.status: publishe