Rječnik hrvatskoga ili srpskoga jezika dovršen

Simple protocols have been devised for peroxyoxalate chemiluminescence demonstrations that use urea–hydrogen peroxide or sodium percarbonate as oxidants in place of aqueous solutions of hydrogen peroxide. The procedures described are compatible with well-known peroxyoxalates and fluorescers and have been found to be convenient for use for outreach activities in venues with limited laboratory facilities.PostprintPeer reviewe

Synthesis, structure and pyrolysis of stabilised phosphonium ylides containing saturated oxygen heterocycles

yesA range of twelve stabilised phosphonium ylides containing tetrahydrofuran, tetrahydropyran or 2,2- dimethyl-1,3-dioxolane rings have been prepared and fully characterised, including one X-ray structure determination of each type. The X-ray structures confirm the PvC and CvO functions to be syn and all the compounds undergo thermal extrusion of Ph3PO to give the corresponding alkynes. In some cases there is also competing loss of Ph3P to give different carbene-derived products and evidence has been obtained for the generation of 2-phenyloxete in this way. Raising the pyrolysis temperature leads in several cases to new secondary reactions of the alkyne products involving a sequence of alkyne to vinylidene isomerisation, intramolecular CH insertion, and retro Diels Alder reaction

Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a “closed” enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility

Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta

Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a “closed” enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility

Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects