Fully Substituted Pyranones via Quasi-Heterogeneous Genuinely Ligand-Free Migita–Stille Coupling of Iodoacrylates

Migita–Stille coupling of (<i>Z</i>)-β-iodoacrylates with (<i>E</i>)-α-stannyl allylic alcohols to furnish 5-alkylidene-4-substituted-5,6-dihydro-2<i>H</i>-pyran-2-ones is efficiently catalyzed by 2% Pd black in DMF, while Pd­(PPh₃)₄ is inactive. Heterogeneous Pd released in solution is most likely responsible for the catalysis. The reaction is applicable to other substrates, without having to resort to ligands, additives, and/or solid support for Pd. The resulting pyranones can be rearranged to fully functionalized pyranones in another single step

Regulating Bioactivity of Cu²⁺ Bis-1,10-phenanthroline Artificial Metallonucleases with Sterically Functionalized Pendant Carboxylates

The synthetic chemical nuclease, [Cu­(1,10-phenanthroline)₂]²⁺, has stimulated research within metallonuclease development and in the area of cytotoxic metallodrug design. Our analysis reveals, however, that this agent is “promiscuous” as it binds both dsDNA and protein biomolecules, without specificity, and induces general toxicity to a diversity of cell lineages. Here, we describe the synthesis and characterization of small-molecule metallonucleases containing the redox-active cation, [Cu­(RCOO)­(1,10-phen)₂]⁺, where 1,10-phen = 1,10-phenanthroline and R = −H, −CH₃, −C₂H₅, −CH­(CH₃)₂, and −C­(CH₃)₃. The presence of coordinated carboxylate groups in the complex cation functions to enhance dsDNA recognition, reduce serum albumin binding, and offer control of toxicity toward human cancer cells, Gram positive and negative bacteria, and fungal pathogens. The induction of genomic dsDNA breaks (DSBs) were identified in ovarian adenocarcinoma cells using immunodetection of γ-H2AX. Formate, acetate, and pivalate functionalized complexes induced DSBs in a higher percentage of cells compared with [Cu­(1,10-phen)₂]²⁺, which supports the importance of inner-sphere modification toward enhancing targeted biological application

2‑(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists

Constitutive androstane receptor (CAR) is a key regulator of xenobiotic and endobiotic metabolism. Together with pregnane X (PXR) and aryl hydrocarbon (AHR) receptors, it is referred to as “xenobiotic receptor”. The unique properties of human CAR, such as its high constitutive activity, both direct (ligand-binding domain-dependent) and indirect activation have hindered the discovery of direct selective human CAR ligands. Herein, we report a novel class of direct human CAR agonists in a group of 2-(3-methoxyphenyl)­quinazoline derivatives. The compounds are even more potent activators of human CAR than is prototype 6-(4-chlorophenyl)­imidazo­[2,1-<i>b</i>]­[1,3]­thiazole-5-carbaldehyde <i>O</i>-(3,4-dichlorobenzyl)­oxime (CITCO). The three most potent ligands are at the same time extremely potent activators of the other xenobiotic or hormonal receptors, namely PXR, AHR, and vitamin D receptor, which regulate major xenobiotic-metabolizing enzymes and efflux transporters. Thus, the novel CAR ligands can be also considered as constituting the first class of potent pan-xenobiotic receptor ligands that can serve as potential antidotes boosting overall metabolic elimination of xenobiotic or toxic compounds

2‑(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists

Constitutive androstane receptor (CAR) is a key regulator of xenobiotic and endobiotic metabolism. Together with pregnane X (PXR) and aryl hydrocarbon (AHR) receptors, it is referred to as “xenobiotic receptor”. The unique properties of human CAR, such as its high constitutive activity, both direct (ligand-binding domain-dependent) and indirect activation have hindered the discovery of direct selective human CAR ligands. Herein, we report a novel class of direct human CAR agonists in a group of 2-(3-methoxyphenyl)­quinazoline derivatives. The compounds are even more potent activators of human CAR than is prototype 6-(4-chlorophenyl)­imidazo­[2,1-<i>b</i>]­[1,3]­thiazole-5-carbaldehyde <i>O</i>-(3,4-dichlorobenzyl)­oxime (CITCO). The three most potent ligands are at the same time extremely potent activators of the other xenobiotic or hormonal receptors, namely PXR, AHR, and vitamin D receptor, which regulate major xenobiotic-metabolizing enzymes and efflux transporters. Thus, the novel CAR ligands can be also considered as constituting the first class of potent pan-xenobiotic receptor ligands that can serve as potential antidotes boosting overall metabolic elimination of xenobiotic or toxic compounds