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

Scalable Synthesis of Human Ultralong Chain Ceramides

Ceramides with ultralong chains (≥30 carbons), also known as acylceramides, play a critical role in the survival of mammals on dry land. An efficient and scalable synthesis of four major classes of ultralong human skin ceramides is reported. The key approach involves the use of a succinimidyl ester that acts as a protective group, helps overcome the extremely low solubility, and simultaneously activates the fatty acid for its clean and high-yielding attachment to a sphingoid base

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