4 research outputs found
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(PPh<sub>3</sub>)<sub>4</sub> 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 Cu<sup>2+</sup> Bis-1,10-phenanthroline Artificial Metallonucleases with Sterically Functionalized Pendant Carboxylates
The
synthetic chemical nuclease, [Cu(1,10-phenanthroline)<sub>2</sub>]<sup>2+</sup>, 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)<sub>2</sub>]<sup>+</sup>, where 1,10-phen = 1,10-phenanthroline and R = −H,
−CH<sub>3</sub>, −C<sub>2</sub>H<sub>5</sub>, −CH(CH<sub>3</sub>)<sub>2</sub>, and −C(CH<sub>3</sub>)<sub>3</sub>.
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)<sub>2</sub>]<sup>2+</sup>, 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