Regioselective and Stereoselective Pd-Catalyzed Intramolecular Arylation of Furans: Access to Spirooxindoles and 5<i>H</i>‑Furo[2,3‑<i>c</i>]quinolin-4-ones

Herein, we report regio- and stereoselective intramolecular direct arylations of <i>N</i>-(2-bromophenyl)-2-furancarboxamides <b>1</b> to produce spirooxindoles <b>2</b> and 5<i>H</i>-furo­[2,3-<i>c</i>]­quinolin-4-ones <b>3</b> under different reaction conditions. Specifically, in the presence of Pd­(PPh₃)₄ as a catalyst, PPh₃ as a ligand, and K₂CO₃ as a base, substrates <b>1</b> underwent intramolecular α-arylation, possibly via a Heck insertion pathway, to provide <b>2</b>, with the <i>Z</i>-isomer being favored. When the base was <i>t</i>-BuOLi and R^<b>1</b> was an aryl group, the reaction favored <i>E</i>-<b>2</b>, possibly via an electrophilic palladation pathway. In contrast, in the presence of PdCl₂ as a catalyst, (<i>o</i>-OMePh)₃P as a ligand, and PivOH as an additive, substrates <b>1</b> underwent intramolecular β-arylation to provide <b>3</b>, possibly via a concerted metalation–deprotonation process

Access to Densely Functionalized Chalcone Derivatives with a 2‑Pyridone Subunit via Pd/Cu-Catalyzed Oxidative Furan–Yne Cyclization of <i>N</i>‑(2-Furanylmethyl) Alkynamides under Air

A protocol for synthesis of chalcone derivatives with a 2-pyridone subunit from <i>N</i>-(2-furanylmethyl) alkynamides is reported. This synthesis involves Pd/Cu-catalyzed oxidative furan–yne cyclization at room temperature in air and may proceed via nucleopalladation of the alkyne to form a vinylpalladium intermediate, with a furan ring acting as the nucleophile

SRC-1 Regulates Blood Pressure and Aortic Stiffness in Female Mice

<div><p>Framingham Heart Study suggests that dysfunction of steroid receptor coactivator-1 may be involved in the development of hypertension. However, there is no functional evidence linking steroid receptor coactivator-1 to the regulation of blood pressure. We used immunohistochemistry to map the expression of steroid receptor coactivator-1 protein in mouse brain, especially in regions implicated in the regulation of blood pressure. Steroid receptor coactivator-1 protein was found in central amygdala, medial amygdala, supraoptic nucleus, arcuate nucleus, ventromedial, dorsomedial, paraventricular hypothalamus, and nucleus of the solitary tract. To determine the effects of steroid receptor coactivator-1 protein on cardiovascular system we measured blood pressures, blood flow velocities, echocardiographic parameters, and aortic input impedance in female steroid receptor coactivator-1 knockout mice and their wild type littermates. Steroid receptor coactivator-1 knockout mice had higher blood pressures and increased aortic stiffness when compared to female wild type littermates. Additionally, the hearts of steroid receptor coactivator-1 knockout mice seem to consume higher energy as evidenced by increased impedance and higher heart rate pressure product when compared to female wild type littermates. Our results demonstrate that steroid receptor coactivator-1 may be functionally involved in the regulation of blood pressure and aortic stiffness through the regulation of sympathetic activation in various neuronal populations.</p></div

Validation of SRC-1-KO mice.

<p>3,3′-diaminobenzidine immunohistochemistry staining for SRC-1 in the medial amygdala of female WT (<b>A</b>) or SRC-1-KO (<b>B</b>) mice. OPT, optic tract; MeA, medial amygdala. Scale bar = 100 μm.</p

Cardiac flow velocity indices.

<p>Peak aortic outflow velocity (<b>A</b>), peak mitral-E flow velocity (<b>B</b>), peak mitral-A flow velocity (<b>C</b>) and mitral E/A ratio (<b>D</b>) obtained from cardiac Doppler flow velocity signals in female WT and SRC-1-KO mice. Data are presented as mean±SEM (n = 4-6/group); <b>*</b>—p<i><</i> 0.05. The information supporting this figure is in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168644#pone.0168644.s004" target="_blank">S4 Dataset</a>.</p

Aortic blood pressure and rate pressure product.

<p>Aortic blood pressure parameters of female WT and SRC-1-KO mice. (<b>A</b>) Systolic blood pressure (SBP), (<b>B</b>) Diastolic blood pressure (DBP), (<b>C</b>) Mean blood pressure (MBP), (<b>D</b>) Pulse pressure, (<b>E</b>) Heart rate, and (<b>F</b>) Rate pressure product (RPP). Data are presented as mean±SEM (n = 5-7/group); <b>*</b>—p<i><</i> 0.05. The information supporting this figure is in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168644#pone.0168644.s001" target="_blank">S1 Dataset</a>.</p

Diameter of the aortic arch.

<p>Representative B-mode images of aortic arch in female WT (<b>A</b>) and SRC-1-KO (<b>B</b>) mice. Quantification (<b>C</b>) revealed a decrease in diameter of the aortic arch in SRC-1-KO mice. Data are presented as mean±SEM (n = 4-5/group); <b>*</b>—p<i><</i> 0.05. The information supporting this figure is in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168644#pone.0168644.s003" target="_blank">S3 Dataset</a>.</p

Expression of SRC-1 in the brain.

<p>Immunofluorescence staining of SRC-1 in various brain regions of WT female mice. 3V, third ventricle; ARC, arcuate nucleus of the hypothalamus; CeA, central amygdala; DMH, dorsal medial nucleus of the hypothalamus; MeA, medial amygdala; NTS, the nucleus of the solitary tract; OPT, optic tract; PVN, paraventricular nucleus of the hypothalamus; Sch, suprachiasmatic nucleus; SON, supraoptic nucleus; VMH, ventromedial nucleus of the hypothalamus (VMH). Scale bars = 100 μm.</p

Echocardiographic parameters of female WT and SRC-1 KO mice.

<p>Echocardiographic parameters of female WT and SRC-1 KO mice.</p

Loss of SRC-1 in female mice results in aortic stiffness.

<p>Parameters of aortic impedance in female WT and SRC-1-KO mice. Total peripheral resistance, Z_P (<b>A</b>), impedance at first harmonic, Z₁ (<b>B</b>), characteristic impedance, Z_C (<b>C</b>), and impedance based pulse wave velocity, PWV_Z (<b>D</b>). Data are presented as mean±SEM (n = 4-6/group); <b>* =</b> p<i><</i> 0.05. The information supporting this figure is in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168644#pone.0168644.s005" target="_blank">S5 Dataset</a>.</p