Synthesis of 3‑Cyanoindole Derivatives Mediated by Copper(I) Iodide Using Benzyl Cyanide

Copper-mediated direct and regioselective C3-cyanation of indoles using benzyl cyanide as the cyanide anion source is presented. A wide range of indoles undergo cyanation smoothly by employing a reaction system of copper­(I) iodide under open-to-air vessels

Carbon–Boron Bond Cross-Coupling Reaction Catalyzed by −PPh₂ Containing Palladium–Indolylphosphine Complexes

This study describes the application of indolylphosphine ligands with a diphenylphosphino moiety to the palladium-catalyzed borylation of aryl chlorides. The combination of palladium metal precursor with PPh₂-Andole-phos, which comprises an inexpensive −PPh₂ group, provides highly effective catalysts for the borylation of aryl chlorides. A range of functional groups such as −CN, −NO₂, −CHO, −COMe, −COOMe, and −CF₃ was compatible, and the catalyst loading down to 0.025 mol % of Pd can be achieved. The Pd/PPh₂-Andole-phos system is able to catalyze both borylation reaction and Suzuki–Miyaura coupling reaction in a one-pot sequential manner for the direct synthesis of biaryl compounds in excellent yields

Image_1_Physiological concentration of protocatechuic acid directly protects vascular endothelial function against inflammation in diabetes through Akt/eNOS pathway.JPEG

BackgroundCardiovascular diseases (CVDs) have been the major cause of mortality in type 2 diabetes. However, new approaches are still warranted since current diabetic medications, which focus mainly on glycemic control, do not effectively lower cardiovascular mortality rate in diabetic patients. Protocatechuic acid (PCA) is a phenolic acid widely distributed in garlic, onion, cauliflower and other plant-based foods. Given the anti-oxidative effects of PCA in vitro, we hypothesized that PCA would also have direct beneficial effects on endothelial function in addition to the systemic effects on vascular health demonstrated by previous studies.Methods and resultsSince IL-1β is the major pathological contributor to endothelial dysfunction in diabetes, the anti-inflammatory effects of PCA specific on endothelial cells were further verified by the use of IL-1β-induced inflammation model. Direct incubation of db/db mouse aortas with physiological concentration of PCA significantly ameliorated endothelium-dependent relaxation impairment, as well as reactive oxygen species overproduction mediated by diabetes. In addition to the well-studied anti-oxidative activity, PCA demonstrated strong anti-inflammatory effects by suppressing the pro-inflammatory cytokines MCP1, VCAM1 and ICAM1, as well as increasing the phosphorylation of eNOS and Akt in the inflammatory endothelial cell model induced by the key player in diabetic endothelial dysfunction IL-1β. Upon blocking of Akt phosphorylation, p-eNOS/eNOS remained low and the inhibition of pro-inflammatory cytokines by PCA ceased.ConclusionPCA exerts protection on vascular endothelial function against inflammation through Akt/eNOS pathway, suggesting daily acquisition of PCA may be encouraged for diabetic patients.</p

Image_2_Physiological concentration of protocatechuic acid directly protects vascular endothelial function against inflammation in diabetes through Akt/eNOS pathway.jpg

BackgroundCardiovascular diseases (CVDs) have been the major cause of mortality in type 2 diabetes. However, new approaches are still warranted since current diabetic medications, which focus mainly on glycemic control, do not effectively lower cardiovascular mortality rate in diabetic patients. Protocatechuic acid (PCA) is a phenolic acid widely distributed in garlic, onion, cauliflower and other plant-based foods. Given the anti-oxidative effects of PCA in vitro, we hypothesized that PCA would also have direct beneficial effects on endothelial function in addition to the systemic effects on vascular health demonstrated by previous studies.Methods and resultsSince IL-1β is the major pathological contributor to endothelial dysfunction in diabetes, the anti-inflammatory effects of PCA specific on endothelial cells were further verified by the use of IL-1β-induced inflammation model. Direct incubation of db/db mouse aortas with physiological concentration of PCA significantly ameliorated endothelium-dependent relaxation impairment, as well as reactive oxygen species overproduction mediated by diabetes. In addition to the well-studied anti-oxidative activity, PCA demonstrated strong anti-inflammatory effects by suppressing the pro-inflammatory cytokines MCP1, VCAM1 and ICAM1, as well as increasing the phosphorylation of eNOS and Akt in the inflammatory endothelial cell model induced by the key player in diabetic endothelial dysfunction IL-1β. Upon blocking of Akt phosphorylation, p-eNOS/eNOS remained low and the inhibition of pro-inflammatory cytokines by PCA ceased.ConclusionPCA exerts protection on vascular endothelial function against inflammation through Akt/eNOS pathway, suggesting daily acquisition of PCA may be encouraged for diabetic patients.</p

Chronic RAS blockade decreases AT₁R expression.

<p>(A) Effects of chronic treatment with enalapril or valsartan on protein levels of angiotensin II type 1 (AT₁R) and type 2 receptor (AT₂R) in aortae of OVX rats. Aortic contraction induced by 100 nmol/l angiotensin II (B) and 60 mmol/l KCl (C) in the presence of 100 µmol/l L-NAME. Results are means±SEM of 4–5 experiments. Statistical significance is indicated by * p<0.05 and *** p<0.001.</p

Chronic RAS blockade prevents endothelial dysfunction.

<p>Concentration-response curves for ACh in aortae from control, OVX rats and OVX rats treated with enalapril (A, OVX+Ena) or valsartan (B, OVX+Val). (C) Lack of effect of HOE-140 on relaxations in aortae from OVX+Ena group. (D) Lack of effect of captopril on relaxations in OVX rats. (E) Phosphorylated levels of eNOS (p-eNOS) at Ser¹¹⁷⁷ in response to 1 µmol/l ACh and the total eNOS in aortae. Results are means±SEM of 6–8 experiments. Intensities were normalized to GAP(D)H and expressed relative to control. Statistical significance between OVX and treatment group is indicated by *** p<0.001. NS, no significance.</p

pD₂ and E_max (%) for acetylcholine-induced relaxations.

<p>Initial tension developed by phenylephrine, pD₂ and E_max (%) for acetylcholine-induced relaxations in aortae from different groups. Results are means±SEM of 6–8 experiments. Statistical significance between (^a) control versus OVX and (^b) OVX versus acute or chronic treatment is indicated by *p<0.05, **p<0.01, and ***p<0.001.</p

Chronic RAS blockade reduces ACE expression and angiotensin II levels after ovariectomy.

<p>Effects of chronic treatment of OVX rats with enalapril or valsartan on the protein level of angiotensin-converting enzyme (ACE) revealed by Western blot (A) and immunohistochemistry (B). Immunohistochemical staining of angiotensin II in the aortic vascular wall (C). Sections are counterstained with hematoxylin. Magnification ×400. Results are means±SEM of 4–6 experiments. Statistical significance is indicated by ** p<0.01 and *** p<0.001.</p

Ovariectomy impairs endothelium-dependent relaxation.

<p>Time-dependent reduction of endothelium-dependent relaxations induced by acetylcholine (ACh, A) but not by sodium nitroprusside (SNP, B) in phenylephrine (Phe)-contracted ring with endothelium following ovariectomy. Results are means±SEM of 6–8 experiments. Statistical significance between control and OVX curves is indicated by *** p<0.001.</p

Chronic RAS blockade decreases oxidative stress.

<p>Effects of chronic treatment with enalapril or valsartan on the protein expression of NAD(P)H oxidase subunits: gp91<i>^phox</i> and p22<i>^phox</i> (A), on ROS production as revealed by DHE fluorescent intensity (B), and on the protein level of nitrotyrosine (C) in rat aortae. Results are means±SEM of 4–5 experiments. Statistical significance is indicated by ** p<0.01 and *** p<0.001.</p