Nickel-Catalyzed Carbofluoroalkylation of 1,3-Enynes to Access Structurally Diverse Fluoroalkylated Allenes.

A nickel-catalyzed 1,4-carbofluoroalkylation of 1,3-enynes to access structurally diverse fluoroalkylated allenes has been established. This method has demonstrated high catalytic reactivity, mild reaction conditions, broad substrate scope, and excellent functional-group tolerance. The key to success is the use of a nickel catalyst to generate different fluoroalkyl radicals from readily available and structurally diverse fluoroalkyl halides to access 1,4-difunctionalization of 1,3-enynes by a radical relay. This strategy provides facile synthesis of structurally diverse multisubstituted allenes, and offers a solution for batch production of various fluorinated bioactive molecules for drug discovery by further transformations.

Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation.

A combinatorial nickel-catalyzed monofluoroalkylation of aryl halides with unactivated fluoroalkyl halides by reductive cross-coupling has been developed. This method demonstrated high efficiency, mild conditions, and excellent functional-group tolerance, thus enabling the late-stage monofluoroalkylation of diverse drugs. The key to success was the combination of diverse readily available bidentate and monodentate pyridine-type nitrogen ligands with nickel, which in situ generated a variety of readily tunable catalysts to promote fluoroalkylation with broad scope with respect to both coupling partners. This combinatorial catalysis strategy offers a solution for nickel-catalyzed reductive cross-coupling reactions and provides an efficient way to synthesize fluoroalkylated druglike molecules for drug discovery.

Photoinduced Copper-Catalyzed Monofluoroalkylation of Terminal Alkynes to Propargylic Fluorides.

A photoinduced copper-catalyzed strategy for the monofluoroalkylation of alkynes with readily available monofluoroalkyl triflates was developed. It provides a new protocol to access valuable propargyl fluoride compounds via C-C bond formation by avoiding the use of highly toxic fluorination reagents. This reaction proceeded under mild conditions to afford propargyl monofluorides in moderate to high yields. Preliminary mechanistic studies reveal that a ligand-matched alkynyl copper complex might be the key photoactive substance.

SIRT1 regulates TNF-α-induced expression of CD40 in 3T3-L1 adipocytes via NF-κB pathway.

Sirtuin1 (SIRT1), a NAD(+)-dependent deacetylase, not only regulates lipid and glucose homeostasis, but also involves the regulation of proinflammatory cytokine involved in inflammation-associated diseases. The activation of CD40 triggers inflammation that plays a crucial role in the development of many chronic inflammatory diseases including obesity. Growing evidence indicated that SIRT1 exerts anti-inflammatory properties by suppressing proinflammatory cytokines production. However, the effect of SIRT1 on the expression of CD40 in adipocytes has not yet been fully elucidated. The present study showed that SIRT1 expressed both in the nucleus and cytoplasm of 3T3-L1 adipocytes. TNF-α significantly reduced the expression of SIRT1 mRNA and protein and increased the expression of CD40 mRNA and protein in time- and concentration-dependent manners. Overexpression of SIRT1 or SIRT1 activation by resveratrol obviously attenuated the expression of CD40 induced by TNF-α in 3T3-L1 adipocytes, whereas knockdown of SIRT1 or SIRT1 inhibition by nicotinamide and sirtinol significantly enhanced TNF-α-induced expression of CD40. Furthermore, overexpression of SIRT1 or SIRT1 activation by resveratrol diminished TNF-α-induced acetylation of NF-κBp65, while knockdown of SIRT1 or SIRT1 inhibition by nicotinamide and sirtinol augmented TNF-α-induced acetylation of NF-κBp65 in 3T3-L1 adipocytes. NF-κB inhibitor PDTC reduced TNF-α-induced mRNA and protein expression of CD40 in 3T3-L1 adipocytes. The combination treatment of resveratrol and PDTC significantly reduced TNF-α-induced expression of CD40, and the inhibitory effects were higher than that of the single treatment. Taken together, SIRT1 exerts anti-inflammatory property by regulating TNF-α-induced expression of CD40 partially through the NF-κB pathway in 3T3-L1 adipocytes. More importantly, the regulation of SIRT1 on the expression of CD40 provides new insight to understand the anti-inflammatory effects of SIRT1.

Effect of exercise training on renal function and renal aquaporin-2 expression in rats with chronic heart failure.

1. Chronic heart failure (CHF) is often accompanied by renal dysfunction. Exercise training may relieve the symptomatic burden and improve the overall prognosis of CHF. In the present study, the effects of exercise training on renal function and renal aquaporin (AQP)-2 expression in CHF rats were examined to determine whether exercise training could relieve renal dysfunction in CHF rats. 2. Male Sprague-Dawley rats were divided into three groups: sham, sedentary CHF (Sed-CHF) and exercise training CHF (Ex-CHF) groups. Cardiorenal function was assessed in each group by haemodynamic measurement and ultraviolet spectrophotometry. Pathological changes in cardiac and renal tissues were evaluated histologically and the collagen volume fraction (CVF) was calculated. The expressions of AQP-2 and ß-tubulin were determined by western blotting and immunohistochemistry. 3. The Sed-CHF rats were found to have increased left ventricular end-diastolic pressure (LVEDP) and CVF in the heart compared with sham rats. Exercise training decreased LVEDP and CVF values in Ex-CHF rats. The Sed-CHF rats were found to have increased serum levels of creatinine (sCr), blood urea nitrogen (BUN) and arginine vasopressin (AVP), as well as increased CVF in the kidney, compared with sham rats. Exercise training decreased levels of sCr, BUN, AVP and CVF in Ex-CHF rats. Moreover, exercise training decreased AQP-2 and ß-tubulin protein expression in the kidney of CHF rats. 4. The results suggest that exercise training can significantly improve the renal dysfunction in CHF rats and that the underlying mechanism may be related to water reabsorption and preventing changes to the cytoskeleton.

Iron-catalyzed remote functionalization of inert C(sp3)-H bonds of alkenes via 1,n-hydrogen-atom-transfer by C-centered radical relay.

As an alternative approach to traditional C-H activation that often involved harsh conditions, and vicinal or primary C-H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp3 C-centered radical to promote selective cleavage of inert C(sp3)-H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido-ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF3-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials.

Nickel-catalyzed monofluoromethylation of (hetero)aryl bromides via reductive cross-coupling.

A mild and efficient nickel-catalyzed direct monofluoromethylation of (hetero)aryl bromides by reductive cross-coupling has been developed. This method exhibits good efficiency, wide functional-group compatibility, and suitability for aryl and heteroaryl bromides with abundant industrial raw material BrCH2F. This strategy provides an efficient way to synthesize monofluoromethylated molecules for drug discovery.

The effects of Buyang Huanwu Decoction on hemorheological disorders and energy metabolism in rats with coronary heart disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine (TCM) formula, has been recognized as a clinical treatment for coronary heart disease (CHD) with qi deficiency and blood stasis syndrome. The effects of BYHWD on hemorheological disorders and energy metabolism in CHD with qi deficiency and blood stasis syndrome are still unclear. AIM OF THE STUDY: To investigate whether the ameliorative effects of BYHWD on CHD rats with qi deficiency and blood stasis syndrome are associated with the regulation of hemorheological disorders and energy metabolism. MATERIALS AND METHODS: The rats were lavaged with 25.68, 12.84 and 6.42 g/kg BYHWD (g weight of mixed crude drugs/kg body weight), respectively, once a day for 21 days. The body weight, exhaustive swimming time and tongue characters were observed and recorded. The whole blood viscosity and plasma viscosity were determined by hematology analyzer. The level of fibrinogen (Fbg) in plasma was determined by using Fbg assay kit. The platelet aggregation induced by adenosine diphosphatase was measured by semi-automatic whole blood platelet analyzer. The level of blood glucose (BG) was determined by LifeScan. The activity of Na(+)-K(+)-ATPase in heart tissues was detected by spectrophotometer. RESULTS: BYHWD improved the exterior signs of qi deficiency and blood stasis syndrome in rats with CHD, including the body weight, exhaustive swimming time and tongue quality. The whole blood viscosity in rats treated with 25.68 g/kg BYHWD decreased at the shear rate of 10s(-1) (P<0.05) and the plasma viscosity decreased in rats treated with 25.68 and 12.84 g/kg BYHWD (P<0.05). The plasma Fbg level and the platelet aggregation decreased in rats treated with 25.68 g/kg BYHWD (P<0.01). The results also revealed that the BG level decreased and the Na(+)-K(+)-ATPase activity in heart tissues increased in rats treated with 25.68 and 12.84 g/kg BYHWD (P<0.01). CONCLUSION: The results suggest that the ameliorative effects of BYHWD on CHD rats with qi deficiency and blood stasis syndrome are mediated by the improvement of hemorheological disorders and energy metabolism.