This communication discloses the first instance of the enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine. The methodology relies on Beak's sparteine-mediated, enantioselective deprotonation of N-Boc-pyrrolidine to form the 2-pyrrolidinolithium specices in high enantiomeric ratio (er). Transmetalation of this intermediate with zinc chloride generates the stereochemically rigid, 2-pyrrolidinozinc reagent, which was readily coupled to a variety of functionalized aryl halides at room temperature using a catalyst generated from Pd(OAc)2 and PtBu3-HBF4. A diverse array of 2-aryl-N-Boc-pyrrolidines was synthesized using this methodology, providing adducts consistently in a 96:4 er. A survey of the stoichiometry revealed that as little as 0.3 equiv of zinc could be used in the coupling reaction, and the 2-pyrrolidinozinc reagent was found to exhibit stereochemical stability up to 60 degrees C. The method allows for the most convergent and reliable preparation of a broad range of functionalized 2-aryl-N-Boc-pyrrolidines in high enantioselectivity, which is highlighted in this report by the enantioselective synthesis of (R)-nicotine.

Inhaled particulate matter 2.5 (PM2.5) can cause lung injury by inducing serious inflammation in lung tissue. Renin-angiotensin system (RAS) is involved in the pathogenesis of inflammatory lung diseases and regulates inflammatory response. Angiotensin-converting enzyme II (ACE2), which is produced through the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II) axis, protects against lung disease. However, few studies have focused on the relationships between PM2.5 and ACE2. Therefore, we aimed to explore the role of ACE2 in PM2.5-induced acute lung injury (ALI). An animal model of PM2.5-induced ALI was established with wild type (C57BL/6, WT) and ACE2 gene knockout (ACE2 KO) mice. The mice were exposed to PM2.5 through intratracheal instillation once a day for 3 days (6.25 mg/kg/day) and then sacrificed at 2 days and 5 days after PM2.5 instillation. The results show that resting respiratory rate (RRR), levels of inflammatory cytokines, ACE and MMPs in the lungs of WT and ACE2 KO mice were significantly increased at 2 days postinstillation. At 5 days postinstillation, the PM2.5-induced ALI significantly recovered in the WT mice, but only partially recovered in the ACE2 KO mice. The results hint that PM2.5 could induce severe ALI through pulmonary inflammation, and the repair after acute PM2.5 postinstillation could be attenuated in the absence of ACE2. Additionally, our results show that PM2.5-induced ALI is associated with signaling p-ERK1/2 and p-STAT3 pathways and ACE2 knockdown could increase pulmonary p-STAT3 and p-ERK1/2 levels in the PM2.5-induced ALI.

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Purpose: The proinflammatory cytokine interleukin-32 (IL-32) is a novel tumor marker highly expressed in various human carcinomas, including gastric cancer. However, its effects on prognosis of patients with gastric cancer and cancer metastasis are virtually unknown at present. The main aim of this study was to explore the clinical significance of IL-32 in gastric cancer and further elucidate the molecular mechanisms underlying IL-32-mediated migration and invasion.Experimental Design: Gastric cancer cells with ectopic expression or silencing of IL-32 were examined to identify downstream molecules and establish their effects on cell motility, invasion, and lung metastasis in vivo.Results: IL-32 was significantly upregulated in gastric cancer and positively correlated with aggressiveness of cancer and poor prognosis. Ectopic expression of IL-32 induced elongated morphology and increased cell migration and invasion via induction of IL-8, VEGF, matrix metalloproteinase 2 (MMP2), and MMP9 expression via phosphor-AKT/phospho-glycogen synthase kinase 3b/active b-catenin as well as hypoxiainducible factor 1a (HIF-1a) signaling pathways. Conversely, depletion of IL-32 in gastric cancer cells reversed these effects and decreased lung colonization in vivo. Examination of gene expression datasets in oncomine and staining of gastric cancer specimens demonstrated the clinical significance of IL-32 and its downstream molecules by providing information on their coexpression patterns.Conclusions: IL-32 contributes to gastric cancer progression by increasing the metastatic potential resulting from AKT, b-catenin, and HIF-1a activation. Our results clearly suggest that IL-32 is an important mediator for gastric cancer metastasis and independent prognostic predictor of gastric cancer. Clin Cancer Res; 20(9); 2276-88. Ó2014 AACR.