Catalytic Asymmetric Synthesis of Chiral α,α-Dialkyl Aminonitriles via Reaction of Cyanoketimines.

Chiral aminonitriles not only are broadly useful building blocks but also increasingly appear as structural motifs in bioactive molecules and pharmaceuticals. The catalytic asymmetric synthesis of chiral aminonitriles, therefore, has been intensively investigated, as reflected in numerous reports of catalytic asymmetric Strecker reactions. Despite such great progress, the catalytic asymmetric synthesis of chiral α,α-dialkyl aminonitriles in a highly selective and efficient manner is still a formidable challenge. Here, we report a new approach for the catalytic asymmetric synthesis of chiral α,α-dialkyl aminonitriles via reaction of cyanoketimines with enals. We demonstrate that this reaction could be carried out with as low as 20 ppm catalyst loading.

Renal Fibrosis Is Alleviated through Targeted Inhibition of IL-11-Induced Renal Tubular Epithelial-to-Mesenchymal Transition.

Renal fibrosis is a pathologic process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in this process. The current study found that aberrant expression of IL-11 is critically involved in tubular EMT. IL-11 and its receptor subunit alpha-1 (IL-11Rα1) were significantly induced in renal tubular epithelial cells (RTECs) in unilateral ureteral obstruction (UUO) kidneys, co-localized with transforming growth factor-ß1. IL-11 knockdown ameliorated UUO-induced renal fibrosis in vivo and transforming growth factor-ß1-induced EMT in vitro. IL-11 intervention directly induced the transdifferentiation of RTECs to the mesenchymal phenotype and increased the synthesis of profibrotic mediators. The EMT response induced by IL-11 was dependent on the sequential activation of STAT3 and extracellular signal-regulated kinase 1/2 signaling pathways and the up-regulation of metadherin in RTECs. Micheliolide (MCL) competitively inhibited the binding of IL-11 with IL-11Rα1, suppressing the activation of STAT3 and extracellular signal-regulated kinase 1/2-metadherin pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide, a pro-drug of MCL for in vivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in the UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and that MCL/dimethylaminomicheliolide exerts its antifibrotic effect by suppressing IL-11/IL-11Rα1 interaction and blocking its downstream effects.

Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis.

BACKGROUND: Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. METHODS: The effects of MCL on BRG1-induced fibrotic responses and TGF-ß1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. RESULTS: BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-ß1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-ß1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-ß1-induced fibrotic responses and blocked TGF-ß1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-ß1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. CONCLUSION: Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.

N-methylpiperazine-diepoxyovatodiolide ameliorates peritoneal fibrosis via suppressing TGF-ß/Smad and JAK/STAT signaling pathway.

Peritoneal fibrosis (PF) is the main cause of peritoneal ultrafiltration failure in patients undergoing long-term peritoneal dialysis (PD). Epithelial-mesenchymal transition (EMT) is the key pathogenesis of PF. However, currently, no specific treatments are available to suppress PF. N-methylpiperazine-diepoxyovatodiolide (NMPDOva) is a newly synthesized compound that involves a chemical modification of ovatodiolide. In this study, we aimed to explore the antifibrotic effects of NMPDOva in PD-related PF and underlying mechanisms. A mouse model of PD-related PF was established via daily intraperitoneal injection of 4.25% glucose PD fluid. In vitro studies were performed using the transforming growth factor-beta1 (TGF-ß1)-stimulated HMrSV5 cell line. Pathological changes were observed, and fibrotic markers were significantly elevated in the peritoneal membrane in mice model of PD-related PF. However, NMPDOva treatment significantly alleviated PD-related PF by decreasing the extracellular matrix accumulation. NMPDOva treatment decreased the expression of fibronectin, collagen Ⅰ, and alpha-smooth muscle actin (α-SMA) in mice with PD-related PF. Moreover, NMPDOva could alleviate TGF-ß1-induced EMT in HMrSV5 cells, inhibited phosphorylation and nuclear translocation of Smad2/3, and increased the expression of Smad7. Meanwhile, NMPDOva inhibited phosphorylation of JAK2 and STAT3. Collectively, these results indicated that NMPDOva prevents PD-related PF by inhibiting the TGF-ß1/Smad and JAK/STAT signaling pathway. Therefore, because of these antifibrotic effects, NMPDOva may be a promising therapeutic agent for PD-related PF.

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/ß-catenin/autophagy axis.

Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/ß-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-ß1 (TGF-ß1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated ß-galactosidase (SA-ß-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/ß-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/ß-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/ß-catenin pathway, which ultimately contributes to the development of renal fibrosis.

Homogeneous Hydrogenation with a Cobalt/Tetraphosphine Catalyst: A Superior Hydride Donor for Polar Double Bonds and N-Heteroarenes.

The development of catalysts based on earth abundant metals in place of noble metals is becoming a central topic of catalysis. We herein report a cobalt/tetraphosphine complex-catalyzed homogeneous hydrogenation of polar unsaturated compounds using an air- and moisture-stable and scalable precatalyst. By activation with potassium hydroxide, this cobalt system shows both high efficiency (up to 24 000 TON and 12 000 h-1 TOF) and excellent chemoselectivities with various aldehydes, ketones, imines, and even N-heteroarenes. The preference for 1,2-reduction over 1,4-reduction makes this method an efficient way to prepare allylic alcohols and amines. Meanwhile, efficient hydrogenation of the challenging N-heteroarenes is also furnished with excellent functional group tolerance. Mechanistic studies and control experiments demonstrated that a CoIH complex functions as a strong hydride donor in the catalytic cycle. Each cobalt intermediate on the catalytic cycle was characterized, and a plausible outer-sphere mechanism was proposed. Noteworthy, external inorganic base plays multiple roles in this reaction and functions in almost every step of the catalytic cycle.