7196 research outputs found
Sort by
Photoassisted Decomposition of DMF for Facile and Selective N,NDimethylamination of Arenes
No full textA reversible Van der Waals complex formation between the electron-deficient fluorinated aromatic ring and DMF molecules followed by light irradiation results in a charge-transfer complex. The complex is stabilized by ammonium formate and further decomposed to form the C–N bond. This methodology is mild, metal-free, and effective for dimethylamination of a variety of
substrates. The reproducibility of this methodology is also verified on gram-scale reactions. The charge transfer states are supported by control UV-Visible and computational studies
Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ
No full textUsing a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγinhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development
SomaScan Novartis proteins (construct, domain, expression) used in development of SomaScan, for PUBLIC disclosure on SomaLogic website
No full textno abstrac
Preclinical evaluation of [11C]YC-72-AB85 for in vivo visualisation of heat shock protein 90 in brain and cancer with positron emission tomography
No full textBackground and Purpose: Aberrant Hsp90 has been implied in cancer and neurodegenerative disorders. The development of a suitable Hsp90 PET probe can provide in vivo quantification of the expression levels of Hsp90 as a biomarker for diagnosis and follow up of cancer and CNS disease progression. In this respect, [11C]YC-72-AB85 was evaluated as an Hsp90 PET probe in B16.F10 melanoma bearing mice and its brain uptake was determined in rats and non-human primate.
Experimental Approach: In vitro binding of [11C]YC-72-AB85 to tissue slices of mouse B16.F10 melanoma, PC3 prostate carcinoma and rodent brain was evaluated using autoradiography. Biodistribution of [11C]YC-72-AB85 was evaluated in healthy and B16.F10 melanoma mice. In vivo brain uptake was assessed by µPET studies in rats and a rhesus monkey.
Key Results: In vitro binding was deemed Hsp90 specific by blocking studies with Hsp90 inhibitors Onalespibonalespib and SNX-0723. Saturable Hsp90 binding was observed in tumour, blood and blood rich organs in mice. In combined pre-treatment and displacement studies, reversible and Hsp90-specific binding of [11C]YC-72-AB85 was observed in rat brain. Dynamic µPET brain scans in baseline and blocking conditions in a rhesus monkey indicated Hsp90 specific binding.
Conclusion and Implications: [11C]YC-72-AB85 is a promising PET tracer for in vivo visualisation of Hsp90 in tumour and brain. Clear differences of Hsp90 binding to blood and blood-rich organs were observed in tumour vs control mice. Further, we clearly demonstrate, for the first time, binding to a saturable Hsp90 pool in brain of rats and a rhesus monkey
Mechanism of nucleic acid sensing in retinal pigment epithelium (RPE): RIG-I mediates type I interferon response in human RPE
No full textAge-related macular degeneration (AMD), a degenerative disease of the outer retina, is the leading cause of blindness among the elderly. A hallmark of geographic atrophy (GA), an advanced type of non-neovascular AMD (dry AMD), is photoreceptor and retinal pigment epithelium (RPE) cell death. Currently, there are no FDA-approved therapies for GA due to a lack of understanding of the disease-causing mechanisms. Increasing evidence suggests that chronic inflammation plays a predominant role in the pathogenesis of dry AMD. Dead or stressed cells release danger signals and inflammatory factors, which causes further damage to neighboring cells. It has been reported that type I interferon (IFN) response is activated in RPE cells in patients with AMD. However, how RPE cells sense stress to initiate IFN response and cause further damage to the retina are still unknown. Although it has been reported that RPE can respond to extracellularly added dsRNA, it is unknown whether and how RPE detect and sense internally generated or internalized nucleic acids. Here, we elucidated the molecular mechanism by which RPE cells sense intracellular nucleic acids. Our data demonstrate that RPE cells can respond to intracellular RNA and induce type I IFN responses via the RIG-I (DExD/H-box helicase 58, DDX58) RNA helicase. In contrast, we showed that RPE cells were unable to directly sense and respond to DNA through the cGAS-STING pathway. We demonstrated that this was due to the absence of the cyclic GMP-AMP synthase (cGAS) DNA sensor in these cells. The activation of IFN response via RIG-I induced expression of cell death effectors and cause barrier function loss in RPE cells. These data suggested that RPE-intrinsic pathways of nucleic acid sensing are biased toward RNA sensing
Control of dynamic cell behaviors during angiogenesis and anastomosis by Rasip 1.
No full textOrgan morphogenesis is driven by a wealth of tightly orchestrated cellular behaviors, which ensure proper organ assembly and function. Many of these cell activities involve cell-cell interactions and remodeling of the F-actin cytoskeleton. Here, we analyze the requirement for Rasip1 (Ras-interacting protein 1), an endothelial-specific regulator of junctional dynamics, during blood vessel formation. Phenotype analysis of rasip1 mutants in zebrafish embryos reveal distinct functions of Rasip1 during sprouting angiogenesis, anastomosis and lumen formation. During angiogenic sprouting, loss of Rasip1 causes cell pairing defects due to a destabilization of tricellular junctions, indicating that stable tri-cellular junctions are essential to maintain multicellular organization within the sprout. During anastomosis, Rasip1 is required to establish a stable apical membrane compartment; rasip1 mutants display ectopic, reticulated junctions and the apical compartment is frequently collapsed. Loss of Ccm1 and Heg1 function mimics junctional defects of rasip1 mutants. Furthermore, downregulation of ccm1 and heg1 leads to a delocalization of Rasip1 at cell junctions, indicating that junctional tethering of Rasip1 is required for its function during junction formation and stabilization during sprouting angiogenesis
Fostering Research Synergies between Chemists in Swiss Academia and at Novartis.
No full textWe present a short overview of the way Novartis chemists interact and collaborate with the academic chemistry community in Switzerland. This article exemplifies a number of collaborations, and illustrates opportunities to foster research synergies between academic and industrial researchers. It also describes established programs available to academic groups, providing them access to Novartis resources and expertise
The conundrum of the pericentral hepatic niche: WNT/β-Catenin signaling, metabolic zonation and many open questions
No full textWNT/β-Catenin signaling promotes stemness, proliferation and cell fate decisions in various tissue stem cell compartments, which maintain organs with a high turnover of cells (e.g. skin, stomach and gut). Thus, the β-Catenin target genes AXIN2 and LGR5 are widely considered as tissue stem cell markers. In contrast, AXIN2 and LGR5 are expressed in pericentral hepatocytes, which do not show overt proliferation during liver homeostasis. Given the low hepatocyte turnover, the liver does not require constant high rates of proliferation, whereas WNT/β-Catenin signaling is critical for metabolic zonation. Yet, WNT/β-Catenin pathway upregulation, including AXIN2 and LGR5 induction in hepatocytes throughout the liver, enables hepatocyte regeneration in response to various injuries. In this mini review, we discuss the role of WNT/β-Catenin in controlling metabolic zonation and the conundrum around pericentral hepatocytes that have been proposed as liver stem cells
A novel diclofenac-hydrogel conjugate system for intraarticular sustained release: Development of 2-pyridylamino-substituted 1-phenylethanol (PAPE) and its derivatives as tunable traceless linkers
No full textA local sustained-release drug delivery system, or depot, for intra-articular injection offers the opportunity to release a therapeutic agent directly to the joint with limited need for reinjection. A successful system would provide more consistent efficacy and minimize systemic side effects. In this paper, we explore the potential use of diclofenac, a non-steroidal anti-inflammatory drug, for use in a polymer-conjugate depot system. During the course of our exploration it was determined that “conventional ester” conjugates of diclofenac were not appropriate as upon incubation in buffer (pH 7.4) or in bovine synovial fluid, a considerable amount of undesired diclofenac-lactam was released. Thus we developed a novel linker system for diclofenac in order to minimize the production of the lactam. This new linker enables a diclofenac conjugate system with tunable release rates and minimizes the production of undesired lactam side-products
