Browsing by Subject "LIGAND"

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  • Lagerspets, Emi; Valbonetti, Evelyn; Eronen, Aleksi; Repo, Timo (2021)
    We report here novel Cu(I) thiophene carbaldimine catalysts for the selective aerobic oxidation of primary alcohols to their corresponding aldehydes and various diols to lactones or lactols. In the presence of the in situ generated Cu(I) species, a persistent radical (2,2,6,6-tetramethylpiperdine-N-oxyl (TEMPO)) and N-methylimidazole (NMI) as an auxiliary ligand, the reaction proceeds under aerobic conditions and at ambient temperature. Especially the catalytic system of 1-(thiophen-2-yl)-N-(4-(trifluoromethoxy)phenyl)methanimine (ligand L2) with copper(I)-iodide showed high reactivity for all kind of alcohols (benzylic, allylic and aliphatic). In the case of benzyl alcohol even 2.5 mol% of copper loading gave quantitative yield. Beside high activity under aerobic conditions, the catalysts ability to oxidize 1,5-pentadiol to the corresponding lactol (86% in 4 h) and Nphenyldiethanolamine to the corresponding morpholine derivate lactol (86% in 24 h) is particularly noteworthy.
  • Räisänen, Ismo T.; Heikkinen, Anna Maria; Pakbaznejad Esmaeili, Elmira; Tervahartiala, Taina; Pajukanta, Riitta; Silbereisen, Angelika; Bostanci, Nagihan; Sorsa, Timo (2019)
    Background This cross-sectional study aims to investigate if a point-of-care (PoC) test of active matrix metalloproteinase-8 (aMMP-8) predicts levels of inflammation amplifier triggering receptor expressed on myeloid cells-1 (TREM-1) and its putative ligand the neutrophil peptidoglycan recognition protein 1 (PGLYRP1) in saliva. Methods Forty-seven adolescents, aged 15 to 17 years, were tested with aMMP-8 PoC test, which was followed by a full-mouth clinical examination of the assessment of periodontal, mucosal, and oral health. TREM-1 and PGLYRP1 levels were analyzed by ELISA. The immunofluorometric assay (IFMA) specific for aMMP-8 was used as the reference method. Results Fourteen saliva samples out of a total of 47 showed positivity for aMMP-8 PoC test. Both the TREM-1 and the aMMP-8 (IFMA) levels were significantly elevated among the aMMP-8 PoC test positives compared with the PoC test negatives (P <0.05). Moreover, aMMP-8 levels assessed by IFMA showed a strong positive correlation with TREM-1 levels in saliva (r = 0.777, P <0.001). The number of sites with a probing depth of >= 4 mm was significantly lower among the adolescents that had a negative aMMP-8 PoC test result, and TREM-1 levels <75 pg/mL (P <0.05). In contrast, adolescents with a positive aMMP-8 PoC test result (i.e., elevated aMMP-8 levels) together with elevated TREM-1 levels had a significantly higher number of periodontal pockets with >= 4 mm (P <0.001). Conclusion The present study validated usability of aMMP-8 PoC test for predicting "proinflammatory" salivary profile and periodontal health status in adolescents.
  • Zippel, Christoph; Spuling, Eduard; Hassan, Zahid; Polamo, Mika; Nieger, Martin; Bräse, Stefan (2020)
    Selective activation/functionalization of C-H bonds has emerged as an atom- and step-economical process at the forefront of modern synthetic chemistry. This work reports palladium-catalyzed exclusivelypara-selective C-H activation/aryl-aryl bond formation with a preference overN-arylation under the Buchwald-Hartwig amination reaction of 4-phenylamino[2.2]paracyclophane. This innovative synthetic strategy allows a facile preparation of [2.2]paracyclophane derivatives featuring disparatepara-substitutions at C-4 and C-7 positions in a highly selective manner, gives access to a series of potential candidates for [2.2]paracyclophane-derived new planar chiral ligands. The unprecedented behavior in reactivity and preferential selectivity of C-C coupling over C-N bond formation via C-H activation is unique to the [2.2]paracyclophane scaffold compared to the non-cyclophane analogue under the same reaction conditions. Selective C-H activation/aryl-aryl bond formation and sequential C-N coupling product formation is evidenced unambiguously by X-ray crystallography.
  • Djikic, Teodora; Vucicevic, Jelica; Laurila, Jonne; Radi, Marco; Veljkovic, Nevena; Xhaard, Henri; Nikolic, Katarina M. (2020)
    Based on the finding that a central antihypertensive agent with high affinity for I1-type imidazoline receptors ? rilmenidine, shows cytotoxic effects on cultured cancer cell lines, it has been suggested that imidazoline receptors agonists might have a therapeutic potential in the cancer therapy. Nevertheless, potential rilmenidine side effects caused by activation of α-adrenoceptors, or other associated receptors and enzymes, might hinder its therapeutic benefits. Considering that human α-adrenoceptors belong to the rhodopsin-like class A of G-protein-coupled receptors (GPCRs) it is reasonable to assume that imidazolines might have the affinity for other receptors from the same class. Therefore, to investigate possible off-target effects of imidazoline ligands we have prepared a reverse docking protocol on class A GPCRs, using imidazoline ligands and their decoys. To verify our in silico results, three ligands with high scores and three ligands with low scores were tested for antagonistic activity on α2- adrenoceptors.
  • Vaughan, Danielle; Kretz, Oliver; Alqallaf, Ali; Mitchell, Robert; von der Heide, Jennie L.; Vaiyapuri, Sakthivel; Matsakas, Antonios; Pasternack, Arja; Collins-Hooper, Henry; Ritvos, Olli; Ballesteros, Randy; Huber, Tobias B.; Amthor, Helge; Mukherjee, Abir; Patel, Ketan (2020)
    Duchenne Muscular Dystrophy is a devastating disease caused by the absence of a functional rod-shaped cytoplasmic protein called dystrophin. Several avenues are being developed aimed to restore dystrophin expression in boys affected by this X-linked disease. However, its complete cure is likely to need combinational approaches which may include regimes aimed at restoring muscle mass. Augmenting muscle growth through the manipulation of the Myostatin/Activin signalling axis has received much attention. However, we have recently shown that while manipulation of this axis in wild type mice using the sActRIIB ligand trap indeed results in muscle growth, it also had a detrimental impact on the testis. Here we examined the impact of administering a powerful Myostatin/Activin antagonist in two mouse models of Duchenne Muscular Dystrophy. We report that whilst the impact on muscle growth was not always positive, both models showed attenuated testis development. Sperm number, motility and ultrastructure were significantly affected by the sActRIIB treatment. Our report suggests that interventions based on Myostatin/Activin should investigate off-target effects on tissues as well as muscle.
  • Liu, Yixin; Ribeiro, Orquidea De Castro; Robinson, James; Goldman, Adrian (2020)
    The receptor tyrosine kinase RET is essential in a variety of cellular processes. RET gain-of-function is strongly associated with several cancers, notably multiple endocrine neoplasia type 2A (MEN 2A), while RET loss-of-function causes Hirschsprung's disease and Parkinson's disease. To investigate the activation mechanism of RET as well as to enable drug development, over-expressed recombinant protein is needed for in vitro functional and structural studies. By comparing insect and mammalian cells expression of the RET extracellular domain (RETECD), we showed that the expression yields of RETECD using both systems were comparable, but mammalian cells produced monomeric functional RETECD, whereas RETECD expressed in insect cells was non-functional and multimeric. This was most likely due to incorrect disulfide formation. By fusing an Fc tag to the C-terminus of RETECD, we were able to produce, in HEK293T cells, dimeric oncogenic RETECD (C634R) for the first time. The protein remained dimeric even after cleavage of the tag via the cysteine disulfide, as in full-length RET in the context of MEN 2A and related pathologies. Our work thus provides valuable tools for functional and structural studies of the RET signaling system and its oncogenic activation mechanisms. (C) 2020 Published by Elsevier B.V.
  • Hirvinen, Mari; Capasso, Cristian; Guse, Kilian; Garofalo, Mariangela; Vitale, Andrea; Ahonen, Marko; Kuryk, Lukasz; Vähä-Koskela, Markus; Hemminki, Akseli; Fortino, Vittorio; Greco, Dario; Cerullo, Vincenzo (2016)
    In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate-and eventually the long-lasting adaptive immunity against cancer.
  • Viciano-Chumillas, Marta; Koprowiak, Florian; Mutikainen, Ilpo; Wernsdorfer, Wolfgang; Mallah, Talal; Bolvin, Helene (2017)
    We report a bimetallic holmium(III) complex showing a S-shaped magnetic hysteresis at low temperature. The complex is investigated by x-ray crystallography, magnetometry, single crystal microsquid measurements, and first-principles calculations. A model Hamiltonian including electronic and nuclear magnetic moments is used to fit all experimental data. We conclude that the Ho(III) may be described as non-Kramers doublets with respective gaps of Delta(A) = 0.8 and Delta(B) = 10 cm(-1) and that there is a small ferromagnetic coupling of J = 1 cm(-1) ((H) over cap (S) = -JS(A) . S-B). As in previous works, the hysteresis arise from the hyperfine structure of the Ho(III) ions. The S-shaped form of the hysteresis reflects the avoided crossing of the electronic states in the non-Kramers doublets.
  • Ruskamo, Salla; Nieminen, Tuomo; Kristiansen, Cecilie K.; Vatne, Guro H.; Baumann, Anne; Hallin, Erik I.; Raasakka, Arne; Joensuu, Paivi; Bergmann, Ulrich; Vattulainen, Ilpo; Kursula, Petri (2017)
    Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies. Recently, three CMT1-associated point mutations (I43N, T51P, and I52T) were discovered in the abundant peripheral myelin protein P2. These mutations trigger abnormal myelin structure, leading to reduced nerve conduction velocity, muscle weakness, and distal limb atrophy. P2 is a myelin-specific protein expressed by Schwann cells that binds to fatty acids and membranes, contributing to peripheral myelin lipid homeostasis. We studied the molecular basis of the P2 patient mutations. None of the CMT1-associated mutations alter the overall folding of P2 in the crystal state. P2 disease variants show increased aggregation tendency and remarkably reduced stability, T51P being most severe. In addition, P2 disease mutations affect protein dynamics. Both fatty acid binding by P2 and the kinetics of its membrane interactions are affected by the mutations. Experiments and simulations suggest opening of the beta barrel in T51P, possibly representing a general mechanism in fatty acid-binding proteins. Our findings demonstrate that altered biophysical properties and functional dynamics of P2 may cause myelin defects in CMT1 patients. At the molecular level, a few malformed hydrogen bonds lead to structural instability and misregulation of conformational changes related to ligand exchange and membrane binding.
  • Rong, Mark K.; Chirila, Andrei; Franciolus, David; Lutz, Martin; Nieger, Martin; Ehlers, Andreas W.; Slootweg, J. Chris; Lammertsma, Koop (2019)
    Protic NHC iridium complexes, obtained from the corresponding azido-phenylene-isocyanide precursor complexes, were investigated for ligand-based reactivity. Under redox-neutral conditions, acetonitrile inserts into the N-H bonds to provide kappa(2)-NHC-imidoyl ligand-based complexes, while under reductive conditions the complex also expels one N-H proton to provide the corresponding deprotonated analogues. Using zinc as a reductor activates the NHC-iridium complex to form an asymmetric bimetallic iridium hydrido complex, in which two anionic N-deprotonated NHCs bridge the bimetallic core. X-ray crystal structures are reported for the azido-phenylene-isocyanide precursor complex, the protic NHC complex, and the asymmetric bimetallic iridium hydride complex. Density functional computations and a QTAIM analysis of the bimetallic iridium hydrido complex are provided.
  • Provenzani, Riccardo; Tarvainen, Ilari Matti Elias; Brandoli, Giulia; Lempinen, Antti Tapani; Artes, Sanna; Turku, Ainoleena; Jäntti, Maria Helena; Talman, Virpi; Yli-Kauhaluoma, Jari Tapani; Tuominen, Raimo Kalevi; Boije af Gennäs, Per Gustav (2018)
    Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. Utilizing the crystal structure of the PKC delta C1B domain, we have developed hydrophobic isophthalic acid derivatives that modify PKC functions by binding to the C1 domain of the enzyme. In the present study, we aimed to improve the drug-like properties of the isophthalic acid derivatives by increasing their solubility and enhancing the binding affinity. Here we describe the design and synthesis of a series of multisubstituted pyrimidines as analogs of C1 domain - targeted isophthalates and characterize their binding affinities to the PKC alpha isoform. In contrast to our computational predictions, the scaffold hopping from phenyl to pyrimidine core diminished the binding affinity. Although the novel pyrimidines did not establish improved binding affinity for PKC alpha compared to our previous isophthalic acid derivatives, the present results provide useful structure-activity relationship data for further development of ligands targeted to the C1 domain of PKC.
  • Li, Xiang-Guo; Autio, Anu; Ahtinen, Helena; Helariutta, Kerttuli; Liljenbäck, Heidi; Jalkanen, Sirpa; Roivainen, Anne; Airaksinen, Anu J. (2013)