- Catalyst-Free Synthesis of O-Heteroacenes by Ladderization of Fluorinated Oligophenylenes
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A novel catalyst-free approach to benzoannulated oxygen-containing heterocycles from fluorinated oligophenylenes is reported. Unlike existing methods, the presented reaction does not require an oxygen-containing precursor and relies on an external oxygen source, potassium tert-butoxide, which serves as an O2? synthon. The radical nature of the reaction facilitates nucleophilic substitution even in the presence of strong electron-donating groups and enables de-tert-butylation required for the complete annulation. Also demonstrated is the applicability of the method to introduce five-, six-, and seven-membered rings containing oxygen, whereas multiple annulations also open up a short synthetic path to ladder-type O-heteroacenes and oligodibenzofurans.
- Feofanov, Mikhail,Akhmetov, Vladimir,Takayama, Ryo,Amsharov, Konstantin
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supporting information
p. 5199 - 5203
(2021/02/21)
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- DMT1 Inhibitors Kill Cancer Stem Cells by Blocking Lysosomal Iron Translocation
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Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.
- Turcu, Andreea L.,Versini, Antoine,Khene, Nadjib,Gaillet, Christine,Ca?eque, Tatiana,Müller, Sebastian,Rodriguez, Rapha?l
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supporting information
p. 7369 - 7373
(2020/06/02)
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- Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation
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Solute carrier proteins (SLCs) control fluxes of ions and molecules across biological membranes and represent an emerging class of drug targets. SLC11A2 (hDMT1) mediates intestinal iron uptake and its inhibition might be used to treat iron overload diseases such as hereditary hemochromatosis. Here we report a micromolar (IC50 = 1.1 μM) pyrazolyl-pyrimidone inhibitor of radiolabeled iron uptake in hDMT1 overexpressing HEK293 cells acting by a non-competitive mechanism, which however does not affect the electrophysiological properties of the transporter. Isothermal titration calorimetry, competition with calcein, induced precipitation of radioactive iron and cross inhibition of the unrelated iron transporter SLC39A8 (hZIP8) indicate that inhibition is mediated by metal chelation. Mapping the chemical space of thousands of pyrazolo-pyrimidones and similar 2,2′-diazabiaryls in ChEMBL suggests that their reported activities might partly reflect metal chelation. Such metal chelating groups are not listed in pan-assay interference compounds (PAINS) but should be checked when addressing SLCs.
- Embaby, Ahmed,Hediger, Matthias A.,Javor, Sacha,Manatschal, Cristina,Poirier, Marion,Reymond, Jean-Louis,Bühlmann, Sven,Pujol-Giménez, Jonai
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supporting information
p. 1023 - 1031
(2020/10/06)
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- Mechanistic basis of the inhibition of slc11/nramp-mediated metal ion transport by bis-isothiourea substituted compounds
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In humans, the divalent metal ion transporter-1 (DMT1) mediates the transport of ferrous iron across the apical membrane of enterocytes. Hence, its inhibition could be beneficial for the treatment of iron overload disorders. Here we characterize the interaction of aromatic bis-isothiourea-substituted compounds with human DMT1 and its prokaryotic homologue EcoDMT. Both transporters are inhibited by a common competitive mechanism with potencies in the low micromolar range. The crystal structure of EcoDMT in complex with a brominated derivative defines the binding of the inhibitor to an extracellular pocket of the transporter in direct contact with residues of the metal ion coordination site, thereby interfering with substrate loading and locking the transporter in its outward-facing state. Mutagenesis and structure-activity relationships further support the observed interaction mode and reveal species-dependent differences between pro-and eukaryotic transporters. Together, our data provide the first detailed mechanistic insight into the pharmacology of SLC11/NRAMP transporters.
- Manatschal, Cristina,Pujol-Giménez, Jonai,Poirier, Marion,Reymond, Jean-Louis,Hediger, Matthias A.,Dutzler, Raimund
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- TRANSITION-METAL FREE REDUCTIVE CLEAVAGE OF AROMATIC C-O, C-N, AND C-S BONDS BY ACTIVATED SILANES
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The present invention describes chemical systems and methods for reducing C—O, C—N, and C—S bonds, said system comprising a mixture of (a) at least one organosilane and (b) at least one strong base, said system being substantially free of a transition-metal compound, and said system optionally comprising at least one molecular hydrogen donor compound, molecular hydrogen, or both.
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Page/Page column
(2014/04/17)
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- Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors
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Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.
- Zhang, Zaihui,Kodumuru, Vishnumurthy,Sviridov, Serguei,Liu, Shifeng,Chafeev, Mikhail,Chowdhury, Sultan,Chakka, Nagasree,Sun, Jianyu,Gauthier, Simon J.,Mattice, Maryanne,Ratkay, Laszlo G.,Kwan, Rainbow,Thompson, Jay,Cutts, Alison Brownlie,Fu, Jianmin,Kamboj, Rajender,Goldberg, Y. Paul,Cadieux, Jay A.
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scheme or table
p. 5108 - 5113
(2012/08/28)
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- TRICYCLIC COMPOUNDS USEFUL IN TREATING IRON DISORDERS
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This invention is directed to, for example, compounds of formula (I): wherein n, m, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of iron disorders. This invention is also directed to pharmaceutical compositions comprising the compounds and methods of using the compounds to treat iron disorders.
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Page/Page column 81
(2008/12/08)
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- Preparation of Di-, Tetra-, Hexa- and Octamethyl-dibenzofurans via Dilithiation/Oxidative Coupling Diphenyl Ethers
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Overnight treatment of methylated diphenyl ethers, e.g. 3,3',5,5'-tetramethyldiphenyl ether, with BuLi-TMEDA in cyclohexane-diethyl ether followed by addition of CuCl2 resulted in excellent yields of the corresponding dibenzofurans, e.g. 1,3,7,9-tetramethyldibenzofuran.
- Radner, Finn,Eberson, Lennart
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p. 2016 - 2030
(2007/10/03)
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