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    Substrates for thioredoxin reductase
    1.
    发明授权
    Substrates for thioredoxin reductase 有权
    硫氧还蛋白还原酶底物

    公开(公告)号：US07671211B1

    公开(公告)日：2010-03-02

    申请号：US09926218

    申请日：2000-03-31

    Applicant: Arne Holmgren ,  Marjan H. Amiri ,  Hiroyuki Masayasu

    Inventor： Arne Holmgren ,  Marjan H. Amiri ,  Hiroyuki Masayasu

    IPC: C07D293/00

    CPC classification number: C07D293/04 ,  A61K31/166 ,  A61K31/167 ,  C07C391/02 ,  C12N9/0036 ,  C12P9/00

    Abstract: A substrate for thioredoxin reductase which comprises a compound represented by the following general formula (I) or (I′): wherein R1 and R2 independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group and the like; R3 represents an aryl group, an aromatic heterocyclic group and the like; R4 represents a hydrogen atom, a hydroxyl group, a —S-α-amino acid group and the like; R5 represents a hydrogen atom or a C1-C6 alkyl group; Y represents oxygen atom or sulfur atom; n represents an integer of from 0 to 5; and the selenium atom may be oxidized, whose example includes 2-phenyl-1,2-benzisoselenazol-3(2H)-one or a ring-opened form thereof. The substrate is reduced by thioredoxin reductase in the presence of NADPH and enhances peroxidase activity of thioredoxin reductase.

    Abstract translation: 用于硫氧还蛋白还原酶的底物，其包含由以下通式（I）或（I'）表示的化合物：其中R 1和R 2独立地表示氢原子，卤素原子，三氟甲基等; R3表示芳基，芳香族杂环基等; R4表示氢原子，羟基，-S-α-氨基酸基等; R5表示氢原子或C1-C6烷基; Y表示氧原子或硫原子; n表示0〜5的整数， 并且硒原子可被氧化，其实例包括2-苯基-1,2-苯并异硒唑-3（2H） - 酮或其开环形式。 在NADPH存在下，底物被硫氧还蛋白还原酶还原，提高硫氧还蛋白还原酶的过氧化物酶活性。

    BACTERIAL THIOREDOXIN REDUCTASE INHIBITORS AND METHODS FOR USE THEREOF
    2.
    发明申请
    BACTERIAL THIOREDOXIN REDUCTASE INHIBITORS AND METHODS FOR USE THEREOF 审中-公开
    细菌三氧化二氮还原酶抑制剂及其使用方法

    公开(公告)号：US20090005422A1

    公开(公告)日：2009-01-01

    申请号：US11751915

    申请日：2007-05-22

    Applicant: Arne Holmgren ,  Jun Lu ,  Alexios Vlamis-Gardikas ,  Rong Zhao ,  K. Kandasamy ,  Lars Engman ,  Lars Engstrand ,  Sven Hoffner

    Inventor： Arne Holmgren ,  Jun Lu ,  Alexios Vlamis-Gardikas ,  Rong Zhao ,  K. Kandasamy ,  Lars Engman ,  Lars Engstrand ,  Sven Hoffner

    IPC: A61K31/4439 ,  A61K31/41 ,  A61K31/428 ,  A61P31/04 ,  A61P31/06

    CPC classification number: C07D421/04 ,  A61K31/381 ,  A61K31/41 ,  C07D293/12 ,  Y02A50/473

    Abstract: The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E. coli TrxR with Ki of 0.14 μM and 0.46 μM, respectively. E. coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.

    Abstract translation: Ebselen的作用机制区分细菌和哺乳动物硫氧还蛋白还原酶（TrxR）。 它显示哺乳动物Trx的快速氧化，并且通过NADPH-TrxR催化依次硒硒酚与过氧化氢的周转，因此是哺乳动物抗氧化剂。 依布硒及其二硒化物是大肠杆菌TrxR的强烈竞争抑制剂，Ki分别为0.14μM和0.46μM。 缺乏谷胱甘肽还原酶或谷胱甘肽的大肠杆菌突变体对依布硒林的抑制更敏感。 由于谷氧还蛋白或硫氧还蛋白系统是核糖核苷酸还原酶的电子供体，依普硒靶主要是谷胱甘肽和谷氧还蛋白阴性细菌，一类包括主要病原体。 因此，依布硒林和类似化合物可用作抗菌剂，即使对于多抗性菌株也是有用的。 以前不知道对ebselen，结核分枝杆菌（结核分枝杆菌）和幽门螺杆菌（胃溃疡和癌症）敏感的两种主要致病菌被证明是优异的靶标。 幽门螺杆菌对硫化硫也敏感。

    Bacterial thioredoxin reductase inhibitors and methods for use thereof
    5.
    发明授权
    Bacterial thioredoxin reductase inhibitors and methods for use thereof 有权
    细菌硫氧还蛋白还原酶抑制剂及其使用方法

    公开(公告)号：US08592468B2

    公开(公告)日：2013-11-26

    申请号：US13070457

    申请日：2011-03-23

    Applicant: Arne Holmgren ,  Jun Lu ,  Alexios Vlamis-Gardikas ,  Rong Zhao ,  Karuppasamy Kandasamy ,  Lars Engman ,  Lars Engstrand ,  Sven Hoffner

    Inventor： Arne Holmgren ,  Jun Lu ,  Alexios Vlamis-Gardikas ,  Rong Zhao ,  Karuppasamy Kandasamy ,  Lars Engman ,  Lars Engstrand ,  Sven Hoffner

    IPC: A61K31/425

    CPC classification number: C07D421/04 ,  A61K31/381 ,  A61K31/41 ,  C07D293/12 ,  Y02A50/473

    Abstract: The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E. coli TrxR with Ki of 0.14 μM and 0.46 μM, respectively. E. coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.

    Abstract translation: Ebselen的作用机制区分细菌和哺乳动物硫氧还蛋白还原酶（TrxR）。 它显示哺乳动物Trx的快速氧化，并且通过NADPH-TrxR催化依次硒硒酚与过氧化氢的周转，因此是哺乳动物抗氧化剂。 依布硒及其二硒化物是大肠杆菌TrxR的强烈竞争抑制剂，Ki分别为0.14μM和0.46μM。 缺乏谷胱甘肽还原酶或谷胱甘肽的大肠杆菌突变体对依布硒林的抑制更敏感。 由于谷氧还蛋白或硫氧还蛋白系统是核糖核苷酸还原酶的电子供体，依普硒靶主要是谷胱甘肽和谷氧还蛋白阴性细菌，一类包括主要病原体。 因此，依布硒林和类似化合物可用作抗菌剂，即使对于多抗性菌株也是有用的。 以前不知道对ebselen，结核分枝杆菌（结核分枝杆菌）和幽门螺杆菌（胃溃疡和癌症）敏感的两种主要致病菌被证明是优异的靶标。 幽门螺杆菌对硫化硫也敏感。

    BACTERIAL THIOREDOXIN REDUCTASE INHIBITORS AND METHODS FOR USE THEREOF
    7.
    发明申请
    BACTERIAL THIOREDOXIN REDUCTASE INHIBITORS AND METHODS FOR USE THEREOF 有权
    细菌三氧化二氮还原酶抑制剂及其使用方法

    公开(公告)号：US20110288130A1

    公开(公告)日：2011-11-24

    申请号：US13070457

    申请日：2011-03-23

    Applicant: Arne Holmgren ,  Jun Lu ,  Alexios Vlamis-Gardikas ,  Rong Zhao ,  K. Kandasamy ,  Lars Engman ,  Lars Engstrand ,  Sven Hoffner

    Inventor： Arne Holmgren ,  Jun Lu ,  Alexios Vlamis-Gardikas ,  Rong Zhao ,  K. Kandasamy ,  Lars Engman ,  Lars Engstrand ,  Sven Hoffner

    IPC: A61K31/4439 ,  A61P31/04 ,  A61K31/41

    CPC classification number: C07D421/04 ,  A61K31/381 ,  A61K31/41 ,  C07D293/12 ,  Y02A50/473

    Abstract: The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E. coli TrxR with Ki of 0.14 μM and 0.46 μM, respectively. E. coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.

    Abstract translation: Ebselen的作用机制区分细菌和哺乳动物硫氧还蛋白还原酶（TrxR）。 它显示哺乳动物Trx的快速氧化，并且通过NADPH-TrxR催化依次硒硒酚与过氧化氢的周转，因此是哺乳动物抗氧化剂。 依布硒及其二硒化物是大肠杆菌TrxR的强竞争性抑制剂，Ki分别为0.14μM和0.46μM。 缺乏谷胱甘肽还原酶或谷胱甘肽的大肠杆菌突变体对依布硒林的抑制更敏感。 由于谷氧还蛋白或硫氧还蛋白系统是核糖核苷酸还原酶的电子供体，依普硒靶主要是谷胱甘肽和谷氧还蛋白阴性细菌，一类包括主要病原体。 因此，依布硒林和类似化合物可用作抗菌剂，即使对于多抗性菌株也是有用的。 以前不知道对ebselen，结核分枝杆菌（结核分枝杆菌）和幽门螺杆菌（胃溃疡和癌症）敏感的两种主要致病菌被证明是优异的靶标。 幽门螺杆菌对硫化硫也敏感。

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