Y Inouye

Hiroshima University, Hiroshima-shi, Hiroshima-ken, Japan

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Publications (32)69.7 Total impact

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    ABSTRACT: 1,1'-(m-Xylenediyl)-bis(1,4,7,10-tetraazacyclododecane)-Z n2II complex (m-xylenediyl-bicyclin-Zn2II), a potent inhibitor of human immunodeficiency virus (HIV), was obtained from cyclin by a combination of dimerization and metal complexation. The ratio of median cytotoxic concentration against host cells (CC50) and median effective concentration against HIV cytopathogenicity (EC50), referred to as the selectivity index (SI), was regarded to be a measure of anti-HIV activity. These two chemical modifications contributed to a potent, in vitro anti-HIV activity of m-xylenediyl-bicyclin-Zn2II by respectively increasing the CC50 and decreasing the EC50 in comparison with those of cyclin.
    Biological & Pharmaceutical Bulletin 04/1996; 19(3):456-8. · 1.85 Impact Factor
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    ABSTRACT: We established an improved production of an antitumor polypeptide anti biotic, phenomycin (PHM), by using a genetically engineered Escherichia coli. Phenomycin consists of 89 natural amino acids without intramolecular disulfide bridge. PHM gene was synthesized as a fusion gene in which PHM at the C-terminus and the residues 1 approximately 20 of Hirudin variant 1 (HV1) at the N-terminus connected by a factor Xa recognition sequence (Ile-Glu-Gly-Arg). E coli JM 109 transformed with a plasmid containing the synthesized gene expressed a fusion protein and the trypsinization of the fusion protein purified by ultrafiltration and ion-exchange chromatography gave efficiently recombinant PHM at a final yield of 50 mg/liter of culture. This PHM yield was six times higher than that obtained by a natural PHM producing strain of Streptoverticillium baldacci. Recombinant PHM was not distinguishable from natural PHM in all aspects observed.
    The Journal of Antibiotics 02/1996; 49(1):81-5. · 2.19 Impact Factor
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    ABSTRACT: The anti-human immunodeficiency virus (HIV) activity of polyoxometalates of representative structural families, such as Keggin, lacunary Keggin, trivacant Keggin, Keggin sandwich, Wells-Dawson and Wells-Dawson sandwich, was determined using two strains of HIV type 1 (HIV-1HTLV-IIIB and HIV-1SF-2H). The compounds were preferably selected to cover both polyoxotungstates and polyoxomolybdates in each structural family. In general, polyoxotungstates of Keggin, lacunary Keggin, trivacant Keggin, Keggin sandwich, Wells-Dawson and Wells-Dawson sandwich structures showed anti-HIV-1HTLVIIIB activity, whereas most compounds not included in these structural categories were inactive. Among the compounds with a potent anti-HIV-1HTLV-IIIB activity, those of Keggin and its closely related structural families (lacunary Keggin, trivacant Keggin and Keggin sandwich) inhibited the cytopathogenicity and syncytium formation caused by HIV-1SF-2 to a much higher extent compared with HIV-1HTLV-IIIB-related ones. The difference between the spectra of anti-HIV-1HTLV-IIIB activity and the specificity for HIV-1SF-2H might result from differential structural requirements in these functions.
    Biological & Pharmaceutical Bulletin 08/1995; 18(7):996-1000. · 1.85 Impact Factor
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    ABSTRACT: The cell-to-cell transmission of human immunodeficiency virus type 1 (HIV-1) was studied using MOLT-4 cells chronically infected with a variant strain of HIV-1SF-2 (MOLT-4/HIV-1SF-2H) and CD4+ human lymphoid MT-4 cells. MOLT-4/HIV-1SF-2H cells produced less than 1 TCID50 infectious particles per day as determined by the cytopathogenicity in MT-4 cells. However, the expression of envelope glycoproteins gp120 and gp41 on the MOLT-4/HIV-1SF-2H cell membrane was satisfactory for syncytium formation with the uninfected MOLT-4 cells. When MOLT-4/HIV-1SF-2H and MT-4 cells were co-cultured, severe cytopathogenicity was observed in MT-4 cells without being accompanied by the formation of multi-nucleated cells. Thus, the system consisting of MOLT-4/HIV-1SF-2H and MT-4 cells is convenient for exclusive study of the mechanism of cell-to-cell transmission of HIV-1. Using various compounds, it was confirmed that cell-to-cell transmission required both gp120/gp41-CD4 binding and de novo DNA synthesis.
    Biological & Pharmaceutical Bulletin 07/1995; 18(6):920-2. · 1.85 Impact Factor
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    ABSTRACT: The macrocyclic polyamines, cyclen and cyclam, and their derivatives have been tested for inhibitory activity against the cytopathogenic effect (CPE) of human immunodeficiency virus type 1 strain HTLV-IIIB (HIV-1IIIB) on CD4+ human lymphoblastoma MT-4 cells. Cyclam and its derivatives were complexed with a variety of transition metal ions NiII, ZnII, CuII, FeIII and CoIII. The divalent metal complexes effected lower toxicity and greater anti-HIV-1 activity, while the trivalent metal complexes had no effect on HIV-1-dependent CPE. When dimerized, the anti-HIV activity of monomers was significantly enhanced. A potent inhibition of CPE by biscyclam was transiently observed 4 d after the virus infection, but was not seen at 6 d due to severe toxicity. The toxicity of biscyclam, referred to as delayed toxicity, could be overcome by a metal complexation. The strain specificities of biscyclams were further studied by testing their effects on syncytium formation between HIV-infected and uninfected human acute lymphoblastic leukemia MOLT-4 cells. The 50% inhibitory concentrations of biscyclams against HIV-2GH-1-dependent syncytium formation were less than one hundredth those for the other HIV strains (HIV-1IIIB, HIV-1RF and HIV-1SF-2).
    Biological & Pharmaceutical Bulletin 03/1994; 17(2):243-50. · 1.85 Impact Factor
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    ABSTRACT: A screening for inhibitors of human immunodeficiency virus type 1 (HIV-1) among various types of isopolyoxomolybdates and heteropolyoxomolybdates was carried out by using an in vitro assay system measuring the cytopathogenicity of HIV-1 in CD4+ human MT-4 cells. A novel heteropolyoxomolybdate named PM-104 with the chemical formula (NH4)12H2(Eu4(MoO4)(H2O)16(Mo7O24)4).13H2O was found to be associated with potent anti-HIV-1 activity. PM-104 interferes with virus infection at a very early step such as adsorption and/or penetration into the cells. In addition to the cytopathic effect of HIV-1 on MT-4 cells, syncytium formation between mock-infected MOLT-4 cells and MOLT-4 cells chronically infected with either HIV-1 or HIV-2 is suppressed by PM-104. PM-104 also blocks the replication of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The antiviral properties of PM-104 could be attributed to the combined effect of europium atoms and its peculiar three-dimensional anion structure.
    Antiviral Research 05/1993; 20(4):317-31. · 3.93 Impact Factor
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    ABSTRACT: A novel anthracycline antibiotic, cinerubin R, was isolated from the fermentation broth of Streptomyces eurythermus strain H1715MY2. The structure of cinerubin R was elucidated to be 4"-aculosyl-4'-rhodinosyl-7-rhodosaminyl-epsilon-py rromycinone. Cinerubin R was active against Gram-positive bacteria and inhibited the growth of divergent multi-drug-resistant cells to the same extent as their parental cells.
    The Journal of Antibiotics 11/1992; 45(10):1599-608. · 2.19 Impact Factor
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    ABSTRACT: One isopolyoxometalate and 42 heteropolyoxometalates consisting of 3 compounds with the trivacant Keggin structure, 2 with the lacunary Keggin structure, 30 with the Keggin structure, one with the Wells-Dawson structure and 6 with miscellaneous structures were tested for their suppressive effect on the cytopathogenicity of human immunodeficiency virus type 1 (HIV-1) in vitro and inhibitory activity against HIV-1 reverse transcriptase. In contrast to the leading interpretations which attribute the suppressive effect of polyoxometalates on the cytopathogenicity of HIV-1 to the inhibition of HIV-1 reverse transcriptase by these compounds, there was no distinct correlation observed between these two functions of polyoxometalates.
    CHEMICAL & PHARMACEUTICAL BULLETIN 04/1992; 40(3):805-7. · 1.56 Impact Factor
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    ABSTRACT: The primary structure of phenomycin, an antitumor polypeptide antibiotic isolated from the culture broth of Streptomyces fervens var. phenomyceticus, was determined. Sequence analysis has revealed that it consists of 89 amino acid residues (Mr 9,524) and no disulfide bridge is present. The sequence of phenomycin at residues 48-70 was found to be hydrophilic, being surrounded by hydrophobic regions at both sides. Furthermore, clustering of half the lysine residues in this hydrophilic region and marked basicity of phenomycin imply the external disposition of this region. Phenomycin does not show significant sequence homology to any known proteins including antitumor polypeptide antibiotics.
    The Journal of Antibiotics 12/1991; 44(11):1222-7. · 2.19 Impact Factor
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    ABSTRACT: A polyoxomolybdoeuropate PM-104 (NH4)12H2[Eu4(MoO4)(H2O)16(Mo7O24)4].13H2O was found to be a potent inhibitor of the growth of human immunodeficiency virus type 1 (HIV-1), a causative agent of acquired immunodeficiency syndrome (AIDS). On the basis of TI50 [median cytotoxic concentration (CC50)/median effective concentration (EC50)], the in vitro anti-HIV-1 activity of PM-104 is favorably comparable to that of a heteropolyoxotungstate PM-19 K7[PTi2W10O40].6H2O, which is one of the most potent HIV-1 inhibitors among the polyoxometalates so far tested. The heteropolyoxomolybdate with a potent anti-HIV-1 activity is introduced for the first time in this communication.
    CHEMICAL & PHARMACEUTICAL BULLETIN 07/1991; 39(6):1638-40. · 1.56 Impact Factor
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    ABSTRACT: Synthetic heterocyclic quinones (107 samples) consisting of o- and p-quinoline quinones, o-isoquinoline quinones and p-quinoxaline quinones as well as o- and p-naphthoquinones (3 samples) were tested for their inhibitory activities against avian myeloblastosis virus reverse transcriptase (AMV-RT) and cytotoxic activities against mouse lymphoblastoma L5178Y cells. In general, o-quinoline quinones (i.e., the 5,6-quinolinedione derivatives) are more potent inhibitors of AMV-RT than p-quinoline quinones (the 5,8-quinolinedione derivatives). Furthermore, the growth of L5178/Y cells were significantly refractory to the 8-methoxy-5,6-quinolinedione derivatives whose suppressive effects on AMV-RT function were fairly comparable to those of the other o-quinoline quinones. The longer the chain length of 7-alkyl substituent in o- or p-quinoline quinones, the lower the biological activities.
    CHEMICAL & PHARMACEUTICAL BULLETIN 05/1991; 39(4):994-8. · 1.56 Impact Factor
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    ABSTRACT: Fifteen heteropolyoxotungstates were tested for their effects on the proliferation of human immunodeficiency virus type 1 (HIV-1) using an in vitro system consisting of MT-4 cells and HTLV-IIIb. Eight heteropolyoxotungstates (HPOTs) with the Keggin structure or dimerized deficient Keggin structure proved to be potent inhibitors of HIV-1. In contrast, seven non-Keggin HPOTs including HPA 23 did not have significant effects on HIV-1 proliferation at non-toxic doses. [PTi2W10O40]7- (PM-19) was the most potent inhibitor of HIV-1 among the 15 HPOTs tested. The inhibition of HIV-1 replication by PM-19 presumably results from impaired virus adsorption and/or penetration into target cells. Viral spread of HIV-1 and HIV-2 on cell-to-cell basis was also susceptible to PM-19. In combination, PM-19 and 3'-azido-3'-deoxythymidine were synergistic in inhibiting HIV-1 proliferation.
    Antiviral Research 03/1991; 15(2):113-24. · 3.93 Impact Factor
  • Y Inouye, K Oogose, S Nakamura
    The Journal of Antibiotics 09/1990; 43(8):1021-7. · 2.19 Impact Factor
  • The Journal of Antibiotics 09/1990; 43(8):1012-7. · 2.19 Impact Factor
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    ABSTRACT: A Keggin polyoxotungstate PM-19 K7[PTi2W10O40].6H2O was found to be a potent inhibitor of the replication of human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS), in OKT4+ cells. In contrast, the effect of HPA 23 (NH4)17Na[NaSb9W21O86], an inhibitor of reverse transcriptase of HIV, was not significant.
    CHEMICAL & PHARMACEUTICAL BULLETIN 02/1990; 38(1):285-7. · 1.56 Impact Factor
  • The Journal of Antibiotics 11/1989; 42(10):1523-5. · 2.19 Impact Factor
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    ABSTRACT: Antitumor antibiotic streptonigrin (STN-COOH) is a potent inhibitor of avian myeloblastosis virus (AMV) and human immunodeficiency virus reverse transcriptases. The carboxyl group at 2'-position of STN-COOH was modified to give esters, hydrazide, amides and amino acid derivatives for biological studies. Against AMV reverse transcriptase, the hydrazide, amides and amino acid derivatives showed inhibitory activity, which compared favorably to that of STN-COOH, with the ID50 values ranging 2-8 micrograms/ml. In contrast, the esters lacked this activity except for those having a dimethylamino group in the substituent. Splenomegaly caused by Friend leukemia virus infection was significantly inhibited by STN-COOH and STN-COO(CH2)3N(CH3)2, but not STN-CONH(CH2)3N(CH3)2. Doxorubicin-resistant murine lymphoblastoma L5178Y cells showed collateral sensitivity to both STN-COOH and STN-COO(CH2)3N(CH3)2 not only in vitro but also in vivo.
    The Journal of Antibiotics 07/1989; 42(6):968-76. · 2.19 Impact Factor
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    ABSTRACT: The structures of neoenactins (NEs) NL1 and NL2, novel antimycotic antibiotics produced by Streptoverticillium olivoreticuli in a precursor-oriented fashion, were elucidated by 1H and 13C NMR and mass spectroscopic studies. The structures of both antibiotics are closely related to that of NE-A, the major component of NE congeners, being classified in the group of hydroxamic acid antimycotic antibiotics in which L-serine and a diketo amine form a hydroxamic acid structure. To study the role of the carbonyl groups in the biological activities of the hydroxamic acid antimycotic antibiotics, NE-A was modified by reaction with various carbonyl reagents. In terms of antimycotic activity, the derivatives are classified into two distinct groups; the first ones are fairly comparable to but not exceeding and the second ones are less active than NE-A depending on their tendency to revert to NE-A by hydrolysis. In general, the biological activities of the derivatives are inversely proportional to their stabilities to hydrolysis.
    The Journal of Antibiotics 03/1989; 42(2):276-82. · 2.19 Impact Factor
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    ABSTRACT: The inhibition of human immunodeficiency virus (HIV) reverse transcriptase by certain antibiotics and related compounds was studied in comparison with that of avian myeloblastosis virus (AMV) reverse transcriptase and cellular DNA polymerases alpha and beta. In general, compounds that inhibited HIV reverse transcriptase also inhibited AMV reverse transcriptase. For example, 10 micrograms/ml of the isoquinoline quinones used in this study inhibited approximately 80% of the activity of reverse transcriptases of HIV and AMV, but did not inhibit the activity of DNA polymerases alpha and beta even at 50 micrograms/ml. AMV enzyme was more sensitive than HIV enzyme to colistin, enduracidins A and B, janiemycin, glysperin A, and thielavins A and B. The streptonigrin alkyl esters, however, inhibited HIV reverse transcriptase only. Sakyomicin A, luzopeptins, ellagic acid and suramine inhibited the activities of reverse transcriptases and cellular DNA polymerases.
    The Journal of Antibiotics 02/1989; 42(1):107-15. · 2.19 Impact Factor
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    ABSTRACT: Inhibition of avian myeloblastosis virus (AMV) reverse transcriptase by natural and synthetic quinones including antibiotics could be accounted for by an oxidation-reduction reaction. The quinones were shown to function as electron acceptors as revealed by the catalytic oxidation of NADH by Clostridium kluyveri diaphorase which was in excellent agreement with enzyme inhibition activity. The kinetics of inhibition of AMV reverse transcriptase by three synthetic quinones with different core structures, i.e., 6-methoxy-5,8-dihydroquinoline-5,8- dione, 5,8-dihydroisoquinoline-5,8-dione and 1,4-naphthoquinone, were studied. These quinones inhibited reverse transcriptase in the same manner as streptonigrin (STN) and were shown to act at a single class of reaction site(s) on the enzyme molecule. In contrast, the quinones with bulky substituents, i.e., 7-(2-nitrophenethylamino)-5,8-dihydroisoquinoline-5,8-dione and 7-methoxy-6-methyl-3-piperidino-5,8-dihydroisoquinoline-5,8-dione, were inactive as inhibitors of reverse transcriptase, whereas they retained competent catalytic activities in the oxidation of NADH by C. kluyveri diaphorase. Based on these observations, the existence of a specific site of interaction on the enzyme molecule, referred to as a quinone pocket, was proposed. The quinone pocket might play a crucial role in the early sequence of events leading to the inhibition of reverse transcriptase by quinones including STN and sakyomicin A (SKM). Access of SKM to a quinone pocket might be restricted due to its bulky structure in the vicinity of the quinone group. This is inferred from unsuccessful inhibition of reverse transcriptase by the quinones with bulky substituents, resulting in much poorer inhibition of reverse transcriptase in spite of more potent electron acceptor activity in the oxidation-reduction system as compared with those of STN.
    The Journal of Antibiotics 11/1988; 41(10):1471-8. · 2.19 Impact Factor