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Yoshiaki Takahashi,
Masayuki Igarashi,
Toshiaki Miyake,
Hiromi Soutome,
Kanae Ishikawa,
Yasuhiro Komatsuki,
Yoshiko Koyama,
Naoko Nakagawa,
Seiko Hattori,
Kunio Inoue,
Norio Doi, Yuzuru Akamatsu
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ABSTRACT: Acidic treatment of a mixture of caprazamycins (CPZs) A-G isolated from a screen of novel antimycobacterial agents gave caprazene, a core structure of CPZs, in high yield. Chemical modification of the resulting caprazene was performed to give its various derivatives. The structure-activity relationships of the caprazene derivatives against several mycobacterial species and pathogenic Gram-positive and Gram-negative bacteria were studied. Although caprazene showed no antibacterial activity, the antibacterial activity was restored for its 1'''-alkylamide, 1'''-anilide and 1'''-ester derivatives. Compounds 4b (CPZEN-45), 4d (CPZEN-48), 4f and 4g (CPZEN-51) exhibited more potent activities against Mycobacterium tuberculosis and M. avium complex strains than CPZ-B. These results suggest that caprazene would be a good precursor from which novel semisynthetic antibacterial antibiotics can be designed for the treatment of mycobacterial diseases such as tuberculosis and M. avium complex infection.
The Journal of Antibiotics 03/2013; 66(3):171-8. · 1.65 Impact Factor
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ABSTRACT: Natural products have contributed to the elucidation of biological mechanisms as well as drug discovery research. Even now, the expectation for natural products is undiminished. We screened prostaglandin release inhibitors that had no effect on in vitro cyclooxygenase activity derived from natural product sources and discovered pronqodine A. Using spectral analysis and total synthesis, the structure of pronqodine A was shown to be a benzo[d]isothiazole-4,7-dione analogue. Evaluation of the biological activity of pronqodine A revealed that the NAD(P)H dehydrogenase quinone 1 (NQO1) converted pronqodine A into a two-electron reductive form. The reductive form underwent autoxidation and reversed to its native form immediately with the generation of reactive oxygen species. Further investigations proved that pronqodine A inhibited cyclooxygenase enzyme activity only in the presence of NQO1. Pronqodine A acts as a potential bioreductive compound, inhibiting prostaglandin release in selectively activated NQO1-expressing cells.
Journal of Natural Products 02/2013; · 3.13 Impact Factor
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Chisato Nosaka,
Hayamitsu Adachi,
Ryuichi Sawa,
Koichi Nakae,
Sonoko Atsumi,
Naoko Kinoshita,
Yumiko Kubota,
Masayuki Igarashi,
Yoshihisa Sei,
Kentaro Yamaguchi,
Masabumi Shibuya,
Yoshio Nishimura, Yuzuru Akamatsu
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ABSTRACT: A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.
Journal of Natural Products 02/2013; · 3.13 Impact Factor
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Ryuichi Sawa,
Yoshiaki Takahashi,
Hideki Hashizume,
Kazushige Sasaki,
Yoshimasa Ishizaki,
Maya Umekita,
Masaki Hatano,
Hikaru Abe,
Takumi Watanabe,
Naoko Kinoshita, [......],
Kunio Inoue,
Syunichi Ohba,
Toru Masuda,
Masayuki Arakawa,
Yoshihiko Kobayashi,
Masa Hamada,
Masayuki Igarashi,
Hayamitsu Adachi,
Yoshio Nishimura, Yuzuru Akamatsu
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ABSTRACT: The abuse of antibacterial drugs imposes a selection pressure on bacteria that has driven the evolution of multidrug resistance in many pathogens. Our efforts to discover novel classes of antibiotics to combat these pathogens resulted in the discovery of amycolamicin (AMM). The absolute structure of AMM was determined by NMR spectroscopy, X-ray analysis, chemical degradation, and modification of its functional groups. AMM consists of trans-decalin, tetramic acid, two unusual sugars (amycolose and amykitanose), and dichloropyrrole carboxylic acid. The pyranose ring named as amykitanose undergoes anomerization in methanol. AMM is a potent and broad-spectrum antibiotic against Gram-positive pathogenic bacteria by inhibiting DNA gyrase and bacterial topoisomerase IV. The target of AMM has been proved to be the DNA gyrase B subunit and its binding mode to DNA gyrase is different from those of novobiocin and coumermycin, the known DNA gyrase inhibitors.
Chemistry 11/2012; · 5.93 Impact Factor
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ABSTRACT: Five human 2,3-oxidosqualnene cyclase (OSC) inhibitors were discovered using the combination of a virtual screening based on a docking study and an isotope-free assay system. All of these inhibitors were revealed to have activities comparable or superior to that of LDAO, a known OSC inhibitor. The computational study of the newly identified inhibitors suggested that CH/π interactions with F444 and W581 contribute to the binding, and these interactions are candidates for additional structural filters in the next generation of virtual screening.
Bioorganic & medicinal chemistry letters 11/2011; 22(1):231-4. · 2.65 Impact Factor
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ABSTRACT: Pyrrole- and 1,2,3-triazole-based 2,3-oxidosqualene cyclase (OSC) inhibitors 3 and 4 were discovered by conducting a virtual screening, a docking study based on the crystallographic structure of OSC, and biological assays. The hit rate of the assays was increased by establishing appropriate substructural filters in the virtual screening stage. Amide derivatives of 8 and 12 preserved the inhibitory activity of parent compound 3, which provided a reasonable starting point for further structure-activity-relationship (SAR) studies on related compounds.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5807-10. · 2.65 Impact Factor
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ABSTRACT: A synthetic route to paleic acid 1, antimicrobial agent effective against Mannheimia haemolytica and Pasteurella multocida, has been established. The absolute configuration of the secondary hydroxyl group was controlled by a catalytic asymmetric alkylation of an aldehyde using a chiral titanium sulfonamide complex and the cis double bond was installed using a Wittig reaction. This synthetic route was also applied to the preparation of structurally related analogs, which were used in structure-activity relationship studies for antibacterial activity.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5843-6. · 2.65 Impact Factor
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ABSTRACT: The structure-activity relationship of the boronic acid derivatives of tyropeptin, a proteasome inhibitor, was studied. Based on the structure of a previously reported boronate analog of tyropeptin (2), 41 derivatives, which have varying substructure at the N-terminal acyl moiety and P2 position, were synthesized. Among them, 3-phenoxyphenylacetamide 6 and 3-fluoro picolinamide 22 displayed the most potent inhibitory activity toward chymotryptic activity of proteasome and cytotoxicity, respectively. The replacement of the isopropyl group in the P2 side chain to H or Me had negligible effects on the biological activities examined in this study.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5839-42. · 2.65 Impact Factor
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Shuichi Sakamoto,
Fukiko Kojima,
Masayuki Igarashi,
Ryuichi Sawa,
Maya Umekita,
Yumiko Kubota,
Koichi Nakae,
Shoichi Yamaguchi,
Hayamitsu Adachi,
Yoshio Nishimura, Yuzuru Akamatsu
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ABSTRACT: Osteoblasts are the cells responsible for bone formation during embryonic development and adult life. Small compounds that could induce osteoblast differentiation might be promising sources of therapies for bone diseases such as osteoporosis. During screening for inducers of osteoblast differentiation of mouse pluripotent mesenchymal C3H10T1/2 cells, we isolated a small compound from the fermentation broth of Penicillium verruculosum CR37010. This compound, named decalpenic acid, bears a decalin moiety with a tetraenoic acid side chain. Treatment of C3H10T1/2 cells with decalpenic acid alone induced the expression of early osteoblast markers, such as alkaline phosphatase activity and osteopontin mRNA, but did not induce the late osteoblast marker osteocalcin mRNA or adipocyte markers under our experimental conditions.
The Journal of Antibiotics 10/2010; 63(12):703-8. · 1.65 Impact Factor
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Ikuko Kurata,
Maya Umekita,
Tsutomu Sawa,
Seiko Hattori,
Chigusa Hayashi,
Naoko Kinoshita,
Yoshiko Homma,
Masayuki Igarashi,
Masa Hamada,
Takumi Watanabe,
Ryuichi Sawa,
Hiroshi Naganawa,
Yoshikazu Takahashi, Yuzuru Akamatsu
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ABSTRACT: Paleic acid (1), an antibiotic, was obtained from a fermentation broth of Paenibacillus sp. BMK771-AF3. The compound is a fatty acid (9Z,16R)-16-hydroxy-9-octadecenoic acid ((R)-16-hydroxyoleic acid), whose isolation required protection of its polar functional groups. Mosher esters of paleic acid yielded information on the absolute configuration of secondary alcohol, and well-resolved (1)H NMR peaks around the double bond suggested that olefin adopted a Z geometry. Paleic acid showed potent antibacterial activity and narrow spectrum against Mannheimia haemolytica with MIC values ranging between 0.78 and 1.56 microg ml(-1).
The Journal of Antibiotics 08/2010; 63(8):519-23. · 1.65 Impact Factor
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The Journal of Antibiotics 03/2010; 63(3):147-9. · 1.65 Impact Factor
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ABSTRACT: The time-kill studies using pargamicin A against Staphylococcus aureus and Enterococcus faecalis were performed. The effects of the incorporation of radioactive precursors into macromolecules, membrane potential and function using fluorescent dyes were also examined. These studies revealed that rapid bactericidal activity of pargamicin A correlates with the perturbation of bacterial cell membrane potential and membrane function.
The Journal of Antibiotics 03/2010; 63(6):279-83. · 1.65 Impact Factor
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The Journal of Antibiotics 11/2009; 63(1):41-4. · 1.65 Impact Factor
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ABSTRACT: Boronic acid derivatives of tyropeptin were synthesized with TP-110 as the lead compound. Due to the lability of the aminoboronic acid moiety, careful design of the deprotection and coupling sequence was required. Liquid-liquid partition chromatography was found to be a powerful tool for purification of compounds of this class. The obtained derivatives showed potent inhibitory activities against the human 20S proteasome in vitro.
Bioorganic & medicinal chemistry letters 05/2009; 19(8):2343-5. · 2.65 Impact Factor
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ABSTRACT: Branched chain amino acids are often utilized as the precursors of many lipid-containing bacterial secondary metabolites. The effect of isoleucine on the composition of the mixture of cyclic lipopeptide antibiotics, tripropeptins from Lysobacter sp. BMK333-48F3 was evaluated. As expected, a novel tripropeptin analog with an anteiso-branched fatty acid was produced. The new compound, TPPaiC shows potent antibacterial activity against Gram-positive bacteria including MRSA and VRE. On the other hand, no increase was observed in the production of other tripropeptins by the addition of isoleucine.
The Journal of Antibiotics 10/2008; 61(9):577-82. · 1.65 Impact Factor
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ABSTRACT: Benanomicins were found as antifungal antibiotics from the culture of an actinomycete with potent antifungal activities in vitro and in vivo. We aimed to generate derivatives superior to benanomicin A by biotransformation using Escherichia coli constructed with bacterial P450 expression system. We found transformation of benanomicin A into two derivatives, 10-hydroxybenanomicin A and 11-O-demethylbenanomicin A by one of the P450-expressed strains which harbored a plasmid carrying a CYP105C1-homologous gene. Unexpectedly, the biotransformed compounds showed weak antifungal activities in vitro compared with those of benanomicin A.
The Journal of Antibiotics 07/2008; 61(6):394-9. · 1.65 Impact Factor
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ABSTRACT: A novel cyclic peptide antibiotic, pargamicin A was isolated from the culture broth of an actinomycete strain. The producing organism, designated ML1-hF4, was identified as a member of the genus Amycolatopsis. Pargamicin A was identified as a novel cyclic hexapeptide antibiotic containing piperazic acid by various spectroscopic analyses. Pargamicin A showed potent antibacterial activity against Staphylococcus aureus strains including MRSA and Enterococcus faecalis/faecium strains including VRE.
The Journal of Antibiotics 07/2008; 61(6):387-93. · 1.65 Impact Factor
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Yushi Futamura,
Ryuichi Sawa,
Yoji Umezawa,
Masayuki Igarashi,
Hikaru Nakamura,
Kimiko Hasegawa,
Mikio Yamasaki,
Etsu Tashiro,
Yoshikazu Takahashi, Yuzuru Akamatsu,
Masaya Imoto
Journal of the American Chemical Society 03/2008; 130(6):1822-3. · 9.91 Impact Factor
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ABSTRACT: Migrastatin and its analogs have various biological activities such as inhibition of cell migration and anchorage-independent growth of cancer cells. Although its biosynthesis and chemical synthesis have been under investigation, little is known about the biological target of migrastatin. Here, we found that migrastatin inhibited intracellular calcium mobilization induced by carbachol in neuroblastoma SK-N-SH cells without affecting Ca2+ mobilization and cAMP accumulation induced by ligands of other receptors. The binding of [3H] N-methylscopolamine, an antagonist for muscarinic receptor was also inhibited by migrastain. Functionally, migrastatin inhibited Ca2+ mobilization induced by carbachol in primary cultures of smooth muscle cells of rat bladder. This study reveals that migrastatin acts as a muscarinic acetylcholine receptor antagonist.
The Journal of Antibiotics 12/2006; 59(11):685-92. · 1.65 Impact Factor
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ABSTRACT: A new teleocidin analog was isolated from the fermentation medium of Streptomyces sp. MM216-87F4 and its structure was elucidated as 14-O-(N-acetylglucosaminyl) teleocidin A (GlcNAc-TA). GlcNAc-TA induces the translocation of protein kinases Calpha and theta fused with enhanced green fluorescent protein (PKCalpha-EGFP and PKCtheta-EGFP) to the plasma membrane in stable transfectants, and reduces intracellular calcium mobilization induced by agonists of G-protein coupled receptors in various cell lines without causing irritation of the mouse ear. Further, GlcNAc-TA sensitizes the release of excitatory neuropeptides substance P induced by capsaicin from primary-cultured dorsal root ganglion (DRG) neurons of the rat and GlcNAc-TA alone also triggers substance P release in a dose-dependent manner. This study provides the first observation that a teleocidin analog without a free hydroxyl group at C-14 acts as a PKC activator and directly induces the release of excitatory neuropeptide.
The Journal of Antibiotics 02/2006; 59(1):11-7. · 1.65 Impact Factor
