Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 28
Filter
Add more filters










Publication year range
2.
J Antibiot (Tokyo) ; 68(12): 741-7, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25990952

ABSTRACT

Arbekacin, an aminoglycoside antibiotic, is an important drug because it shows a potent efficacy against methicillin-resistant Staphylococcus aureus. However, resistance to arbekacin, which is caused mainly by the bifunctional aminoglycoside-modifying enzyme, has been observed, becoming a serious problem in medical practice. To create new arbekacin derivatives active against resistant bacteria, we modified the C-4″ and 6″ positions of its 3-aminosugar portion. Regioselective amination of the 6″-position gave 6″-amino-6″-deoxyarbekacin (1), and it was converted to a variety of 6″-N-alkanoyl derivatives (6a-z). Furthermore, regioselective modifications of the 4″-hydroxyl group were performed to give 4″-deoxy-4″-epiaminoarbekacin (2) and its 4″-N-alkanoyl derivatives (12 and 13). Their antibacterial activity against S. aureus, including arbekacin-resistant bacteria, was evaluated. It was observed that 6″-amino-6″-N-[(S)-4-amino-2-hydroxybutyryl]-6″-deoxyarbekacin (6o) showed excellent antibacterial activity, even better than arbekacin.


Subject(s)
Anti-Bacterial Agents/pharmacology , Dibekacin/analogs & derivatives , Methicillin-Resistant Staphylococcus aureus/drug effects , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dibekacin/chemical synthesis , Dibekacin/chemistry , Dibekacin/pharmacology , Drug Resistance, Bacterial
4.
J Antibiot (Tokyo) ; 66(3): 171-8, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23532021

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.


Subject(s)
Anti-Bacterial Agents/pharmacology , Azepines/pharmacology , Lipids/pharmacology , Nucleosides/pharmacology , Uridine/analogs & derivatives , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Azepines/chemical synthesis , Azepines/chemistry , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Lipids/chemical synthesis , Lipids/chemistry , Mycobacterium avium/drug effects , Mycobacterium tuberculosis/drug effects , Nucleosides/chemical synthesis , Nucleosides/chemistry , Structure-Activity Relationship , Uridine/chemical synthesis , Uridine/chemistry , Uridine/pharmacology
5.
J Nat Prod ; 76(4): 510-5, 2013 Apr 26.
Article in English | MEDLINE | ID: mdl-23425216

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.


Subject(s)
Benzoquinones/pharmacology , Prostaglandins/metabolism , Thiazoles/pharmacology , Benzoquinones/chemistry , Humans , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , NAD(P)H Dehydrogenase (Quinone)/physiology , Oxidation-Reduction , Prostaglandins/genetics , Reactive Oxygen Species , Sarcoma, Synovial/metabolism , Thiazoles/chemistry
6.
J Nat Prod ; 76(4): 715-9, 2013 Apr 26.
Article in English | MEDLINE | ID: mdl-23414235

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.


Subject(s)
Benzoquinones/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Streptomyces/chemistry , Animals , Benzoquinones/chemistry , Humans , Immunoblotting , Japan , Mice , Molecular Structure , NIH 3T3 Cells , Nuclear Magnetic Resonance, Biomolecular , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Vascular Endothelial Growth Factor/metabolism
7.
Proc Jpn Acad Ser B Phys Biol Sci ; 88(10): 536-53, 2012.
Article in English | MEDLINE | ID: mdl-23229749

ABSTRACT

By using "our devised up-to-the-second technique" over 30 years ago, we succeeded in the first isolation in the world of the three different kinds of mammalian cell mutants defective in the biosynthesis on each of phosphatidylserine (PS), cardiolipin (CL) and sphingomyelin (SM) from the parental CHO cells. As the results, we found that during the biosyntheses of PS and SM, the biosynthetic precursor or the final lipids are transported from their synthesized intracellular organelles to the plasma membranes via the other intracellular organelles. We further clarified the presence of the reversed routes for PS and SM from the plasma membranes to their synthesized organelles too. Our first epoch-making finding is not only the cycling inter-conversion reactions between PS and PE catalyzed by PSS-II and PSD but also their simultaneous transferring between MAM and Mit (found by O. Kuge). Our second finding is "the ceramide-trafficking protein (CERT)" working as the specific transfer protein of ceramide from the ER to the Golgi apparatus, during the SM biosynthesis (by K. Hanada). As for their new biological roles, we clarified possible contribution of PS and/or PE to the fusion process between viral envelope and endosomal membrane, releasing the genetic information of the virus to the host cytoplasm. CL is contributing to the functional NADH-ubiquinone reductase activity by keeping the right structure of Coenzyme Q9 for its functioning. SM and cholesterol form the microdomain within the plasma membrane, so-called "the raft structure" where the GPI-anchored proteins are specifically located for their functioning.


Subject(s)
Phospholipids , Animals , Cardiolipins/biosynthesis , Cardiolipins/metabolism , Cell Line , History, 20th Century , History, 21st Century , Humans , Phosphatidylserines/biosynthesis , Phosphatidylserines/metabolism , Phospholipids/biosynthesis , Phospholipids/history , Phospholipids/metabolism , Sphingolipids/biosynthesis , Sphingolipids/metabolism
8.
Chemistry ; 18(49): 15772-81, 2012 Dec 03.
Article in English | MEDLINE | ID: mdl-23129443

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.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , DNA Topoisomerase IV/chemistry , Glucosides/chemistry , Glucosides/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Topoisomerase II Inhibitors , Bacteria/drug effects , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests
9.
Antimicrob Agents Chemother ; 56(7): 3657-63, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22526318

ABSTRACT

The WalK (histidine kinase)/WalR (response regulator) two-component signal transduction system is a master regulatory system for cell wall metabolism and growth. This system is conserved in low G+C Gram-positive bacteria, including Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, and Streptococcus mutans. In this study, we found the first antibiotic that functions as a WalK inhibitor (signermycin B) by screening 10,000 Streptomyces extracts. The chemical structure (C(23)H(35)NO(4); molecular weight, 389.5) comprises a tetramic acid moiety and a decalin ring. Signermycin B exhibited antimicrobial activity, with MIC values ranging from 3.13 µg/ml (8 µM) to 6.25 µg/ml (16 µM) against Gram-positive bacteria that possess the WalK/WalR two-component signal transduction system, including the drug-resistant bacteria methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. The half-maximal inhibitory concentrations of signermycin B against WalK in these organisms ranged from 37 to 61 µM. To determine the mechanism of action of signermycin B, surface plasmon resonance response analysis with the two WalK domains of Bacillus subtilis and competition assay with ATP were performed. The results showed that signermycin B binds to the dimerization domain but not the ATP-binding domain of WalK. In the presence of the cross-linker glutaraldehyde, signermycin B did not cause protein aggregation but interfered with the cross-linking of WalK dimers. These results suggest that signermycin B targets the conserved dimerization domain of WalK to inhibit autophosphorylation. In Bacillus subtilis and Staphylococcus aureus, signermycin B preferentially controlled the WalR regulon, thereby inhibiting cell division. These phenotypes are consistent with those of cells starved for the WalK/WalR system.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Protein Kinases/metabolism , Bacillus subtilis/drug effects , Bacillus subtilis/genetics , Bacillus subtilis/metabolism , Bacterial Proteins/genetics , Histidine Kinase , Microbial Sensitivity Tests , Protein Kinases/genetics , Protein Multimerization/drug effects , Regulon/drug effects , Regulon/genetics , Staphylococcus aureus/drug effects , Staphylococcus aureus/genetics , Staphylococcus aureus/metabolism , Streptomyces/metabolism
10.
Int J Antimicrob Agents ; 39(6): 478-85, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22534508

ABSTRACT

By screening cultures of soil bacteria, we re-discovered an old antibiotic (nybomycin) as an antibiotic with a novel feature. Nybomycin is active against quinolone-resistant Staphylococcus aureus strains with mutated gyrA genes but not against those with intact gyrA genes against which quinolone antibiotics are effective. Nybomycin-resistant mutant strains were generated from a quinolone-resistant, nybomycin-susceptible, vancomycin-intermediate S. aureus (VISA) strain Mu 50. The mutants, occurring at an extremely low rate (<1 × 10(-11)/generation), were found to have their gyrA genes back-mutated and to have lost quinolone resistance. Here we describe nybomycin as the first member of a novel class of antibiotics designated 'reverse antibiotics'.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Quinolones/pharmacology , Staphylococcus aureus/drug effects , Vancomycin Resistance/drug effects , DNA Gyrase/genetics , Humans , Methicillin/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/genetics , Microbial Sensitivity Tests , Mutation , Staphylococcus aureus/genetics , Vancomycin/pharmacology
11.
Bioorg Med Chem Lett ; 22(1): 231-4, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-22137785

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.


Subject(s)
Chemistry, Pharmaceutical/methods , Intramolecular Transferases/antagonists & inhibitors , Catalysis , Catalytic Domain , Computer Simulation , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Isotopes/chemistry , Models, Chemical , Molecular Conformation , Risk Factors , Software
12.
J Antibiot (Tokyo) ; 63(12): 703-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20940725

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.


Subject(s)
Carboxylic Acids/isolation & purification , Macrolides/isolation & purification , Mesenchymal Stem Cells/drug effects , Naphthalenes/isolation & purification , Osteoblasts/drug effects , Penicillium/chemistry , Pluripotent Stem Cells/drug effects , Alkaline Phosphatase/genetics , Alkaline Phosphatase/metabolism , Animals , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Differentiation/drug effects , Cell Line , DNA/chemistry , DNA/genetics , Macrolides/chemistry , Macrolides/pharmacology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Mice , Molecular Structure , Naphthalenes/chemistry , Naphthalenes/pharmacology , Nuclear Magnetic Resonance, Biomolecular , Osteoblasts/cytology , Osteoblasts/metabolism , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/metabolism , Polymerase Chain Reaction , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet
13.
Bioorg Med Chem Lett ; 20(19): 5839-42, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20727746

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.


Subject(s)
Boron Compounds/chemistry , Boronic Acids/chemistry , Dipeptides/chemistry , Enzyme Inhibitors/chemistry , Oligopeptides/chemistry , Proteasome Inhibitors , Boron Compounds/chemical synthesis , Boron Compounds/toxicity , Boronic Acids/chemical synthesis , Boronic Acids/toxicity , Cell Line, Tumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , Humans , Oligopeptides/chemical synthesis , Oligopeptides/toxicity , Proteasome Endopeptidase Complex/metabolism , Structure-Activity Relationship
14.
Bioorg Med Chem Lett ; 20(19): 5843-6, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20728353

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.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Mannheimia haemolytica/drug effects , Oleic Acids/chemical synthesis , Pasteurella multocida/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity Tests , Oleic Acids/chemistry , Oleic Acids/pharmacology , Stereoisomerism , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 20(19): 5807-10, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20728352

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.


Subject(s)
Enzyme Inhibitors/chemistry , Intramolecular Transferases/antagonists & inhibitors , Pyrroles/chemistry , Squalene/analogs & derivatives , Triazoles/chemistry , Binding Sites , Computer Simulation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Intramolecular Transferases/metabolism , Protein Structure, Tertiary , Squalene/chemical synthesis , Squalene/chemistry , Squalene/pharmacology , Structure-Activity Relationship
16.
J Antibiot (Tokyo) ; 63(8): 519-23, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20664607

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).


Subject(s)
Anti-Bacterial Agents/pharmacology , Fatty Acids/pharmacology , Mannheimia haemolytica/drug effects , Oleic Acids/pharmacology , Paenibacillus/chemistry , Pasteurella/drug effects , Anti-Bacterial Agents/isolation & purification , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , DNA, Ribosomal/chemistry , DNA, Ribosomal/genetics , Fatty Acids/chemistry , Fatty Acids/isolation & purification , Fatty Acids/metabolism , Fermentation , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Oleic Acids/chemistry , Oleic Acids/isolation & purification , Oleic Acids/metabolism , Paenibacillus/classification , Paenibacillus/genetics , Paenibacillus/metabolism , Phylogeny , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Soil Microbiology
17.
J Antibiot (Tokyo) ; 63(6): 279-83, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20339400

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.


Subject(s)
Actinomycetales/metabolism , Anti-Bacterial Agents/pharmacology , Cell Membrane/drug effects , Enterococcus faecalis/drug effects , Membrane Potentials/drug effects , Peptides, Cyclic/pharmacology , Staphylococcus aureus/drug effects , Dibekacin/analogs & derivatives , Dibekacin/pharmacology , Fluorescent Dyes , Microbial Sensitivity Tests , Novobiocin/pharmacology , Vancomycin/pharmacology
20.
Bioorg Med Chem Lett ; 19(8): 2343-5, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19307118

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.


Subject(s)
Boronic Acids/chemical synthesis , Dipeptides/chemical synthesis , Protease Inhibitors/chemical synthesis , Proteasome Inhibitors , Boronic Acids/pharmacology , Cell Line, Tumor , Dipeptides/pharmacology , Humans , Oligopeptides/chemistry , Oligopeptides/pharmacology , Protease Inhibitors/pharmacology , Proteasome Endopeptidase Complex/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...