chloropeptin-i and complestatin

Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of Staphylococcus aureus enoyl-ACP reductase (FabI), complestatin was isolated as a potent inhibitor of S. aureus FabI together with neuroprotectin A and chloropeptin I from Streptomyces chartreusis AN1542. Complestatin and related compounds inhibited S. aureus FabI with IC₅₀ of 0.3-0.6 µM. They also prevented the growth of S. aureus as well as methicillin-resistance S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA), with minimum inhibitory concentrations (MICs) of 2-4 µg/mL. Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in S. aureus, whereas it did not affect the macromolecular biosynthesis of other cellular components, such as DNA, RNA, proteins, and the cell wall. Additionally, supplementation with exogenous fatty acids reversed the antibacterial effect of complestatin, demonstrating that it targets fatty acid synthesis. In this study, we reported that complestatin and related compounds showed potent antibacterial activity via inhibiting fatty acid synthesis.

Topics: Anti-Bacterial Agents; Chlorophenols; Drug Resistance; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Enzyme Inhibitors; Fatty Acids; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oligopeptides; Peptides, Cyclic; Staphylococcal Infections; Staphylococcus aureus; Streptomyces

The first total synthesis of chloropeptin II (1, complestatin) is disclosed. Key elements of the approach include the use of an intramolecular Larock indole synthesis for the initial macrocyclization, adopting conditions that permit utilization of a 2-bromoaniline, incorporating a terminal alkyne substituent (-SiEt(3)) that sterically dictates the indole cyclization regioselectivity, and benefiting from an aniline protecting group (-Ac) that enhances the atropdiastereoselectivity and diminishes the strained indole reactivity toward subsequent electrophilic reagents. Not only did this key reaction provide the fully functionalized right-hand ring system of 1 in superb conversion (89%) and good atropdiastereoselectivity (4:1 R:S), but it also represents the first reported example of what will prove to be a useful Larock macrocyclization strategy. Subsequent introduction of the left-hand ring system enlisting an aromatic nucleophilic substitution reaction for macrocyclization with biaryl ether formation completed the assemblage of the core bicyclic structure of 1. Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2.

Topics: Chlorophenols; Cyclization; Indoles; Macrocyclic Compounds; Peptides, Cyclic

Topics: Anti-HIV Agents; Chlorophenols; HIV-1; Humans; Peptides, Cyclic; Stereoisomerism; Streptomyces

Palladium-catalyzed intramolecular Suzuki-Miyaura reaction of linear tripeptide (23) afforded the 16-membered DEFG ring of complestatin (3) in good yield with an excellent atropdiastereoselectivity. Acidic treatment of 3 triggers a stereospecific rearrangement leading to the corresponding DEFG ring 4 of chloropeptin I.

Topics: Catalysis; Chlorophenols; Cyclization; Molecular Conformation; Palladium; Peptides; Peptides, Cyclic; Stereoisomerism

Three condensed aromatic peptides SCH79235 (1), SCH79236 (2), and SCH204698 (3) were isolated from the fermentation broth of a Streptomycete microorganism. The structure of SCH204698 (3) was established by extensive NMR spectral data. All these compounds exhibited good activity against CD28-CD80 binding with an IC(50) of 0.42, 0.38 and 0.22 microM, respectively.

Topics: B7-1 Antigen; Binding, Competitive; CD28 Antigens; Chlorophenols; Fermentation; Magnetic Resonance Spectroscopy; Peptides; Peptides, Cyclic; Spectrometry, Mass, Fast Atom Bombardment; Spectrophotometry, Ultraviolet; Streptomyces

[formula: see text] Two syntheses of a model system of the DEF ring system of complestatin and chloropeptin are described. The key step in both of these syntheses involves the formation of the biaryl linkage using a palladium-catalyzed Suzuki cross-coupling reaction and a catalytic enantioselective ene reaction to form the 6-bromo-D-tryptophan. Additionally, ring contraction of the 17-membered DEF ring system of complestatin generates the 16-membered DEF ring system of chloropeptin in a biomimetic fashion.

Topics: Chlorophenols; Molecular Structure; Oligopeptides; Peptides, Cyclic

Chloropeptins I and II, which are gp120-CD4 binding inhibitors, were isolated as pale yellow-brown powders from the mycelia of a soil actinomycete, Streptomyces sp, WK-3419. Their physico-chemical properties showed that they are chlorinated peptides. Chloropeptin I (C61H45N7O15Cl6) is a novel compound, but chloropeptin II was identified as complestatin. Both compounds inhibited gp120-CD4 binding (IC50: 1.3 and 2.0 microM, respectively), the cytopathic effect of HIV in MT-4 cells (EC50: 1.6 and 1.7 microM, respectively) and syncytium formation in co-cultured HIV-1-infected and uninfected MOLT-4 cells (IC50. 0.5 and 1.1 microM, respectively). Chloropeptin I was synergistic in the inhibition of the cytopathic effect when combined with other anti-HIV drugs such as zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) and nevirapine.

Topics: Anti-Bacterial Agents; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Chlorophenols; Fermentation; HeLa Cells; HIV Envelope Protein gp120; Humans; Oligopeptides; Peptides, Cyclic; Streptomyces; Zidovudine

The structure of chloropeptin I, a gp120-CD4 binding inhibitor having a potent anti-HIV activity, was elucidated by 1H and 13C NMR experiments and chemical degradation. It is a peptide antibiotic consisting of six aryl amino acids residues and an alpha-oxo aryl acid some of which have chlorine atoms.

Topics: Anti-Bacterial Agents; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Chlorophenols; HIV Envelope Protein gp120; Oligopeptides; Peptides, Cyclic

Plasminogen is a zymogen of the fibrinolytic serine protease, plasmin. Plasminogen binds, through its lysine binding sites in the kringle domain, to blood and vascular cells or fibrin, where it is efficiently activated and exerts fibrinolytic activity (1,2). We have recently found that complestatin, a peptide-like metabolite of streptomyces (3,4), enhances plasminogen binding to U937 cells and fibrin, thus potentiating fibrinolysis (5). In the present study, complestatin was found to be converted by an acid treatment to a more active isomer in enhancing plasminogen binding to U937 cells. This isomer was identified to be chloropeptin I, which was recently isolated from a culture of Streptomyces sp. by Matsuzaki et al. as an inhibitor of gp 120-CD4 binding (6). The present paper deals with the stimulation of fibrinolysis by chloropeptin I.

Topics: Anti-Bacterial Agents; Binding Sites; Chlorophenols; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Kinetics; Lysine; Oligopeptides; Peptides, Cyclic; Plasma; Plasminogen; Protein Binding; Tissue Plasminogen Activator; Tumor Cells, Cultured

Topics: Antiviral Agents; CD4 Antigens; Chlorophenols; HIV; HIV Envelope Protein gp120; Humans; Oligopeptides; Peptides, Cyclic; Streptomycin