| 18368162 |
Total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, from a microorganism |
10.1039/b718310k. |
Chem Commun (Camb) |
Total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, from a microorganism
Abstract
- The first total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, was achieved in a convergent manner; the synthesis established stereochemistry at the C5'' position.
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| 18375793 |
Identification of the nonribosomal peptide synthetase gene responsible for bassianolide synthesis in wood-decaying fungus Xylaria sp. BCC1067 |
10.1099/mic.0.2007/013995-0. |
Microbiology (Reading) |
Identification of the nonribosomal peptide synthetase gene responsible for bassianolide synthesis in wood-decaying fungus Xylaria sp. BCC1067
Abstract
- Intensive study of gene diversity of bioactive compounds in a wood-rot fungus, Xylaria sp. BCC1067, has made it possible to identify polyketides and nonribosomal peptides (NRPs) unaccounted for by conventional chemical screening methods. Here we report the complete nonribosomal peptide synthetase (NRPS) gene responsible for the biosynthesis of an NRP, bassianolide, using a genetic approach. Isolation of the bassianolide biosynthetic gene, nrpsxy, was achieved using degenerate primers specific to the adenylation domain of NRPS. The complete ORF of nrpsxy is 10.6 kb in length. Based on comparisons with other known NRPSs, the domain arrangement of NRPSXY is most likely to be C-A-T-C-A-M-T-T-C-R. The other ORF found upstream of nrpsxy, designated efxy, is 1.8 kb in length and shows high similarity to members of the major facilitator superfamily of transporters. Functional analysis of the nrpsxy gene was conducted by gene disruption, and the missing metabolite in the mutant was identified. Chemical analysis revealed the structure of the metabolite to be a cyclooctadepsipeptide, bassianolide, which has been found in other fungi. A bioassay of bassianolide revealed a wide range of biological activities other than insecticidal uses, which have been previously reported, thus making bassianolide an interesting candidate for future structural modification. This study is the first evidence for a gene involved in the biosynthesis of bassianolide.
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| 18387372 |
Conformational analysis of the broad-spectrum antibacterial peptide, ranatuerin-2CSa: identification of a full length helix-turn-helix motif |
10.1016/j.bbapap.2008.02.019. |
Biochim Biophys Acta |
Conformational analysis of the broad-spectrum antibacterial peptide, ranatuerin-2CSa: identification of a full length helix-turn-helix motif
Abstract
- Design of clinically valuable antibacterial agents based upon naturally occurring peptides requires the use of spectroscopic methods, particularly NMR, to determine the three-dimensional structure of the native peptide so that analogues with improved therapeutic properties can be made. Ranatuerin-2CSa (GILSSFKGVAKGVAKDLAG KLLETLKCKITGC), first isolated from skin secretions of the Cascades frog, Rana cascadae, represents a promising candidate for drug development. The peptide shows potent growth inhibitory activity against Escherichia coli (MIC=5 microM) and Staphylococcus aureus (MIC=10 microM) but displays haemolytic activity against human erythrocytes (LC(50)=160 microM). The solution structure of ranatuerin-2CSa was investigated by proton NMR spectroscopy and molecular modelling. In aqueous solution, the peptide lacks secondary structure but, in a 2,2,2-trifluoroethanol (TFE-d(3))-H(2)O solvent mixture, the structure is characterised by a full length helix-turn-helix conformation between residues I(2)-L(21), L(22)-L(25) and K(26)-T(30) respectively. This structural information will facilitate the design of novel therapeutic agents based upon the ranatuerin-2CSa structure with improved antimicrobial potencies but decreased cytolytic activities against mammalian cells.
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| 18397260 |
Purification and structural characterization of bacillomycin F produced by a bacterial honey isolate active against Byssochlamys fulva H25 |
10.1111/j.1365-2672.2008.03797.x. |
J Appl Microbiol |
Purification and structural characterization of bacillomycin F produced by a bacterial honey isolate active against Byssochlamys fulva H25
Abstract
- Isolate and characterize antifungal peptides exhibiting activity against Byssochlamys fulva H25, a spoilage mould associated with juices and beverages.
A bacterium (H215) isolated from honey showed high antifungal activity against B. fulva H25. The antifungal producer strain was identified as Bacillus subtilis using 16S rDNA sequencing. The antifungal peptide was purified by 20% ammonium sulfate precipitation of the bacterial culture supernatant, followed by Octyl-Sepharose CL-4B and reverse phase-high performance liquid chromatography. The five active fractions were lyophilized and subjected to mass, tandem mass spectrometry and amino acid analysis to deduce their corresponding molecular masses and structural characteristics. The five peaks were determined to be identical to bacillomycin F, varying in the length of the fatty acid chain moiety from C14 to C16.
The broad-spectrum antifungal activity produced by a bacterium from honey was determined to be due to the production of bacillomycin F.
The antifungal compound produced by a bacterial strain isolated from honey was determined to be stable over a broad pH range and was stable to heat treatments up to 100 degrees C. This is the first report of honey microflora producing bacillomycin F or any antifungal compound.
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| 18407693 |
Kahalalides V-Y isolated from a Hawaiian collection of the sacoglossan mollusk Elysia rufescens |
10.1021/np070508g. |
J Nat Prod |
Kahalalides V-Y isolated from a Hawaiian collection of the sacoglossan mollusk Elysia rufescens
Abstract
- Four new kahalalides, V (1), W (2), X (3), and Y (4), as well as six previously characterized kahalalides have been isolated from a two-year collection of the sacoglossan mollusk Elysia rufescens. Curiously, kahalalide B, previously isolated in high yield from E. rufescens, was found to be essentially absent from these collections despite identical collection sites and times with previous collections. In addition, kahalalide K, which to date has only been reported from Bryopsis sp., was found in this collection of E. rufescens, suggesting that the production of these metabolites could potentially be from a microbial association with the mollusk and algae, and this relationship is continuously evolving in response to changes in the environment and predation. The structures of new peptides have been established on the basis of extensive 1D and 2D NMR spectroscopic data analysis. Kahalalide V (1) was ascertained to be an acyclic derivative of kahalalide D (5), while kahalalide W (2) was determined to have a 4-hydroxy-L-proline residue instead of the proline in 5. The arginine residue of kahalalide X (3), an acyclic derivative of kahalalide C, was determined to have an L configuration. Kahalalide Y (4) was found to have an L-proline residue instead of the hydroxyproline in kahalalide K. It is clear from this collection of E. rufescens that the discovery of new kahalalide-related metabolites is still highly feasible.
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| 18412398 |
Scopularides A and B, cyclodepsipeptides from a marine sponge-derived fungus, Scopulariopsis brevicaulis |
10.1021/np070580e. |
J Nat Prod |
Scopularides A and B, cyclodepsipeptides from a marine sponge-derived fungus, Scopulariopsis brevicaulis
Abstract
- Two novel cyclodepsipeptides, scopularides A and B, were found in the fungus Scopulariopsis brevicaulis, which was isolated from the marine sponge Tethya aurantium. In addition, the known fungal metabolite paxilline was identified. The structures of the scopularides were elucidated by NMR, MS, and chemical derivatization methods as cyclo-(3-hydroxy-4-methyldecanoyl-Gly-L-Val-D-Leu-L-Ala-L-Phe) and cyclo-(3-hydroxy-4-methyloctanoyl-Gly-L-Val-D-Leu-L-Ala-L-Phe) for scopularide A and B, respectively. Antibiotic activity against Gram-negative bacteria was absent and against Gram-positive bacteria was weak, but activity against several tumor cell lines was significant at 10 microg/mL.
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| 18416310 |
Histone deacetylase inhibitors from microorganisms: the Astellas experience |
10.1007/978-3-7643-8595-8_7. |
Prog Drug Res |
Histone deacetylase inhibitors from microorganisms: the Astellas experience
Abstract
- Histone deacetylase (HDAC) inhibitors, such as trichostatin A and trapoxin, which were first found in microorganisms, potently and selectively inhibit HDAC enzymes. They have made a strong contribution to research on HDACs, chromatin control, abnormal epigenetic control in various diseases and the significance of acetylation in posttranslational modification. Recently, HDAC inhibitors have been focused on as potential drugs for the treatment of several diseases, including cancer, although trichostatin A and trapoxin show no effects in animal models because of their metabolic instability in vivo. Chemical modification has been conducted in order to overcome this drawback. We discovered the microbial metabolites FK228 (also known as FR901228, romidepsin, depsipeptide, NSC-630176 and NSC-630176D) and YM753 (spiruchostatin A). Both compounds have bicyclic structures and represent a novel structural class of HDAC inhibitor. The enzyme and tumor cell growth inhibitory activities of FK228 were found to be very potent. It also showed potent HDAC inhibitory activity in vivo. FK228 is the first potent HDAC inhibitor to undergo clinical development as a potential treatment for solid and hematological cancers. Due to its dramatic effect in patients with refractory cutaneous T-cell lymphoma (CTCL), in October 2004 the US Food & Drug Administration (FDA) granted fast-track status to FK228 as monotherapy for the treatment of CTCL in patients who have relapsed following, or become refractory to, another systemic therapy. Thus HDAC inhibitors such as FK228 and YM753 have potential as tools for life science studies and also as therapeutic agents for various intractable diseases.
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| 18423796 |
Novel brevinins from Chinese piebald odorous frog (Huia schmackeri) skin deduced from cloned biosynthetic precursors |
10.1016/j.peptides.2008.03.009. |
Peptides |
Novel brevinins from Chinese piebald odorous frog (Huia schmackeri) skin deduced from cloned biosynthetic precursors
Abstract
- Antimicrobial peptides represent the most characterized and diverse class of peptides within the defensive skin secretions of anuran amphibians. With an ever expanding database of primary structures, the current accepted rules for nomenclature have become increasingly difficult to apply to peptides whose primary structural attributes are either unique or that fall between those that define existing groups. An additional factor that adds to the confusion is the regular re-classification or revision of existing taxa. In the present study, we have identified five new antimicrobial peptide homologs in the defensive skin secretion of the Chinese piebald odorous frog, Huia schmackeri (formerly Rana (Odorrana) schmackeri), by cloning of their respective biosynthetic precursors. As these peptides are obvious homologs of the brevinin-1 and brevinin-2 families we have named these in accordance: (1) brevinin-1HS1, (2) brevinin-2HS1, (3) brevinin-2HS2, (4) brevinin-2HS3 and (5) brevinin-1HS2. The reasons for adopting these names are discussed. It is clear that with an ever-increasing number of amphibian skin antimicrobial peptides appearing in the literature that a consistent nomenclature scheme needs to be established.
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| 18424132 |
Novel echinocandin antifungals. Part 2: Optimization of the side chain of the natural product FR901379. Discovery of micafungin |
10.1016/j.bmcl.2008.03.093. |
Bioorg Med Chem Lett |
Novel echinocandin antifungals. Part 2: Optimization of the side chain of the natural product FR901379. Discovery of micafungin
Abstract
- Further optimization of the potent antifungal activity of side chain analogs of the natural product FR901379 led to the discovery of compound 8 with an excellent, well-balanced profile. Potent compounds with reduced hemolytic potential were designed based upon a disruption of the linearity of the terphenyl lipophilic side chain. The optimized compound (8, FK463, micafungin) displayed the best balance and was selected as the clinical candidate.
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| 18438403 |
Protein lysine methyltransferase G9a acts on non-histone targets |
10.1038/nchembio.88. |
Nat Chem Biol |
Protein lysine methyltransferase G9a acts on non-histone targets
Abstract
- By methylation of peptide arrays, we determined the specificity profile of the protein methyltransferase G9a. We show that it mostly recognizes an Arg-Lys sequence and that its activity is inhibited by methylation of the arginine residue. Using the specificity profile, we identified new non-histone protein targets of G9a, including CDYL1, WIZ, ACINUS and G9a (automethylation), as well as peptides derived from CSB. We demonstrate potential downstream signaling pathways for methylation of non-histone proteins.
|
| 18444611 |
Coibamide A, a potent antiproliferative cyclic depsipeptide from the Panamanian marine cyanobacterium Leptolyngbya sp |
10.1021/ja801383f. |
J Am Chem Soc |
Coibamide A, a potent antiproliferative cyclic depsipeptide from the Panamanian marine cyanobacterium Leptolyngbya sp
Abstract
- Coibamide A (1) is a new, potent antiproliferative depsipeptide which was isolated from a marine Leptolyngbya cyanobacterium collected from the Coiba National Park, Panama. The planar structure of 1 was elucidated by a combination of NMR spectroscopy and mass spectrometry. Exhaustive 1D and 2D NMR spectroscopy included natural abundance 15N and variable temperature experiments; mass spectrometry included TOF-ESI-MSn and FT-MSn experiments. Chemical degradation followed by chiral HPLC- and GC-MS analyses was used to assign the absolute configuration of 1. This highly methylated cyclized depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism.
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| 18444683 |
Apratoxin D, a potent cytotoxic cyclodepsipeptide from papua new guinea collections of the marine cyanobacteria Lyngbya majuscula and Lyngbya sordida |
10.1021/np800121a. |
J Nat Prod |
Apratoxin D, a potent cytotoxic cyclodepsipeptide from papua new guinea collections of the marine cyanobacteria Lyngbya majuscula and Lyngbya sordida
Abstract
- Cancer cell toxicity-guided fractionation of extracts of the Papua New Guinea marine cyanobacteria Lyngbya majuscula and Lyngbya sordida led to the isolation of apratoxin D (1). Compound 1 contains the same macrocycle as apratoxins A and C but possesses the novel 3,7-dihydroxy-2,5,8,10,10-pentamethylundecanoic acid as the polyketide moiety. The planar structures and stereostructures of compound 1 were determined by extensive 1D and 2D NMR and MS data analyses and by comparison with the spectroscopic data of apratoxins A and C. Apratoxin D (1) showed potent in vitro cytotoxicity against H-460 human lung cancer cells with an IC 50 value of 2.6 nM.
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| 18451569 |
New cytotoxic bicyclic hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L |
10.1248/cpb.56.730. |
Chem Pharm Bull (Tokyo) |
New cytotoxic bicyclic hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L
Abstract
- Two new bicyclic hexapeptides, RA-XXIII and RA-XXIV, were isolated from the roots of Rubia cordifolia L. (Rubiaceae). Their structures were determined by the analysis of their 2D NMR spectra, chemical methods, and X-ray crystallography. The IC50 values of RA-XXIII and RA-XXIV against P-388 leukemia cells were 0.16 and 0.48 microg/ml, respectively.
|
| 18491867 |
Linear and cyclic peptides from the entomopathogenic bacterium Xenorhabdus nematophilus |
10.1021/np800053n. |
J Nat Prod |
Linear and cyclic peptides from the entomopathogenic bacterium Xenorhabdus nematophilus
Abstract
- Three new peptides, xenortides A and B and xenematide, were isolated from a culture of the nematode-associated entomopathogenic bacterium Xenorhabdus nematophilus. Their structures were elucidated using NMR, MS, and chemical derivatization methods. Xenortides A and B are the N-phenethylamide and tryptamide derivatives, respectively, of the dipeptide (NMe-L-Leu-NMe-L-Phe). The cyclodepsipeptide xenematide has the sequence (Thr-Trp-Trp-Gly), with a 2-phenylacetamide substituent at the threonine residue and one d-tryptophan. The new peptides and the two known compounds xenocoumacin II and nematophin were tested for antibacterial, antifungal, insecticidal, and anti-Artemia salina activities. Xenematide and xenocoumacin II showed moderate antibacterial activities. Xenocoumacin II, nematophin, and the two xenortides were active in the Artemia salina assay, and xenematide acted weakly insecticidal.
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| 18501599 |
Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment |
10.1016/j.bmcl.2008.04.044. |
Bioorg Med Chem Lett |
Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment
Abstract
- Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. This receptor is over-expressed or activated in tumor cells and is emerging as a novel target in cancer therapy. Efforts in our "Hit to Lead" group have generated a novel series of submicromolar IGF-1R inhibitors based on a isoquinolinedione template originating from a Lance enzyme HTS screen. Chemical triage and parallel synthesis incorporating focused library arrays were instrumental in moving these investigations through the Wyeth exploratory medicinal chemistry process. The strategies, synthesis, and SAR behind this interesting kinase scaffold will be described.
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