Arylomycins A and B,new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tü 6075. II. Structure elucidation

The structures of new lipopeptide antibiotics, arylomycins A and B, were elucidated by a combination of ESI-FTICR-mass spectrometry, NMR spectroscopy, Edman sequencing, and fatty acid and chiral amino acid analyses. The colourless arylomycins A share the peptide sequence of D-N-methylseryl2(D-MeSer2)-D-alanyl3-glycyl4-N-methyl- 4-hydroxyphenylglycyl5(MeHpg5)-L-alanyl6-tyrosine7 cyclised by a [3,3]biaryl bond between MeHpg5 and Tyr7. The yellow arylomycins B differ from arylomycins A by nitro substitution of Tyr7. The N-termini of arylomycins A and B are acylated with saturated C11-C15 fatty acids (fa1) comprising n, iso, and anteiso isomers. Arylomycins A and B represent the first examples of biaryl-bridged lipopeptides.     

Streptocidins A-D, novel cyclic decapeptide antibiotics produced by Streptomyces sp. Tü 6071. I. Taxonomy, fermentation, isolation and biological activities

Four novel cyclic homodecapetide antibiotics, streptocidins A-D were detected in the mycelium extract of Streptomyces sp. Tü 6071 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The peptides which were closely related in structure to the tyrocidines and gramicidins of Bacillus brevis show antibiotic activities against Gram-positive bacteria.     

Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tü 6040. I. Taxonomy, fermentation, isolation and biological activities

Two novel angucyclinone-type antibiotics, simocyclinones D4 and D8, were detected in the mycelium extract of Streptomyces antibioticus Tü 6040 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The compounds show antibiotic activities against Gram-positive bacteria and cytostatic effects on various tumor cell lines.     

Retymicin, galtamycin B, saquayamycin Z and ribofuranosyllumichrome, novel secondary metabolites from Micromonospora sp. Tü 6368. I. Taxonomy, fermentation, isolation and biological activities

A new xanthone compound named retymicin (1) was isolated together with galtamycin B (2) and saquayamycin Z (3), new members of the galtamycin and saquayamycin families, respectively, and the new lumichrome derivative 1-(alpha-ribofuranosyl)-lumichrome (4) from Micromonospora strain Tü 6368, isolated from a soil sample collected in Romania. Retymicin, galtamycin B and saquayamycin Z show cytostatic effects to various human tumor cell lines whereas saquayamycin Z is also active against Gram-positive bacteria.     

Ripromycin and other polycyclic macrolactams from Streptomyces sp. Tü 6239: taxonomy,fermentation, isolation and biological properties

Strain Tü 6239 was isolated from a soil sample collected in Brazil and determined as a new species of the genus Streptomyces. In the course of our HPLC-diode array screening program three metabolites were detected in the culture filtrate and mycelium extracts of strain Tü 6239. They were characterised as members of the macrolactam group, the new compound ripromycin (1), the previously described ikarugamycin (2) and a new derivative of it, ikarugamycin epoxide (3). They show antibiotic activities against gram-positive bacteria and cytostatic effects to various human tumor cell lines.     

Streptocidins A-D, novel cyclic decapeptide antibiotics produced by Streptomyces sp. Tü 6071. II. Structure elucidation

The structures of the new antibiotics streptocidins A approximately D were elucidated as cyclic decapeptides cyclo[L-Val1-L-Orn2-L-Leu3-D-Phe4-L-Pro5-L-Leu6-X7-L-Asn8-L-Gln9-X10] with X7=D-Trp (A, B, C) or D-Phe (D) and X10=L-Tyr (A), L-Trp (B, D), or D-Trp (C). The amino acid composition (including the configuration) of the substances was determined by chiral-phase GC-MS of the hydrolysates. The sequences were established by EDMAN degradation following linearisation of the cyclic peptides upon treatment with LiAlH4. NMR spectroscopic studies of streptocidins C and D confirmed the proposed sequences and provided conformational data which indicate a molecular topology of streptocidins C and D similar to those of tyrocidine A and gramicidin S.     

Phenalinolactones A-D, terpenoglycoside antibiotics from Streptomyces sp. Tü 6071

Four new terpenoglycoside antibiotics, phenalinolactones A-D were isolated from Streptomyces sp. Tü 6071. The structures were elucidated on the basis of detailed NMR and MS analyses. Phenalinolactones combine a diterpenoid tricycle, a 2,3,6-trideoxysugar, a pyrrole-carboxylic acid and an uncommonly oxidized unsaturated γ-lactone in a unique manner. Phenalinolactones show an inhibitory activity against gram-positive bacteria.     

Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tü 6040 II. Structure elucidation and biosynthesis

The simocyclinones D4 (1) and D8 (2), members of a novel class of antibiotics, were isolated from the mycelial extract of Streptomyces antibioticus Tü 6040 and consist of angucyclinone, deoxysugar, octatetraene dicarboxylate and aminocoumarin structural elements. The structure elucidation was done by one and two dimensional NMR experiments, and other spectroscopic methods in combination with incorporation experiments using 13C labelled precursors.     

Silvalactam, a 24-membered macrolactam antibiotic produced by Streptomyces sp. Tü 6392*

Streptomycetes were isolated out of a soil sample taken from the rhizosphere of a spruce stand and screened by HPLC-diode array analysis for the production of secondary metabolites. This led to the detection of silvalactam, a novel 24-membered macrolactam antibiotic in extracts of Streptomyces strain Tü 6392. The structure was determined by MS and NMR spectroscopy experiments. Silvalactam shows a potent antiproliferative activity against various cancerous and non-cancerous cell lines.     

Fogacin, a novel cyclic octaketide produced by Streptomyces strain Tü 6319

A new octaketide named fogacin (1) was isolated from Streptomyces sp. (strain Tü 6319). Furthermore two shunt metabolites, SEK4b (2) and anhydroSEK4b (3), were detected and identified as non-enzymatically cyclized products of polyketide intermediates built during the biosynthesis of actinorhodin. SEK4b (2) as well as anhydroSEK4b (3) were previously described as metabolites of genetically engineered strains.     

Retymicin, galtamycin B, saquayamycin Z and ribofuranosyllumichrome, novel secondary metabolites from Micromonospora sp. Tü 6368. II. Structure elucidation

A detailed screening of the secondary metabolite pattern from Micromonospora sp. strain Tü 6368 resulted in the isolation of ten compounds belonging to five different structural families. The structures of the novel compounds 1-(alpha-ribofuranosyl)-lumichrome (3), retymicin (7), galtamycin B (11) and saquayamycin Z (14) were assigned by spectroscopic methods and chemical transformations. This strain fits our hypothesis that the metabolite analysis of biosynthetically talented strains leads readily to novel compounds.     

A Review of: “Design and Analysis of Vaccine Studies,by M. E. Halloran,I. M. Longini,Jr., and C. J. Struchiner,”

Joint modeling of longitudinal measurements and time to event data is often performed by fitting a shared parameter model. Another method for joint modeling that may be used is a marginal model. As a marginal model, we use a Gaussian model for joint modeling of longitudinal measurements and time to event data. We consider a regression model for longitudinal data modeling and a Weibull proportional hazard model for event time data modeling. A Gaussian copula is used to consider the association between these two models. A Monte Carlo expectation-maximization approach is used for parameter estimation. Some simulation studies are conducted in order to illustrate the proposed method. Also, the proposed method is used for analyzing a clinical trial dataset.     

A Review of: “Statistics: Concepts and Controversies,Sixth Edition,by D. S. Moore and W. I. Notz (Eds.)”

Contrasts were evaluated for the maximum blood or plasma concentration (C _max) of drugs measured after repeated and single oral administrations. Variances C _max of were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (C V) of C _max was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (k_a )In turn, the CV of C _max was substantially lower following repeated than after single drug administration when the variability of k_a dominated that of k.The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k) The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C _maxfollowing repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates