A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus.

A new, competitive, nonpeptide cholecystokinin (CCK) antagonist, asperlicin, was isolated from the fungus Aspergillus alliaceus. The compound has 300 to 400 times the affinity for pancreatic, ileal, and gallbladder CCK receptors than proglumide, a standard agent of this class. Moreover, asperlicin is highly selective for peripheral CCK receptors relative to brain CCK and gastrin receptors. Since asperlicin also exhibits long-lasting CCK antagonist activity in vivo, it should provide a valuable tool for investigating the physiological and pharmacological actions of CCK.

Identification and possible role of D-mannitol and 2-O-methyl-chiro-inositol (quebrachitol) in Eimeria tenella.

Analysis of polyol extracts from various stages of Eimeria tenella has revealed the presence of mannitol and 2-O-methyl-chiro-inositol (quebrachitol). Previously, both compounds had been found almost exclusively in plants, and in the case of mannitol in a few species of bacteria. Identification was achieved by various analytical techniques including nuclear magnetic resonance (NMR), capillary gas-liquid chromatography (GLC), and GLC-mass spectrometry. Unsporulated oocysts contain a high level of mannitol (300 mM) which diminished during sporulation to 10 mM in sporulated oocysts.

The design and development of an integrated natural products screening database.

We designed and developed NEXUS--a new natural products screening database and related suite of software applications--to utilize the spectacular increases in assay capacity of the modern high throughput screening (HTS) environment. NEXUS not only supports seamless integration with separate HTS systems, but supports user-customized integration with external laboratory automation, particularly sample preparation systems. Designed and developed based on a detailed process model for natural products drug discovery, NEXUS comprises two integrated parts: (1) a single schema of Oracle tables and callable procedures and functions, and (2) software "front-ends" to the database developed using Microsoft Excel and Oracle Discovery/2000. Many of the back-end processing functions were written in Programming Language/Structured Query Language (PL/SQL) to provide an Application Programmer's Interface, which allows end users to create custom applications with little input from information technology professionals.

Structure, histone deacetylase, and antiprotozoal activities of apicidins B and C, congeners of apicidin with proline and valine substitutions.

[structure: see text]. Isolation and structure elucidation of two novel cyclic tetrapeptides that show a variety of potent antiprotozoal activities by reversibly inhibiting HDAC have been reported. These are the new members of a unique family of cyclic tetrapeptides that do not require the electrophilic alpha-epoxyketone moiety of HC-toxin, trapoxin A, or chlamydocin for their potent activities against HDAC and the malarial parasite.

Solvation of acylium fragment ions in electrospray ionization quadrupole ion trap and Fourier transform ion cyclotron resonance mass spectrometry.

In electrospray ionization (ESI) quadrupole ion trap and Fourier transform ion cyclotron resonance mass spectrometry, certain fragment ions (e.g. acylium ions) generated either during the ion transportation process (in the source interface region) or in the ion trap are found to undergo ion--molecule reactions with ESI solvent molecules (water, acetonitrile and aliphatic alcohols) to form adduct species. These unexpected solvated fragment ions severely complicate the interpretation of mass spectrometic data. High-resolution accurate mass measurements are important in establishing the elemental compositions of these adduct species and preventing erroneous data interpretation.

Structure elucidation of angiotensin converting enzyme inhibitor L-681,176 from Streptomyces sp. MA 5143a.

L-681,176 (1, C12H23N5O7) is an inhibitor of angiotensin converting enzyme produced by Streptomyces sp. MA 5143a. The structure of L-681,176 has been determined by NMR and mass spectral analysis.

Novel antinematodal and antiparasitic agents from Penicillium charlesii. II. Structure determination of paraherquamides B, C, D, E, F, and G.

Paraherquamides B (2, C27H33N3O4), C (3, C28H33N3O4), D (4, C28H33N3O5), E (5, C28H35N3O4), F (6, C28H35N3O3), and G (7, C28H35N3O4) are novel metabolites of Penicillium charlesii. The structures of these compounds have been determined by NMR and MS analysis.

L-671,329, a new antifungal agent. II. Structure determination.

Based on spectroscopic data L-671,329, isolated from a filamentous fungus ATCC 20868, has been assigned the structure 1. The compound is a lipopeptide antifungal agent and a structural analog of echinocandin B.

Novel cholecystokinin antagonists from Aspergillus alliaceus. II. Structure determination of asperlicins B, C, D, and E.

Asperlicins B (1, C31H29N5O5), C (2, C25H18N4O2), D (3, C25H18N4O2), and E (4, C25H18N4O3) are novel cholecystokinin antagonists produced by Aspergillus alliaceus. The structures of these compounds have been determined by 1H NMR and MS analysis.

Northienamycin and 8-epi-thienamycin, new carbapenems from Streptomyces cattleya.

Two new carbapenem antibiotics, northienamycin and 8-epi-thienamycin have been isolated from culture broth of Streptomyces cattleya grown under conditions for thienamycin production. The isolation, structure elucidation and in vitro antibacterial spectra of the new carbapenems are reported. In addition, comparison of the in vitro potency of the corresponding formamidine derivatives to that of MK787 is presented.

Asperlicin, a novel non-peptidal cholecystokinin antagonist from Aspergillus alliaceus. Structure elucidation.

Asperlicin (1, C31H29N5O4) is a novel cholecystokinin antagonist produced by Aspergillus alliaceus. The structure of asperlicin has been determined by NMR and mass spectral analysis, and X-ray crystallography.

Cochinmicins, novel and potent cyclodepsipeptide endothelin antagonists from a Microbispora sp. II. Structure determination.

Cochinmicins I, II, and III are competitive endothelin antagonists produced by Microbispora sp. ATCC 55140. The cochinmicins are cyclic depsipeptides containing six alpha-amino acids and a pyrrolecarboxylic acid. Based upon MS, 1D and 2D NMR, and LC data, the structures and absolute stereochemistries of the cochinmicins have been assigned. All three components have the same basic sequence and contain one equivalent each of D-allo-threonine, D-alanine, L-phenylalanine, D-phenylalanine, 5-chloropyrrole-2-carboxylic acid (or pyrrole-2-carboxylic acid in cochinmicin I), plus two equivalents of 3,5-dihydroxyphenylglycine (DHPG). The phenylalanine residues were differentiated via a methanolysis product which contained only one of the phenylalanine residues. Both DHPG residues have the D configuration in the more active cochinmicins I and III. Cochinmicin II contains both D- and L-DHPG and these residues have been differentiated in the sequence based upon 1H NMR data.

Difficidin and oxydifficidin: novel broad spectrum antibacterial antibiotics produced by Bacillus subtilis. II. Isolation and physico-chemical characterization.

The isolation of difficidin (1) and oxydifficidin (2) from fermentation broth of Bacillus subtilis ATCC 39320 and the physico-chemical characterization of these labile antibiotics are described. The structures of the compounds represent a new class of antibiotics, characterized as highly unsaturated 22-membered macrolide phosphates. Difficidin and oxydifficidin undergo reversible thermal isomerization to 3 and 4 respectively. Biological evaluation of the isomers is presented.

Cochlioquinone A, a nematocidal agent which competes for specific [3H]ivermectin binding sites.

Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.

Pneumocandins from Zalerion arboricola. III. Structure elucidation.

Pneumocandin B0 (6) and six related lipopeptides are antifungal and anti-Pneumocystis carinii agents from mutants of Zalerion arboricola, whose structures were determined mainly on the basis of spectroscopic analysis. They belong, along with pneumocandin A0 (L-671,329) previously isolated from these laboratories, to the echinocandin class of antifungal agents. The product from base-catalyzed ring opening involving the hemiaminal position of the dihydroxyornithine residue of B0, has been clearly defined as 6b. Modifications were limited to the 3-hydroxy-4-methylproline, 3,4-dihydroxyhomotyrosine and 4,5-dihydroxyornithine residues of pneumocandin A0.

Biosynthesis of fluorothreonine and fluoroacetic acid by the thienamycin producer, Streptomyces cattleya.

An antimetabolite, THX, was isolated from fermentation broths of the thienamycin producer, Streptomyces cattleya, when the organism was grown in the presence of a fluorine-containing substrate. THX was subsequently identified as one of the four possible stereoisomers of 4-fluorothreonine. Inorganic fluoride or any one of a number of organofluorine compounds can be used as precursors of 4-fluorothreonine. In addition, 19F NMR has provided evidence that the organism synthesizes fluoroacetate under the same fermentation conditions. The in vitro antibacterial spectrum of 4-fluorothreonine is also presented.

L-155,175: a new antiparasitic macrolide. Fermentation, isolation and structure.

A new antiparasitic macrolide, L-155,175, produced by a strain of Streptomyces hygroscopicus, has been isolated; its structure was determined by physico-chemical means. It is active against the tapeworm Hymenolepis diminuta in rats.

Quinoxapeptins: novel chromodepsipeptide inhibitors of HIV-1 and HIV-2 reverse transcriptase. I. The producing organism and biological activity.

Quinoxapeptin A and B are novel chromodepsipeptides which were isolated from a nocardioform actinomycete with indeterminant morphology. Quinoxapeptins A and B are potent inhibitors of HIV-1 and HIV-2 reverse transcriptase and almost equally active against two single mutants forms as well as a double mutant form of HIV-1 reverse transcriptase. Quinoxapeptin A and B are specific inhibitors of HIV-1 and HIV-2 reverse transcriptase because they did not inhibit human DNA polymerase alpha, beta, gamma and delta. Quinoxapeptin A and B are structurally similar to luzopeptin A which was also active against HIV-1 and HIV-2 reverse transcriptase.

Mouse submaxillary gland renin contains a noncovalently attached fatty acid.

Renin A from the submaxillary gland of male mice has been shown by a gas chromatography/mass spectrometry method to contain near stoichiometric amounts of a fatty acid mixture. The fatty acids on mouse renin were partially exchangeable with free tridecanoic acid in solution, with the tridecanoic acid truly exchanged and not just adsorbed in addition to the fatty acids already present. A gas chromatography/mass spectrometry analysis of the composition of the free fatty acids of the submaxillary gland of male mice showed that the mixture of fatty acids extracted from the gland was significantly different from the mixture of free fatty acids extracted from renin A. The renin-extracted fatty acids were relatively richer in saturated fatty acids, like myristic and palmitic acids, and poorer in polyunsaturated fatty acids, like linoleic and arachidonic acid, than the free fatty acids of the gland. The enzymatic activity of mouse renin was markedly stimulated by saturated fatty acids in 50 mM sodium acetate, pH 5.38, in a concentration-dependent, saturable manner. Palmitic acid stimulated renin activity versus synthetic tetradecapeptide renin substrate about 7-fold in this buffer, with half-maximal stimulation at 14 microM. Stearic and myristic acids also showed good stimulation but linoleic acid and ethyl myristate were much less effective at the stimulation. A possible physiological role for the loss of renin activity at acid pH due to loss of bound fatty acids would be to protect the mouse against internalized renin.