Antibacterial, Resistance Modulation, Anti-Biofilm Formation, and Efflux Pump Inhibition Properties of (Willd.) N. Halle (Celastraceae) Stem Extract and Its Constituents.

This study investigated the antibacterial, resistance modulation, biofilm inhibition, and efflux pump inhibition potentials of stem extract and its constituents. The antimicrobial activity was investigated by the high-throughput spot culture growth inhibition (HT-SPOTi) and broth microdilution assays. The resistance modulation activity was investigated using the anti-biofilm formation and efflux pump inhibition assays.

Efficient Screening of Target-Specific Selected Compounds in Mixtures by F NMR Binding Assay with Predicted F NMR Chemical Shifts.

Ligand-based F NMR screening is a highly effective and well-established hit-finding approach. The high sensitivity to protein binding makes it particularly suitable for fragment screening. Different criteria can be considered for generating fluorinated fragment libraries.

Simple Classification of RNA Sequences of Respiratory-Related Coronaviruses.

A very simple, fast, and efficient approach to analyze and identify respiratory-related virus sequences based on machine learning is proposed. Such schemes are very important in identifying viruses, especially in view of spreading pandemics. The method is based on genetic code rules and the open reading frame (ORF).

Deciphering the chemical instability of sphaeropsidin A under physiological conditions - degradation studies and structural elucidation of the major metabolite.

The fungal metabolite sphaeropsidin A (SphA) has been recognised for its promising cytotoxicity, particularly towards apoptosis- and multidrug-resistant cancers. Owing to its intriguing activity, the development of SphA as a potential anticancer agent has been pursued. However, this endeavour is compromised since SphA exhibits poor physicochemical stability under physiological conditions.

Gas-Phase Rearrangement of the -Glucuronide of Vildagliptin Forms Product-Ion Fragments Suggesting Wrongly an -Glucuronide.

The -glucuronide of vildagliptin, a dipeptidyl peptidase 4 inhibitor, is a major metabolite in monkeys and a minor metabolite in humans, rats, and dogs. Its product ion spectrum shows fragments that can be explained only by an -glucuronide. Biotransformation using rat liver yielded milligram amounts of the -glucuronide, and its structure was assigned unambiguously by nuclear magnetic resonance.

FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p.

FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (Saccharomyces cerevisiae--Erg26p, Homo sapiens--NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells.

Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon.

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon complex, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target.

Chemical constituents from Gouania longipetala and Glyphaea brevis.

Five compounds were isolated altogether from the two medicinal plants. Glycerol monotricosanoate (1), palmarumycin BG1 (2) and de-O-methyllasiodiplodin (3) were isolated from Gouania longipetala. In addition, epicatechin (4) and its dimer procyanidin B2 (5) were isolated from the stem bark of Glyphaea brevis.

Flavonoid glycosides from the stem bark of Margaritaria discoidea demonstrate antibacterial and free radical scavenging activities.

One new flavonoid glycoside, along with three known flavonoid glycosides were isolated from the stem bark of Margaritaria discoidea, which is traditionally used in the management of wounds and skin infections in Ghana. The new flavonoid glycoside was elucidated as hydroxygenkwanin-8-C-[α-rhamnopyranosyl-(1 → 6)]-β-glucopyranoside (1) on the basis of spectroscopic analysis. The isolated compounds demonstrated free-radical scavenging as well as some level of antibacterial activities.

An oral sphingosine 1-phosphate receptor 1 (S1P(1)) antagonist prodrug with efficacy in vivo: discovery, synthesis, and evaluation.

A prodrug approach to optimize the oral exposure of a series of sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists for chronic efficacy studies led to the discovery of (S)-2-{[3'-(4-chloro-2,5-dimethylphenylsulfonylamino)-3,5-dimethylbiphenyl-4-carbonyl]methylamino}-4-dimethylaminobutyric acid methyl ester 14. Methyl ester prodrug 14 is hydrolyzed in vivo to the corresponding carboxylic acid 15, a potent and selective S1P(1) antagonist. Oral administration of the prodrug 14 induces sustained peripheral blood lymphocyte reduction in rats.

Biocatalytic synthesis and structure elucidation of cyclized metabolites of the deacetylase inhibitor panobinostat (LBH589).

Panobinostat (LBH589) is a novel pan-deacetylase inhibitor that is currently being evaluated in phase III clinical trials for treatment of Hodgkin's lymphoma and multiple myeloma. Under catalysis of recombinant human CYP3A4 and CYP2D6 coexpressed with human cytochrome P450 reductase in Escherichia coli JM109, five metabolites of panobinostat were produced via whole-cell biotransformation. The structures of the metabolites were elucidated with the spectroscopic methods mass spectrometry (MS) and NMR and revealed an oxidative cyclization of the ethyl-amino group to the methylindole moiety.

Antimicrobial selaginellin derivatives from Selaginella pulvinata.

Six selaginellin derivatives, including three new analogues selaginellins D-F (1-3), were isolated from the EtOAc extract of the whole plant of Selaginella pulvinata (Hook. et Grev.) Maxim.

Special ergolines are highly selective, potent antagonists of the chemokine receptor CXCR3: discovery, characterization and preliminary SAR of a promising lead.

The special ergoline 1 is a highly potent, selective antagonist of the chemokine receptor CXCR3. The surprising selectivity of this LSD-related compound can be explained by different electronic and steric properties of the ergoline core structure caused by the urea portion of the molecule. Discovery, biopharmaceutical properties and first derivatives of this promising lead compound are discussed.

Ribosomally synthesized thiopeptide antibiotics targeting elongation factor Tu.

We identified the thiomuracins, a novel family of thiopeptides produced by a rare-actinomycete bacterium typed as a Nonomuraea species, via a screen for inhibition of growth of the bacterial pathogen Staphylococcus aureus. Thiopeptides are a class of macrocyclic, highly modified peptides that are decorated by thiazoles and defined by a central six-membered heterocyclic ring system. Mining the genomes of thiopeptide-producing strains revealed the elusive biosynthetic route for this class of antibiotics.

Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR.

Careful regulation of mRNA half-lives is a fundamental mechanism allowing cells to quickly respond to changing environmental conditions. The mRNA-binding Hu proteins are important for stabilization of short-lived mRNAs. Here we describe the identification and mechanistic characterization of the first low-molecular-weight inhibitors for Hu protein R (HuR) from microbial broths (Actinomyces sp.

Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers.

Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [(14)C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose.

Efficient synthesis of [3H]-sanglifehrin A via selective oxidation/reduction of alcohols at C31 and C35.

[Reaction: see text]. Sanglifehrin A is a novel complex natural product showing strong immunosuppressive activity and remarkably high affinity for cyclophilin A. To assess its pharmacokinetic properties in vivo, an efficient synthetic route was developed to introduce a tritium label in position C35 of sangliferin A via an oxidation/reduction strategy.

Cyanopeptolin 954, a chlorine-containing chymotrypsin inhibitor of Microcystis aeruginosa NIVA Cya 43.

A new depsipeptide, cyanopeptolin 954 (1), was isolated from the freshwater cyanobacterium Microcystis aeruginosa NIVA Cya 43. The structure of the compound was elucidated by chemical and spectroscopic analyses, including 2D NMR and GC-MS of the hydrolysate. The major structural differences compared to previously characterized heptadepsipeptides of Microcystis are the replacement of the basic amino acid in position 4 by L-leucine, the presence of L-phenylalanine in position 6, and the uncommon residue 3'-chloro-N-Me-L-tyrosine in position 7.

Quality control in combinatorial chemistry: determinations of amounts and comparison of the "purity" of LC-MS-purified samples by NMR, LC-UV and CLND.

The absolute purities of 20 purified samples from a combinatorial library have been determined by a new method that uses the DMSO sidebands [1J[13C-1H]] as an internal standard for quantification. The obtained absolute amounts are compared with the amounts of sample obtained by weighing, with the calculated weights obtained by chemiluminescent nitrogen detection (CLND) chromatography and with the relative purities obtained by LC-UV chromatography.

Orally bioavailable competitive CCR5 antagonists.

The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists.

Hofmannolin, a cyanopeptolin from Scytonema hofmanni PCC 7110.

Two depsipeptide metabolites, scyptolin A and B, were reported recently from the axenically grown terrestrial cyanobacterium Scytonema hofmanni PCC 7110. A related, novel depsipeptide was isolated from this Scytonema and designated hofmannolin. The amino acid analysis in context with infrared, mass and 1H/13C-NMR spectroscopies revealed a cyclic depsipeptide structure of M(r) 1073 belonging to the class of cyanopeptolins.

Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data.

Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.

Argyrins, immunosuppressive cyclic peptides from myxobacteria. II. Structure elucidation and stereochemistry.

The structures of argyrins A-H were elucidated by NMR spectroscopy, chemical degradation and X-ray analysis as cyclic octapeptides. Argyrins A and B, in addition to the common amino acids tryptophan, glycine, dehydroalanine and alanine or alpha-aminobutyric acid, sarcosine, contain 2-(1-aminoethyl)thiazol-4-caboxylic acid and the novel amino acid 4'-methoxytryptophan. In argyrins C and D the latter is replaced by 4'-methoxy 2'-methyltryptophan.

New insights into rifamycin B biosynthesis: isolation of proansamycin B and 34a-deoxy-rifamycin W as early macrocyclic intermediates indicating two separated biosynthetic pathways.

Proansamycin B, the formerly postulated intermediate of rifamycin B biosynthesis, was isolated from cultures of the Amycolatopsis mediterranei mutant F1/24. The structure was determined using UV, IR, NMR and MS techniques. Biotransformation studies demonstrate that proansamycin B is an intermediate of a shunt pathway, a 8-deoxy variant, of rifamycin B biosynthesis leading to 8-deoxy-rifamycin B as the final product.