Chirality Transfer Intramolecular Pauson-Khand Reaction with N-C Axially Chiral Sulfonamides Bearing an Ene-Yne Structure.

An intramolecular Pauson-Khand reaction with enantioenriched N-C axially chiral N-allyl-N-(2-alkynylphenyl)sulfonamide derivatives proceeded with complete chirality transfer from axial chirality (P configuration) to central chirality (R configuration), affording chiral nitrogen-containing tricyclic compounds (tetrahydrocyclopentaquinolin-2-one derivatives).

Characterization of the surugamide biosynthetic gene cluster of TUA-NKU25, a Streptomyces diastaticus strain isolated from Kusaya, and its effects on salt-dependent growth.

Kusaya, a traditional Japanese fermented fish product, is known for its high preservability, as it contains natural antibiotics derived from microorganisms, and therefore molds and yeasts do not colonize it easily. In this study, the Streptomyces diastaticus strain TUA-NKU25 was isolated from Kusaya, and its growth as well as the production of antibiotics were investigated. Strain TUA-NKU25 showed advantageous growth characteristics in the presence, but not in the absence, of sodium chloride (NaCl). Antimicrobial assay, high-performance liquid chromatography, and electrospray ionization-mass spectrometry analysis showed that this strain produced surugamide A and uncharacterized antimicrobial compound(s) during growth in the presence of NaCl, suggesting that the biosynthesis of these compounds was upregulated by NaCl. Draft genomic analysis revealed that strain TUA-NKU25 possesses a surugamide biosynthetic gene cluster (sur BGC), although it is incomplete, lacking surB/surC. Phylogenetic analysis of strain TUA-NKU25 and surugamide-producing Streptomyces showed that sur BGC formed a clade distinct from other known groups.

18 O/16 O-Encoding Strategy for Microscale Stereochemical Determination of Peptidic Natural Products.

The demand for more efficient methods of establishing the undetermined stereochemistries of peptidic natural products continues unabated. A new method for microscale stereochemical determination was devised by integrating solid-phase synthesis, split-and-mix randomization, 18 O/16 O-encoding of d/l-configurations, tandem mass spectrometry, and biological evaluation. Here we applied gramicidin A as the molecule for a blind test. Gramicidin A and its 31 diastereomers were randomly prepared in microgram scale with 18 O/16 O-stereochemical encoding and subjected to MS/MS-structural determination and cytotoxicity assay. Only the parent gramicidin A was selected from among the 32 stereoisomers, validating the high reliability of the present strategy.

Machine learning-based prediction of adverse drug effects: An example of seizure-inducing compounds.

Various biological factors have been implicated in convulsive seizures, involving side effects of drugs. For the preclinical safety assessment of drug development, it is difficult to predict seizure-inducing side effects. Here, we introduced a machine learning-based in vitro system designed to detect seizure-inducing side effects. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices, while 14 drugs were bath-perfused at 5 different concentrations each. For each experimental condition, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which indeed were reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to detect the seizure-inducing side effects of preclinical drugs.