New chloptosins B and C from an Embleya strain exhibit synergistic activity against methicillin-resistant Staphylococcus aureus when combined with co-producing compound L-156,602.

Two new dimeric cyclohexapeptides, chloptosins B and C, were discovered from the culture broth of Embleya sp. MM621-AF10 together with the known compounds chloptosin and L-156,602. The structures of the new chloptosins were determined by spectroscopic studies and advanced Marfey's methods. The stereo structure of the constituent isoleucine was determined by C3 Marfey's analysis. Chloptosins demonstrated potent antimicrobial activity against Gram-positive bacteria including drug-resistant strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci with MICs of 0.5-2 µg ml-1. The antimicrobial activities of chloptosins were enhanced by addition of co-producing compound L-156,602, as shown by checkerboard analysis.

Flupyranochromene, a novel inhibitor of influenza virus cap-dependent endonuclease, from Penicillium sp. f28743.

Influenza virus RNA polymerase has cap-dependent endonuclease activity that produces capped RNA fragments for priming viral mRNA synthesis. This enzymatic activity is essential for viral propagation, but it is not present in any host cellular enzyme, making it an attractive target for the development of anti-influenza drugs. Here, we isolated a novel inhibitor of cap-dependent endonuclease, named flupyranochromene, from the fermentation broth of the fungus Penicillium sp. f28743. Structural analysis revealed that this compound bears a putative pharmacophore that chelates divalent metal ion(s) present in the endonuclease active site in the PA subunit of the polymerase. Consistently, in vitro endonuclease assays showed that flupyranochromene exerts its inhibitory effects by blocking endonucleolytic cleavage by the PA subunit of viral RNA polymerase complex.

Stereospecific ß-l-Rhamnopyranosylation through an SN i-Type Mechanism by Using Organoboron Reagents.

Stereospecific ß-l-rhamnopyranosylations were conducted using a 1,2-anhydro-l-rhamnopyranose donor and mono-ol or diol acceptors in the presence of a glycosyl-acceptor-derived borinic or boronic ester. Reactions proceeded smoothly to provide the corresponding ß-l-rhamnopyranosides (ß-l-Rhap) with complete stereoselectivity in moderate to high yields without any further additives under mild conditions. Mechanistic studies of the borinic ester mediated glycosylation using 13 C kinetic isotope effect (KIE) measurements and DFT calculations were consistent with a concerted SN i mechanism with an exploded transition state. In addition, the present glycosylation method was applied successfully to the synthesis of a trisaccharide, α-l-Rhap-(1,2)-ß-l-Rhap-(1,4)-Glcp, derived from Streptococcus pneumoniae serotypes 7B, 7C, and 7D.

Boronic-Acid-Catalyzed Regioselective and 1,2- cis-Stereoselective Glycosylation of Unprotected Sugar Acceptors via SNi-Type Mechanism.

Regio- and 1,2- cis-stereoselective chemical glycosylation of unprotected glycosyl acceptors has been in great demand for the efficient synthesis of natural glycosides. However, simultaneously regulating these selectivities has been a longstanding problem in synthetic organic chemistry. In nature, glycosyl transferases catalyze regioselective 1,2- cis-glycosylations via the SNi mechanism, yet no useful chemical glycosylations based on this mechanism have been developed. In this paper, we report a highly regio- and 1,2- cis-stereoselective SNi-type glycosylation of 1,2-anhydro donors and unprotected sugar acceptors using p-nitrophenylboronic acid (10e) as a catalyst in the presence of water under mild conditions. Highly controlled regio- and 1,2- cis-stereoselectivities were achieved via the combination of boron-mediated carbohydrate recognition and the SNi-type mechanism. Mechanistic studies using the KIEs and DFT calculations were consistent with a highly dissociative concerted SNi mechanism. This glycosylation method was applied successfully to the direct glycosylation of unprotected natural glycosides and the efficient synthesis of a complex oligosaccharide with minimal protecting groups.

Corrigendum: Structures and biological activities of novel 4'-acetylated analogs of chrysomycins A and B.

This corrects the article DOI: 10.1038/ja.2017.99.

Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4.

In the course of optimizing pargamicin A production in Amycolatopsis sp. ML1-hF4, we discovered novel cyclic depsipeptide compounds in the broth and designated them valgamicins A, C, T and V. The structures of these molecules were determined by spectroscopic studies, advanced Marfey's method and X-ray crystal structural analysis. Valgamicin C contains the extremely rare amino acid cleonine. To our knowledge, this is the first report of a cleonine-containing metabolite from a naturally isolated microorganism without any breeding or mutation treatment. None of the valgamicins showed potent antibacterial activity against either Gram-positive or -negative bacteria. Valgamicins A, C and T exhibited moderate cytotoxicity against human tumor cell lines.The Journal of Antibiotics advance online publication, 15 November 2017; doi:10.1038/ja.2017.135.

Structures and biological activities of novel 4'-acetylated analogs of chrysomycins A and B.

Two new 4'-acetylated analogs of chrysomycin were discovered during the screening for antitumor agents from the metabolites of actinomycetes. Their structures and physicochemical properties were determined by standard spectrometric analyses. Their cytotoxicities and antimicrobial activities were evaluated against a panel of cancer cell lines and microbes. While acetylation reinforced the cytotoxicity of chrysomycin B, it weakened the activity of chrysomycin A. Chrysomycin A and its acetylated analog showed high cytotoxicity toward most of the cancer cells with IC50s less than 10 ng ml-1. The 4'-acetyl-chrysomycin A was predominantly observed in nuclei at concentrations where the autofluorescence was observable. Chrysomycins were effective toward Gram-positive bacteria. The 4'-acetylated-chrysomycin A and B had MICs of 0.5-2 µg ml-1 and 2 to greater than 64 µg ml-1, respectively, toward Gram-positive bacteria including MRSA and VRE.

Stability and Bioavailability of Lentztrehaloses A, B, and C as Replacements for Trehalose.

Trehalose is widely used as a sweetener, humectant, and stabilizer, but is ubiquitously degraded by the enzyme trehalase expressed in a broad variety of organisms. The stability of the new trehalose analogues lentztrehaloses A, B, and C in microbial and mammalian cell cultures and their pharmacokinetics in mice were analyzed to evaluate their potential as successors of trehalose. Among the 12 species of microbes and 2 cancer cell lines tested, 7 digested trehalose, whereas no definitive digestion of the lentztrehaloses was observed in any of them. When orally administered to mice (0.5 g/kg), trehalose was not clearly detected in blood and urine and only slightly detected in feces. However, lentztrehaloses were detected in blood at >1 µg/mL over several hours and were eventually excreted in feces and urine. These results indicate that lentztrehaloses may potentially replace trehalose as nonperishable materials and drug candidates with better bioavailabilities.