Two new adenopeptins B and C inhibit sphere formation of pancreatic cancer cells.

Cancer remains one of the leading causes of death worldwide, particularly pancreatic cancer being lethal because of its aggressiveness and lack of early detection methods. A factor that contributes to malignancy are cancer stem cell-like characteristics promoted by the tumor-stromal interaction. Given that fibroblast conditioned medium (CM) promotes sphere formation of cancer cells, a cancer stem cell-like characteristic, its inhibitor could be a new anticancer agent. By exploring microbial cultures as a source, we found new compounds, namely, adenopeptins B (1) and C (2), from Acremonium sp. ESF00140. 1 and 2 selectively and potently inhibited the sphere formation of pancreatic cancer cells cultured in the fibroblast CM compared with the control medium. Oxygen consumption rate (OCR) assays showed that 1 and 2 inhibit OCR in pancreatic cancer cells. Studies of similar compounds suggested mitochondrial complex V inhibition. Therefore, results of measuring the activity of human mitochondrial complex V revealed that 1 and 2 inhibited its activity. Oligomycin A, an inhibitor of mitochondrial complex V, as well as 1 and 2, strongly inhibited the sphere formation of pancreatic cancer cells cultured in fibroblast CM. The addition of 1 and 2 to pancreatic cancer cells cultured in fibroblast CM increased reactive oxygen species (ROS) production compared with that in the control medium. In pancreatic cancer cells cultured in fibroblast CM, mitochondria significantly influence sphere formation, and targeting their function with 1 and 2 might provide a new therapeutic approach for pancreatic cancer.

Structure-activity relationships of natural quinone vegfrecine analogs with potent activity against VEGFR-1 and -2 tyrosine kinases.

A series of analogs of vegfrecine, a natural quinone vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, was synthesized via oxidative amination of 2,5-dihydroxybenzamide with functionalized arylamine followed by ammonolysis and substitution of the quinone ring. The inhibitory activities of the analogs against the VEGFR-1 and -2 tyrosine kinases were assayed in vitro with the aim to identify a compound suitable to treat cancer and inflammatory diseases. Alterations of the functionality of the phenyl group, substitution of the quinone ring, and oxidative cyclization of the 1-carboxamide-2-aminoquinone moiety to form an isoxazole quinone ring were examined. Introduction of halo- and alkyl-substituents at the 5'-position of the phenyl ring resulted in potent inhibition of the VEGFR-1 and -2 tyrosine kinases. In particular, structural modification at C-5' on the phenyl ring was shown to significantly affect the selectivity of the inhibition between the VEGFR-1 and -2 tyrosine kinases. Compound 8, 5'-methyl-vegfrecine, showed superior selectivity toward the VEGFR-2 tyrosine kinase over the VEGFR-1 tyrosine kinase.

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.

Corrigendum: Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology.

This corrects the article DOI: 10.1038/ja.2017.138.

Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology.

Microbial metabolites have attracted increasing interest as a source of therapeutics and as probes for biological mechanisms. New microbial metabolites and derivatives targeted at inflammation and bone disease therapy have been identified by focusing on prostaglandin release, osteoblast differentiation and immune cell functions. These modulators of inflammatory processes and bone disease contribute to our understanding of biological mechanisms and support identification of the therapeutic potential of drug lead candidates. The present review describes recent advances in the chemistry and analysis of inhibitors of prostaglandin release or other functional molecules of immune cells, as well as inducers of osteoblast differentiation, including biological and pharmacological activities.The Journal of Antibiotics advance online publication, 1 November 2017; doi:10.1038/ja.2017.138.

New anti-cancer chemicals Ertredin and its derivatives, regulate oxidative phosphorylation and glycolysis and suppress sphere formation in vitro and tumor growth in EGFRvIII-transformed cells.

BACKGROUND: EGFRvIII is a mutant form of the epidermal growth factor receptor gene (EGFR) that lacks exons 2-7. The resulting protein does not bind to ligands and is constitutively activated. The expression of EGFRvIII is likely confined to various types of cancer, particularly glioblastomas. Although an anti-EGFRvIII vaccine is of great interest, low-molecular-weight substances are needed to obtain better therapeutic efficacy. Thus, the purpose of this study is to identify low molecular weight substances that can suppress EGFRvIII-dependent transformation. METHODS: We constructed a new throughput screening system and searched for substances that decreased cell survival of NIH3T3/EGFRvIII spheres under 3-dimensional (3D)-culture conditions, but retained normal NIH3T3 cell growth under 2D-culture conditions. In vivo activity was examined using a mouse transplantation model, and derivatives were chemically synthesized. Functional characterization of the candidate molecules was investigated using an EGFR kinase assay, immunoprecipitation, western blotting, microarray analysis, quantitative polymerase chain reaction analysis, and measurement of lactate and ATP synthesis. RESULTS: In the course of screening 30,000 substances, a reagent, "Ertredin" was found to inhibit anchorage-independent 3D growth of sphere-forming cells transfected with EGFRvIII cDNA. Ertredin also inhibited sphere formation in cells expressing wild-type EGFR in the presence of EGF. However, it did not affect anchorage-dependent 2D growth of parental NIH3T3 cells. The 3D-growth-inhibitory activity of some derivatives, including those with new structures, was similar to Ertredin. Furthermore, we demonstrated that Ertredin suppressed tumor growth in an allograft transplantation mouse model injected with EGFRvIII- or wild-type EGFR-expressing cells; a clear toxicity to host animals was not observed. Functional characterization of Ertredin in cells expressing EGFRvIII indicated that it stimulated EGFRvIII ubiquitination, suppressed both oxidative phosphorylation and glycolysis under 3D conditions, and promoted cell apoptosis. CONCLUSION: We developed a high throughput screening method based on anchorage-independent sphere formation induced by EGFRvIII-dependent transformation. In the course of screening, we identified Ertredin, which inhibited anchorage-independent 3D growth and tumor formation in nude mice. Functional analysis suggests that Ertredin suppresses both mitochondrial oxidative phosphorylation and cytosolic glycolysis in addition to promoting EGFRvIII degradation, and stimulates apoptosis in sphere-forming, EGFRvIII-overexpressing cells.

Vegfrecine, an inhibitor of VEGF receptor tyrosine kinases isolated from the culture broth of Streptomyces sp.

A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.