Jun-ya Ueda

A Novel Indole-diterpenoid, JBIR-03 with Anti-MRSA Activity from Dichotomomyces cejpii var. cejpii NBRC 103559

A new indole-diterpene, JBIR-03 (1), was isolated from the fungus Dichotomomyces cejpii var. cejpii NBRC 103559 and its structure was determined based on the spectroscopic data. 1 exhibited anti-MRSA (methicillin-resistant Staphylococcus aureus) activity and antifungal activity against apple Valsa canker-causing fungus, Valsa ceratosperma, while it exhibited no toxicity towards human cancer cells.

JBIR-59, a new sorbicillinoid, from a marine-derived fungus Penicillium citrinum SpI080624G1f01

JBIR-59, a new sorbicillinoid, from a marine-derived fungus Penicillium citrinum SpI080624G1f01

Aminocaprophenone- and Pyrrolidine-Type Alkaloids from the Leaves of Ficus septica

Two new aminocaprophenone alkaloids, ficuseptamines A (1) and B (2), and a new pyrrolidine alkaloid, ficuseptamine C (3), together with 12 known alkaloids and a known acetophenone derivative were isolated from a methanolic extract of the leaves of Ficus septica. The structures of 1-3 were determined on the basis of their spectroscopic data. The compounds obtained were evaluated for cytotoxicity against two cancer cell lines.

Antiausterity Agents from Uvaria dac and Their Preferential Cytotoxic Activity against Human Pancreatic Cancer Cell Lines in a Nutrient-Deprived Condition

Human pancreatic cancer cell lines are known for their inherent tolerance to nutrition starvation, which enables them to survive under a hypovascular (austerity) tumor microenvironment. The search for agents that preferentially retard the survival of cancer cells under low nutrition conditions (antiausterity agent) is a novel approach to anticancer drug discovery. In this study, it was found that a dichloromethane extract of the stem of Uvaria dac preferentially inhibited PANC-1 human pancreatic cancer cells survival under nutrition-deprived conditions at a concentration of 10 μg/mL. Workup of this bioactive extract led to the discovery of (+)-grandifloracin (8) as a potent antiausterity agent as evaluated in a panel of four human pancreatic cancer cell lines, PANC-1 (PC(50), 14.5 μM), PSN-1 (PC(50), 32.6 μM), MIA PaCa-2 (PC(50), 17.5 μM), and KLM-1 (32.7 μM). (+)-Grandifloracin (8) has been isolated from a natural source for the first time. Its absolute stereochemistry was established by single-crystal X-ray crystallography and circular dichroism spectroscopic analysis. In addition to this, seven other new highly oxygenated cyclohexene derivatives, named uvaridacanes A (1) and B (2), uvaridacols A-D (3, 4, 6, 7), and uvaridapoxide A (5), were also isolated and structurally characterized.

(+)-Grandifloracin, an antiausterity agent, induces autophagic PANC-1 pancreatic cancer cell death.

Human pancreatic tumors are known to be highly resistant to nutrient starvation, and this prolongs their survival in the hypovascular (austere) tumor microenvironment. Agents that retard this tolerance to nutrient starvation represent a novel antiausterity strategy in anticancer drug discovery. (+)-Grandifloracin (GF), isolated from Uvaria dac, has shown preferential toxicity to PANC-1 human pancreatic cancer cells under nutrient starvation, with a PC50 value of 14.5 μM. However, the underlying mechanism is not clear. In this study, GF was found to preferentially induce PANC-1 cell death in a nutrient-deprived medium via hyperactivation of autophagy, as evidenced by a dramatic upregulation of microtubule-associated protein 1 light chain 3. No change was observed in expression of the caspase-3 and Bcl-2 apoptosis marker proteins. GF was also found to strongly inhibit the activation of Akt, a key regulator of cancer cell survival and proliferation. Because pancreatic tumors are highly resistant to current therapies that induce apoptosis, the alternative cell death mechanism exhibited by GF provides a novel therapeutic insight into antiausterity drug candidates.

Cassane diterpenes from the seed kernels of Caesalpinia sappan

Eight structurally diverse cassane diterpenes named tomocins A-H were isolated from the seed kernels of Vietnamese Caesalpinia sappan Linn. Their structures were determined by extensive NMR and CD spectroscopic analysis. Among the isolated compounds, tomocin A, phanginin A, F, and H exhibited mild preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived condition without causing toxicity in normal nutrient-rich conditions.

Analysis of the biological activity of a novel 24-membered macrolide JBIR-19 in Saccharomyces cerevisiae by the morphological imaging program CalMorph

To investigate the biological activity of a novel 24-membered macrolide compound, JBIR-19, isolated from the culture broth of the entomopathogenic fungus Metarhizium sp. fE61, morphological changes in yeast cells were examined using the automated image-processing program CalMorph. Principal components analysis was used to elucidate dynamic changes in the phenotypes, revealing two independent effects of JBIR-19 in yeast cells: bud elongation and increased size of the actin region. Using a fitness assay, we identified the genes required for robust growth in the presence of JBIR-19. Among these were CCW12, YLR111W, and DHH1, which are also involved in abnormal bud morphology. Based on these results and others, we predict intracellular targets of JBIR-19 and its functional interactions.

Efficient Synthesis of the Deoxysugar Part of Versipelostatin by Direct and Stereoselective Glycosylation and Revision of the Structure of the Trisaccharide Unit

Efficient synthesis of the deoxysugar part of versipelostatin (VST) was achieved by direct and stereoselective glycosylation of the reduced VST aglycon. Activation of 2-deoxyglycosyl imidate with IBr under basic conditions enables alpha-selective glycosylation of beta-2-deoxylglycosides without anomerization. Comparison of the synthetic and natural VST products using NMR indicates that versipelostatin has a beta-D-digitoxose-(1,4)-alpha-L-oleandrose-(1,4)-beta-D-digitoxose trisaccharide. In addition, results of a biological assay indicate that the deoxyoligosaccharide unit of the synthetic glycoside was important for biological activity of the compound.

Novel GRP78 Molecular Chaperone Expression Down-regulators JBIR-04 and -05 Isolated from Streptomyces violaceoniger

In the course of our screening program for regulators of the expression of GRP78 molecular chaperone, JBIR-04 (1) and -05 (2) were isolated from Streptomyces violaceoniger 4541-SVS3 as congeners of prunustatin A (3). The structures of 1 and 2 were determined by the analyses of the spectroscopic data. These compounds mainly consist of an amino acid and amino acid derived α-hydroxy acid residues. 1 and 2 inhibited the expression of GRP78 induced by 2-deoxyglucose in human fibrosarcoma HT1080 cells, but their activities were highly reduced compared with those of 3 and SW-163A.

Geranyl dihydrochalcones from Artocarpus altilis and their antiausteric activity.

Human pancreatic cancer cell lines have remarkable tolerance to nutrition starvation, which enables them to survive under a tumor microenvironment. The search for agents that preferentially inhibit the survival of cancer cells under low nutrient conditions is a novel antiausterity strategy in anticancer drug discovery. In this study, the methanolic extract of the leaves of Artocarpus altilis showed 100 % preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions at a concentration of 50 µg/mL. Further investigation of this extract led to the isolation of eight new geranylated dihydrochalcones named sakenins A-H (1-8) together with four known compounds (9-12). Among them, sakenins F (6) and H (8) were identified as potent preferentially cytotoxic candidates with PC50 values of 8.0 µM and 11.1 µM, respectively.