Kazufumi Toume

Yoropyrazone, a new naphthopyridazone alkaloid isolated from Streptomyces sp. IFM 11307 and evaluation of its TRAIL resistance-overcoming activity

A new naphthopyridazone derivative, yoropyrazone (1), has been isolated from Streptomyces sp. IFM 11307. The structure of the new compound was established on the basis of spectroscopic analyses. Compound 1 (10 μM) in combination with TRAIL moderately showed cytotoxic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

Isolation and structure elucidation of izuminosides A–C: a rare phenazine glycosides from Streptomyces sp. IFM 11260

Three new glycosylated phenazine derivatives, named izuminosides A–C (1–3) have been isolated from the ethyl acetate extract of Streptomyces sp. IFM 11260. The structures of the new compounds were determined on the basis of their spectral data. Compounds 1–3 were evaluated for their activity in overcoming tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in human gastric adenocarcinoma cells. Compounds 2 (10 μM) and 3 (60 μM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistance AGS cells.

Cryptolepine, isolated from Sida acuta, sensitizes human gastric adenocarcinoma cells to TRAIL-induced apoptosis.

Bioassay guided separation of Sida acuta whole plants led to the isolation of an alkaloid, cryptolepine (1), along with two kaempferol glycosides (2–3). Compound 1 showed strong activity in overcoming TRAIL‐resistance in human gastric adenocarcinoma (AGS) cells at 1.25, 2.5 and 5 μm. Combined treatment of 1 and TRAIL sensitized AGS cells to TRAIL‐induced apoptosis at the aforementioned concentrations. Copyright

Cycloartane triterpenes isolated from Combretum quadrangulare in a screening program for death-receptor expression enhancing activity.

In our screening program for natural products that increase DR5 (death-receptor 5) expression, nine new cycloartane triterpenes, combretanones A-G (1-7), combretic acid A (8), and combretic acid B (9), were isolated from a MeOH extract of Combretum quadrangulare leaves. The known oleanane triterpenes (10, 11) and six known flavonols (12-17) were also isolated. The structures of 1-9 were elucidated by spectroscopic studies. Compounds 7, 9, 12, 16, and 17 enhanced DR5 expression, and 16 showed TRAIL-resistance abrogating activity.

Constituents of Amoora cucullata with TRAIL resistance-overcoming activity

In search of bioactive natural products for overcoming TRAIL resistance from natural resources, we previously reported a number of active compounds. Bioassay-guided fractionation of mangrove, Amoora cucullata, collected from Sundarbans Mangrove Forest, Bangladesh, led to the isolation of four new compounds (1-4), along with seven known compounds (5-11). Of the isolates, compounds 1, 5, 8, and 9 showed TRAIL resistance-overcoming activity, among which 8 showed the most potent activity and enhanced TRAIL-induced apoptosis in TRAIL-resistant human gastric adenocarcinoma (AGS) cells through the activation of caspase-3/7, enhancing the expression of DR4 and DR5 mRNA in AGS cells. Cell death caused by the combined treatment of 8 and TRAIL was inhibited by human recombinant DR5/Fc and DR4/Fc chimera proteins, indicating that 8 sensitizes TRAIL-resistant AGS cells to TRAIL through the induction of DR4 and DR5.

9-Hydroxycanthin-6-one, a β-Carboline Alkaloid from Eurycoma longifolia, Is the First Wnt Signal Inhibitor through Activation of Glycogen Synthase Kinase 3β without Depending on Casein Kinase 1α.

Wnt signaling regulates various processes such as cell proliferation, differentiation, and embryo development. However, numerous diseases have been attributed to the aberrant transduction of Wnt signaling. We screened a plant extract library targeting TCF/β-catenin transcriptional modulating activity with a cell-based luciferase assay. Activity-guided fractionation of the MeOH extract of the E. longifolia root led to the isolation of 9-hydroxycanthin-6-one (1). Compound 1 exhibited TCF/β-catenin inhibitory activity. Compound 1 decreased the expression of Wnt signal target genes, mitf and zic2a, in zebrafish embryos. Treatment of SW480 cells with 1 decreased β-catenin and increased phosphorylated β-catenin (Ser 33, 37, Tyr 41) protein levels. The degradation of β-catenin by 1 was suppressed by GSK3β-siRNA, while compound 1 decreased β-catenin even in the presence of CK1α-siRNA. These results suggest that 1 inhibits Wnt signaling through the activation of GSK3β independent of CK1α.

Xylogranin B: A Potent Wnt Signal Inhibitory Limonoid from Xylocarpus granatum

Xylogranin B (2) was isolated from Xylocarpus granatum (Meliaceae) leaves, by use of a cell-based luciferase screening system targeting a Wnt signaling pathway. Compound 2 inhibited TCF/β-catenin transcriptional activity (IC50 48.9 nM) and exhibited strong cytotoxicity against colon cancer cell lines. Compound 2 significantly decreased β-catenin protein levels in nuclei but not in the cytosol. These results indicated that a decrease in β-catenin levels in nuclei by 2 resulted in the Wnt signal inhibitory effects of 2.

Cycloartane triterpenes and ingol diterpenes isolated from Euphorbia neriifolia in a screening program for death-receptor expression-enhancing activity.

In our screening program for natural products that increase death-receptor 5 expression, seven new cycloartane triterpenes, euphonerins A-G (1-7), and 3-O-acetyl-8-O-tigloylingol (8), a new ingol diterpene, were isolated from the MeOH extract of Euphorbia neriifolia leaves, together with 3,12-di-O-acetyl-8-O-tigloylingol (9), (24R)-cycloartane-3β,24,25-triol (10), and three known flavonols (11-13). The structures of 1-8 were elucidated by spectroscopic analysis. Among these compounds, 1-11 showed death-receptor 5 expression enhancing activity.

Chromomycins A2 and A3 from marine actinomycetes with TRAIL resistance-overcoming and Wnt signal inhibitory activities.

A biological screening study of an actinomycetes strain assembly was conducted using a cell-based cytotoxicity assay. The CKK1019 strain was isolated from a sea sand sample. Cytotoxicity-guided fractionation of the CKK1019 strain culture broth, which exhibited cytotoxicity, led to the isolation of chromomycins A2 (1) and A3 (2). 1 and 2 showed potent cytotoxicity against the human gastric adenocarcinoma (AGS) cell line (IC50 1; 1.7 and 2; 22.1 nM), as well as strong inhibitory effects against TCF/β-catenin transcription (IC50 1; 1.8 and 2; 15.9 nM). 2 showed the ability to overcome tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance. To the best of our knowledge, the effects of chromomycins A2 (1) and A3 (2) on TRAIL resistance-overcoming activity, and on the Wnt signaling pathway, have not been reported previously. Thus, 1 and 2 warrant potential drug lead studies in relation to TRAIL-resistant and Wnt signal-related diseases and offer potentially useful chemical probes for investigating TRAIL resistance and the Wnt signaling pathway.

Cadinane Sesquiterpenes from Curcuma parviflora

Two new cadinane sesquiterpenes (1 and 2) were isolated from Curcuma parviflora, and their structures were elucidated by spectroscopic data. Compound 1, 4alpha-acetoxycadina-2,9-diene-1,8-dione, possesses two conjugated enone chromophores, while compound 2, 1alpha,3alpha,4beta-trihydroxy-9-cadinen-8-one, has an enone moiety with three hydroxy groups. Isolation of these cadinane monomers may reasonably suggest that parviflorenes are biogenetically classified as cadinane dimers.