Published papers

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 A(2) (1) and A(3) (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/beta-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 A(2) (1) and A(3) (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.

High accuracy is paramount when predicting biochemical characteristics using Quantitative Structural-Property Relationships (QSPRs). Although existing graph-theoretic kernel methods combined with machine learning techniques are efficient for QSPR model construction, they cannot distinguish topologically identical chiral compounds which often exhibit different biological characteristics. In this paper, we propose a new method that extends the recently developed tree pattern graph kernel to accommodate stereoisomers. We show that Support Vector Regression (SVR) with a chiral graph kernel is useful for target property prediction by demonstrating its application to a set of human vitamin D receptor ligands currently under consideration for their potential anti-cancer effects.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent because of its ability to selectively kill tumor cells. But TRAIL-resistance is a major problem of its therapy. A search for compounds for abrogating TRAIL-resistance has, thus, become an important strategy for anticancer drug discovery. In search of bioactive natural products for overcoming TRAIL-resistance, we previously reported some compounds with TRAIL-resistance overcoming activity. Bioassay guided fractionation of Entada scandens led to the isolation of four compounds (1-4). Of the isolates, compounds 1 and 3 showed moderate TRAIL-resistance overcoming activity in TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

Activity-guided fractionation of the Curcuma comosa rhizome MeOH extract that inhibited Wnt signal activity led to the characterization of two new diarylheptanoids (1 and 2) together with six known diarylheptanoids (3-8) and two known sesquiterpenoids (9 and 10). Their structures were identified by 1D and 2D NMR, HRESIMS, optical rotation, and chemical evidences. Compounds 1 and 8 exhibited dose-dependent inhibitory activity against beta-catenin/TCF transcriptional 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.

In a search for natural products with activity to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance, we performed the bioassay-guided fractionation of a semi mangrove, Pongamia pinnata, collected from Bangladesh, and isolated a new compound, (2S)-(2 '',3 '':7,8)-furanoflavanone (1), along with six known flavonoids (2-7). Two of the compounds significantly overcame TRAIL-resistance in human gastric adenocarcinoma (AGS) cell lines.

Four alkaloids, voacangine (1), isovoacangine (2), coronaridine (3), and coronaridine hydroxyindolenine (4), were isolated from the MeOH extract of Tabernaemontana divaricata aerial parts by activity-guided fractionation for Wnt signal inhibitory activity. Compounds 1-4 exhibited TCF/beta-catenin inhibitory activities with IC50 values of 11.5, 6.0, 5.8, and 7.3 mu M, respectively. Of these, coronaridine (3) decreased beta-catenin levels in SW480 colon cancer cells, while this decrease in beta-catenin was not suppressed by a co-treatment with 3 and MG132, a proteasome inhibitor. These results suggested that the decrease observed in beta-catenin levels by coronaridine (3) did not depend on a proteasomal degradation process. On the other hand, the treatment of SW480 cells with coronaridine (3) caused a decrease in beta-catenin mRNA levels. Thus, coronaridine (3) may inhibit the Wnt signaling pathway by decreasing the mRNA expression of beta-catenin. (C) 2015 Elsevier Ltd. All rights reserved.

We report new analogs of 1 alpha,25-dihydroxyvitamin D-3 (1) in three categories. First, design and synthesis of ligands for a mutant vitamin D receptor (VDR)(Arg274Leu), which possess proper functional groups at both C1 alpha and C2 alpha positions of 1 to study the biological activity of the mutant VDR. Among our synthetic analogs, 1 alpha-methyl-2 alpha-(3-hydroxypropyl)-25-hydroxyvitamin D-3 (8) showed 7.3-fold greater transcriptional activity for the VDR(Arg274Leu) than that of 1. Next, we examined the anti proliferative activity of 2-substituted 19-norvitamin D3 analogs on an immortalized normal prostate cell line, PZ-HPV-7, and we found MART 10 (14) showed the activity even at very low concentration of 10(-10) to 10(-11) M. We also synthesized 25-hydroxy-19-norvitamin D-3 (13) using Julia-type olefination to connect between the C5 and C6 positions, effectively, to test it as a prohormone type agent for antiprostate diseases. Synthesized compound 13 showed potent antiproliferative activity in PZ-HPV-7, which has high 1 alpha-hydroxylase activity. Finally, we describe design and synthesis of a new TEI-9647 analog, 2 alpha-(3-hydroxypropoxy)-24-propyl-25-dehydro-1 alpha-hydroxyvitamin D-3-26,23-lactone (17), which showed the strongest VDR antagonism. Its IC50 value is 7.4 pM to inhibit differentiation of HL-60 cells induced by 10 nM of 1. (c) 2006 Elsevier Ltd. All rights reserved.

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-3 beta,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.

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 DRS expression, and 16 showed TRAIL-resistance abrogating activity.

Novel chiral hybrid ligands containing an unsymmetrical spiro[4.5]decane skeleton with isoxazole and isoxazoline as the two coordinating units have been synthesized. Pd complexes of these ligands were found to be effective in activating olefins towards enantioselective tandem cyclization of a dialkenyl alcohol, providing the cyclized products in up to 97% ee. (c) 2007 Elsevier Ltd. All rights reserved.

A novel C20 natural product, acacienone (1), was isolated from the leaves of Acacia mangium collected in Bangladesh. The structure of compound 1 was elucidated by spectral studies and X-ray crystallographic analysis. Acacienone (1) possesses a terpenoid-related tetracyclic framework containing 20 carbons with biogenetically unusual structural features: (i) vicinal C1-branches at the C-3 and C-4 positions in the A ring, and (ii) a cyclopentenone D ring in an androsterone-like assembly, lacking a methyl group at the C-13 position.

A screening study using a luciferase assay to identify natural products which inhibit Wnt signaling was carried out. The bioassay-guided fractionation of aerial parts of a plant, Impatiens balsamina, led to the isolation of 2-methoxy-1,4-naphthoquinone (1) as an active compound. Compound 1 inhibited the TCF/beta-catenin (TOP) transcriptional activity (IC(50) 2.9 A mu M), while it decreased the transcriptional activity of FOP (mutated TCF-binding site)-transfected cells at > 5 A mu M.

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/beta-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/beta-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 beta-catenin and increased phosphorylated beta-catenin (Ser 33, 37, Tyr 41) protein levels. The degradation of beta-catenin by 1 was suppressed by GSK3 beta-siRNA, while compound 1 decreased beta-catenin even in the presence of CK1 alpha-siRNA. These results suggest that 1 inhibits Wnt signaling through the activation of GSK3 beta independent of CK1 alpha.

6-Hydroxy-9'-methoxystaurosporinone (1), a new bisindole alkaloid, was isolated from field-collected fruiting bodies of the myxomycete Perichaena chrysosperma, together with two known compounds. The structure of the new alkaloid was elucidated from spectral data, and compound 1 was shown to have hedgehog signal inhibitory activity. A related new alkaloid, 6,9'-dihydroxystaurosporinone (4), was also isolated from Arcyria cinerea.

A highly efficient screening method for naturally occurring products that bind to a specific target protein was demonstrated by using hVDR magnetic beads. The native ligand 1 alpha,25(OH)(2) VD(3) (1) was selectively bound by hVDR magnetic beads when present in a mixture of natural compounds. Furthermore, this method was shown to be applicable to the identification of natural products that interact with a specific protein immobilized on the beads from an extract of a natural resource. Two new natural compounds were isolated by this method. This approach will be helpful for the discovery of novel, naturally occurring products that bind to specific target proteins. This method has the further advantages that it can identify the HPLC peak corresponding to the target compound for isolation, as well as provide important UV, CD, or MS profile information.

A new resin glycoside (1) was isolated from the aerial part of Ipomoea maxima, together with three known compounds, pescaprein XX (2), stoloniferin X (3), and stoloniferin IX (4). The structure of 1 was elucidated on the basis of ID NMR spectroscopy, a fragmentation study by APCIMS, and HRESIMS analysis.

Complete (1)H and (13)C NMR assignments of acoschimperoside P, 2'-acetate (1) and a new cardiac glycoside (2), isolated from the leaves of Vallaris glabra, are described. Compound 1 was active in the assay for Hedgehog signaling inhibition. In further experiments, this compound showed a strong cytotoxicity against human pancreatic (PANC1) and human prostate (DU145) cancer cells. The expression of GLI-related proteins (PTCH and BCL-2) in a dose-dependent manner was also inhibited by 1.

We have developed "protein- and cell-based screen methods" for the isolation of new natural products. By using VDR (vitamin D receptor) immabilized magnetic beads, two new natural products were isolated rapidly. To find inhibitors of Hes1 protein, which is one of the important transcriptional factors in neural stem cells, a Hes1 dimer plate assay was developed, and then first Hes1 dimer inhibitors were found from our natural products library. As a "cell-based screen method," a reporter gene assay for screening Hh (hedgehog) signaling inhibitors was constructed. New Hh signaling inhibitors were isolated from our natural extracts library. We evaluated their Hh inhibitory activity in Hh related protein synthesis and cytotoxicity against cancers, in which Hh signaling is aberrantly activated. In addition to the naturally made compounds library (extracts library), "small molecules based on natural products" were synthesized. The total synthesis of Melleumin A, B, which were isolated by our group, was achieved. From their synthetic derivatives, inhibitors of the Wnt signal, which has been reported to cause colon cancers, were discovered. Moreover, flavanone and chromone were selected as natural product scaffolds. Many flavonoids and chromones with diverse heterocyclic units were constructed using our efficient synthetic method.