160 results on '"Midori A. Arai"'
Search Results
52. Prenylflavonoids isolated from Artocarpus champeden with TRAIL-resistance overcoming activity
- Author
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Masami Ishibashi, Kazufumi Toume, Takashi Koyano, Thaworn Kowithayakorn, Midori A. Arai, and Tomohiro Minakawa
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Antineoplastic Agents ,Apoptosis ,Caspase 3 ,Plant Science ,Horticulture ,CHOP ,Plant Roots ,Biochemistry ,TNF-Related Apoptosis-Inducing Ligand ,Cell Line, Tumor ,Humans ,Cytotoxic T cell ,RNA, Messenger ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,Flavonoids ,Messenger RNA ,Base Sequence ,Molecular Structure ,biology ,Chemistry ,General Medicine ,Thailand ,Ligand (biochemistry) ,Moraceae ,biology.organism_classification ,Molecular biology ,Up-Regulation ,Immunology ,Tumor necrosis factor alpha ,Drug Screening Assays, Antitumor ,Artocarpus - Abstract
In a screening program for bioactive natural products which can overcome Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-resistance, three prenylflavonoids, named pannokin A–C, were isolated from a MeOH extract of Artocarpus champeden (Moraceae) roots, together with three known prenylflavonoids. The structures of pannokin A–C were elucidated by spectroscopic analysis. These of the prenylflavonoids in combination with TRAIL, showed cytotoxic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma (AGS) cells. Of these compounds, heterophyllin increased caspase 3/7 activity when combined with TRAIL in AGS cells, and enhanced the expression of DR4 and DR5 mRNA. Moreover, heterophyllin up-regulated mRNA expression of CCAAT/enhancer-binding protein-homologous protein (CHOP) which was reported to be an important regulator of DR5 expression. Thus, heterophyllin was presumed to cause a CHOP-dependent up-regulation of DR5 expression resulting in apoptosis in AGS cells.
- Published
- 2013
53. Merging Chemistry and Biology in Emerging Countries
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Takayoshi Suzuki, Midori A. Arai, Motonari Uesugi, and Mitsue Nakashima
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Pharmacology ,Clinical Biochemistry ,Drug Discovery ,Molecular Medicine ,Engineering ethics ,Nanotechnology ,General Medicine ,Chemistry (relationship) ,Biology ,Emerging markets ,Molecular Biology ,Biochemistry ,Nature versus nurture - Abstract
Summary Chemical biology is not a new discipline, as research at the interface of chemistry and biology has been growing for decades. However, the field still needs regional and global support in emerging countries. The meeting organized by Asian Chemical Biology Initiative in Bangkok, Thailand in January 2013, brought together regional communities of young and established researchers to nurture chemical biology research programs and highlight some of the newer developments. Here, we report on the meeting and some of the key research topics discussed.
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- 2013
54. Catalytic Asymmetric Synthesis of Mixed 3,3′-Bisindoles and Their Evaluation as Wnt Signaling Inhibitors
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Masami Ishibashi, Takayoshi Arai, Yushi Yamamoto, Kentaro Kamiya, Atsuko Awata, and Midori A. Arai
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Models, Molecular ,Indoles ,Stereochemistry ,Chemistry ,Ligand ,Enantioselective synthesis ,Wnt signaling pathway ,Imidazoline receptor ,Stereoisomerism ,Homogeneous catalysis ,Biological activity ,General Medicine ,General Chemistry ,Crystallography, X-Ray ,Catalysis ,Coupling reaction ,Wnt Signaling Pathway - Abstract
TOP class: The first efficient catalytic asymmetric coupling reaction of indoles with isatin-derived nitroalkenes was accomplished by using a complex consisting of a chiral imidazoline aminophenol ligand (1; see scheme) and Cu(OTf)(2). Biological activity of the newly formed chiral 3,3'-bisindoles was also confirmed in a Wnt signaling inhibitory assay.
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- 2013
55. Cerasoidine, a Bis-aporphine Alkaloid Isolated from Polyalthia cerasoides during Screening for Wnt Signal Inhibitors
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Naoki Ishikawa, Thaworn Kowithayakorn, Midori A. Arai, Takumi Shono, Kazufumi Toume, Takashi Koyano, Masami Ishibashi, and Hyuma Masu
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Circular dichroism ,Aporphines ,Stereochemistry ,Pharmaceutical Science ,Cerasoidine ,Biology ,01 natural sciences ,Plant Roots ,Analytical Chemistry ,chemistry.chemical_compound ,Alkaloids ,Drug Discovery ,T Cell Transcription Factor 1 ,Humans ,Aporphine ,IC50 ,Nuclear Magnetic Resonance, Biomolecular ,beta Catenin ,Pharmacology ,Molecular Structure ,010405 organic chemistry ,Alkaloid ,Organic Chemistry ,Wnt signaling pathway ,Thailand ,0104 chemical sciences ,Chiral column chromatography ,Wnt Proteins ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,Biochemistry ,chemistry ,Polyalthia ,Molecular Medicine ,Polyalthia cerasoides - Abstract
A new bis-aporphine alkaloid, cerasoidine (1), was isolated from the root extract of Polyalthia cerasoides together with the known bis-aporphine bidebiline E (2) during screening for compounds with Wnt signal inhibitory activities. The structure of cerasoidine (1) was established by X-ray analysis and shown by chiral HPLC analyses and electronic circular dichroism to be a 57:43 mixture of R(-)- and S(+)-atropisomers. Bidebiline E (2) exhibited inhibition of transcriptional activity of TCF/β-catenin with an IC50 value of 20.2 μM and was also found to inhibit Wnt signaling by decreasing nuclear β-catenin.
- Published
- 2016
56. Valosin-containing Protein is a Target of 5'-l Fuligocandin B and Enhances TRAIL Resistance in Cancer Cells
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Kento Uchiyama, Shota Taguchi, Kazuhiro Komatsuzaki, Mamoru Satoh, Midori A. Arai, Sayaka Kado, Ayaka Masuda, Masami Ishibashi, and Mana Sampei
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0301 basic medicine ,Programmed cell death ,natural products ,Valosin-containing protein ,Biology ,01 natural sciences ,03 medical and health sciences ,target identification ,Full Paper ,010405 organic chemistry ,valosin-containing protein ,Endoplasmic reticulum ,Biological activity ,General Chemistry ,Full Papers ,Molecular biology ,AAA proteins ,TRAIL resistance ,0104 chemical sciences ,030104 developmental biology ,Biochemistry ,Cancer cell ,biology.protein ,endoplasmic reticulum stress ,Target protein ,Intracellular - Abstract
Fuligocandin B (2) is a novel natural product that can overcome TRAIL resistance. We synthesized enatiomerically pure fuligocandin B (2) and its derivative 5′‐I fuligocandin B (4), and found that the latter had an improved biological activity against the human gastric cancer cell line, AGS. We attached a biotin linker and photoactivatable aryl diazirine group to 5′‐I fuligocandin B (4), and employed a pull‐down assay to identify valosin‐containing protein (VCP/p97), an AAA ATPase, as a 5′‐I fuligocandin B (4) target protein. Knock‐down of VCP by siRNA enhanced sensitivity to TRAIL in AGS cells. In addition, 4 enhanced CHOP and DR5 protein expression, and overall intracellular levels of ubiquitinated protein. These data suggest that endoplasmic reticulum stress caused through VCP inhibition by 4 increases CHOP‐mediated DR5 up‐regulation, which enhances TRAIL‐induced cell death in AGS cells. To the best of our knowledge, this is the first example to show a relationship between VCP and TRAIL‐resistance‐overcoming activity in cancer cells.
- Published
- 2016
57. ChemInform Abstract: Bioactive Secondary Metabolites with Unique Aromatic and Heterocyclic Structures Obtained from Terrestrial Actinomycetes Species
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Masami Ishibashi, Midori A. Arai, and Mohamed S. Abdelfattah
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Biochemistry ,Chemistry ,Drug discovery ,Cellular pathways ,Wnt signaling pathway ,General Medicine - Abstract
Natural products from actinomycetes are important and valuable sources for drug discovery and the development of biological tools. The present review describes our recent study on the isolation of new natural products mainly possessing heterocyclic and aromatic ring structures with biological effects on cancer-related cellular pathways such as tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) and Wnt signaling.
- Published
- 2016
58. Stereochemical Assignment and Biological Evaluation of BE-14106 Unveils the Importance of One Acetate Unit for the Antifungal Activity of Polyene Macrolactams
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Shinichi Nishimura, Kohei Fujita, Masami Ishibashi, Ryosuke Sugiyama, Hideaki Kakeya, Naoki Ishikawa, and Midori A. Arai
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Antifungal Agents ,Lactams ,Stereochemistry ,Lactams, Macrocyclic ,Pharmaceutical Science ,Marine Biology ,010402 general chemistry ,01 natural sciences ,Analytical Chemistry ,Actinobacteria ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Schizosaccharomyces ,Structure–activity relationship ,Molecule ,Pharmacology ,chemistry.chemical_classification ,biology ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Biological activity ,biology.organism_classification ,Polyene ,Yeast ,0104 chemical sciences ,Anti-Bacterial Agents ,Hydrocarbon ,Complementary and alternative medicine ,chemistry ,Molecular Medicine ,Growth inhibition - Abstract
Heronamides are a class of potent antifungal metabolites produced by marine-derived actinomycetes. The number of hydroxy groups and the stereochemistry of the two hydroxylated methine carbons are important for the activity of heronamide C, whereas the effect of the hydrocarbon chains is not known. In this study, the stereochemistry and the biological activity of BE-14106, another member of the heronamide class of antibiotics, isolated from an actinomycete Actinoalloteichus cyanogriseus IFM 11549 was investigated. Spectroscopic analysis coupled with photo- and O2-induced conversion revealed that BE-14106 and the heronamides had the same stereochemistry. BE-14106 showed potent growth inhibition against fission yeast cells with an MIC value of 0.50 μM (0.21 μg/mL), being 4 times less potent than heronamide C, which revealed the importance of the structure of the hydrocarbon tail for the activity.
- Published
- 2016
59. Bioassay-Guided Isolation of Compounds from Datura stramonium with TRAIL-Resistance Overcoming Activity
- Author
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Utpal K, Karmakar, Kazufumi, Toume, Naoki, Ishikawa, Midori A, Arai, Samir K, Sadhu, Firoj, Ahmed, and Masami, Ishibashi
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TNF-Related Apoptosis-Inducing Ligand ,Datura stramonium ,Alkaloids ,Gene Expression Regulation ,Cell Survival ,Drug Resistance, Neoplasm ,Plant Extracts ,Humans ,Biological Assay ,Antineoplastic Agents, Phytogenic ,Cell Line - Abstract
TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids--scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 µM, respectively in TRAIL-resistant AGS cells.
- Published
- 2016
60. Synthesis of rocaglamide derivatives and evaluation of their Wnt signal inhibitory activities
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Utpal Kumar Karmakar, Kazuki Yamaku, Masami Ishibashi, Yuuki Tanaka, Rolly G. Fuentes, Midori A. Arai, Natsuki Yanase, and Yuuki Kofuji
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Models, Molecular ,Stereochemistry ,010402 general chemistry ,Inhibitory postsynaptic potential ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Rocaglamide ,Humans ,Physical and Theoretical Chemistry ,Benzofuran ,Wnt Signaling Pathway ,Benzofurans ,Flavonoids ,Biological Products ,Natural product ,Methyl cinnamate ,Cycloaddition Reaction ,010405 organic chemistry ,Organic Chemistry ,Wnt signaling pathway ,Total synthesis ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,Wnt Proteins ,HEK293 Cells ,chemistry ,Cinnamates - Abstract
Rocaglamides are bioactive natural compounds which have a cyclopenta[b]benzofuran core structure. The total synthesis of a reported natural product, 3′-hydroxymethylrocaglate (5), was achieved using [3 + 2] cycloaddition between 3-hydroxyflavone and methyl cinnamate. We also describe the synthesis of rocaglamide heterocycle derivatives and evaluate their Wnt signal inhibitory activities. Compounds 4, 5, 22a, 22b, 22c and 23c showed potent Wnt signal inhibitory activity.
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- 2016
61. Eudesmane-Type Sesquiterpenoid and Guaianolides from Kandelia candel in a Screening Program for Compounds to Overcome TRAIL Resistance
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Kazufumi Toume, Samir Kumar Sadhu, Firoj Ahmed, Midori A. Arai, Masami Ishibashi, and Tomohiro Minakawa
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Pharmacology ,Bangladesh ,Molecular Structure ,biology ,Traditional medicine ,Stereochemistry ,Organic Chemistry ,Pharmaceutical Science ,Kandelia candel ,Rhizophoraceae ,biology.organism_classification ,Analytical Chemistry ,Plant Leaves ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,Gastric adenocarcinoma ,Complementary and alternative medicine ,Stomach Neoplasms ,Drug Discovery ,Humans ,Sesquiterpenes, Eudesmane ,Molecular Medicine ,Trail resistance ,Nuclear Magnetic Resonance, Biomolecular - Abstract
In a screening program for natural products that can overcome TRAIL resistance, a new eudesmane-type sesquiterpenoid (1), three new guaianolides, mehirugins A-C (2-4), and two known guaianolides (5 and 6) were isolated from a MeOH extract of Kandelia candel leaves. Compounds 1 and 3-6 in combination with TRAIL showed cytotoxic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma cells.
- Published
- 2012
62. Mechanism of the anti-proliferative action of 25-hydroxy-19-nor-vitamin D3 in human prostate cells
- Author
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Toshiyuki Sakaki, Kaori Yasuda, Atsushi Kittaka, Masaki Kamakura, Tai C. Chen, Eiji Munetsuna, Midori A. Arai, Shinichi Ikushiro, Rie Kawanami, Miho Ohta, and Sachie Nakabayashi
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Reverse Transcriptase Polymerase Chain Reaction ,Blotting, Western ,Vitamin D3 24-Hydroxylase ,Calcitriol receptor ,Molecular biology ,Cell Line ,Hydroxylation ,Protein Transport ,chemistry.chemical_compound ,Transactivation ,Endocrinology ,Calcitriol ,chemistry ,CYP24A1 ,Steroid Hydroxylases ,Vitamin D and neurology ,Humans ,Receptors, Calcitriol ,RNA, Small Interfering ,Cholecalciferol ,Receptor ,Molecular Biology ,Cell Proliferation - Abstract
According to the prevailing paradigm, 1α-hydroxylation of 25-hydroxyvitamin D3 (25(OH)D3) and its analogs is a pre-requisite step for their biological effects. We previously reported that 25-hydroxy-19-nor-vitamin D3 (25(OH)-19-nor-D3) had anti-proliferative activity in a cell line, PZ-HPV-7, which was derived from human non-cancerous prostate tissue, and suggested that 25(OH)-19-nor-D3 acted after 1α-hydroxylation by vitamin D 1α-hydroxylase (CYP27B1). However, metabolic studies of 25(OH)-19-nor-D3 using recombinant CYP27B1 revealed that 25(OH)-19-nor-D3 was rarely subjected to 1α-hydroxylation. Therefore, in this report, we attempted to clarify the mechanism of 25(OH)-19-nor-D3 action in intact cells using PZ-HPV-7 prostate cells. After incubating the cells with 25(OH)-19-nor-D3, eight metabolites of 24-hydroxylase (CYP24A1) were detected, whereas no products of CYP27B1 including 1α,25-dihydroxy-19-nor-vitamin D3 (1α,25(OH)2-19-nor-D3) were found. Furthermore, the time-dependent nuclear translocation of vitamin D receptor (VDR) and the subsequent transactivation of cyp24A1 gene in the presence of 25(OH)-19-nor-D3 were almost identical as those induced by 1α,25(OH)2-19-nor-D3. These results strongly suggest that 25(OH)-19-nor-D3 directly binds to VDR as a ligand and transports VDR into the nucleus to induce transcription of cyp24A1 gene. In addition, knock down of cyp27B1 gene did not affect the anti-proliferative activity of 25(OH)-19-nor-D3, whereas knock down of VDR attenuated the inhibitory effect. Thus, our results clearly demonstrate that the anti-proliferative activity of 25(OH)-19-nor-D3 is VDR dependent but 1α-hydroxylation independent, suggesting that 25(OH)D3 analogs such as 25(OH)-19-nor-D3 could be attractive candidates for anticancer therapy.
- Published
- 2011
63. Cycloartane Triterpenes Isolated from Combretum quadrangulare in a Screening Program for Death-Receptor Expression Enhancing Activity
- Author
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Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi, Takashi Ohtsuki, Midori A. Arai, Takafumi Nakazawa, and Kazufumi Toume
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Receptor expression ,Pharmaceutical Science ,Pharmacognosy ,Analytical Chemistry ,Terpene ,Flavonols ,Triterpene ,Drug Discovery ,Combretum quadrangulare ,Pharmacology ,chemistry.chemical_classification ,Combretaceae ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Thailand ,biology.organism_classification ,Triterpenes ,Terpenoid ,Plant Leaves ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,Complementary and alternative medicine ,Biochemistry ,Combretum ,Molecular Medicine - Abstract
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.
- Published
- 2011
64. Approaches to Neural Stem Cells and Cancer Cells Based on Natural Products
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Midori A. Arai
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Homeodomain Proteins ,Biological Products ,Reporter gene ,Natural product ,Wnt signaling pathway ,Total synthesis ,General Chemistry ,General Medicine ,Small molecule ,Hedgehog signaling pathway ,Wnt Proteins ,chemistry.chemical_compound ,Neural Stem Cells ,chemistry ,Biochemistry ,Depsipeptides ,Drug Discovery ,Cancer cell ,Basic Helix-Loop-Helix Transcription Factors ,Neoplastic Stem Cells ,Humans ,Transcription Factor HES-1 ,Hedgehog Proteins ,Cytotoxicity ,Signal Transduction - Abstract
We have developed "protein- and cell-based screen methods" for the isolation of new natural products. By using VDR (vitamin D receptor) immobilized 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.
- Published
- 2011
65. New Hedgehog/GLI signaling inhibitors from Excoecaria agallocha
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Midori A. Arai, Samir Kumar Sadhu, Masami Ishibashi, Firoj Ahmed, and Yusnita Rifai
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Male ,Patched Receptors ,Transcriptional Activation ,Cell Survival ,Clinical Biochemistry ,Pharmaceutical Science ,Receptors, Cell Surface ,Excoecaria agallocha ,Zinc Finger Protein GLI1 ,Biochemistry ,GLI1 ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Humans ,Hedgehog Proteins ,Glycosides ,Molecular Biology ,Hedgehog ,Transcription factor ,Flavonoids ,integumentary system ,biology ,Chemistry ,Organic Chemistry ,Euphorbiaceae ,Prostatic Neoplasms ,biology.organism_classification ,Antineoplastic Agents, Phytogenic ,Hedgehog signaling pathway ,Cell biology ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Patched-1 Receptor ,biology.protein ,Molecular Medicine ,Signal transduction ,Smoothened ,Signal Transduction ,Transcription Factors - Abstract
The inhibition of the Hedgehog (Hh) signaling pathway has emerged as an anti-cancer strategy. Three flavonoid glycosides including 2 new compounds (1-2) were isolated from Excoecaria agallocha as Hedgehog/GLI1-mediated transcriptional inhibitors and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compound 1 clearly inhibited the expression of GLI-related proteins (PTCH and BCL-2) and blocked the translocation of GLI1 transcription factors into the nucleus in PANC1. Deleting the Smoothened (Smo) function in PANC1 treated with 1 led to downregulation of the mRNA expression of Ptch. This study describes the first Hh signaling inhibitor which blocks GLI1 movement into the nucleus without interfering with Smo.
- Published
- 2011
66. Practical Total Synthesis of Fuligocandins A and B
- Author
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Firoj Ahmed, Midori A. Arai, Junya Seto, Masami Ishibashi, and Kento Uchiyama
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Chemistry ,Stereochemistry ,Fuligo candida ,Organic Chemistry ,High selectivity ,Organic chemistry ,Total synthesis ,Meyer–Schuster rearrangement ,Optically active ,Optical rotation - Abstract
Fuligocandins A and B, cycloanthranilylproline derivatives isolated from the myxomycete Fuligo candida, were synthesized efficiently by a Meyer―Schuster rearrangement, which gave Z-isomer with high selectivity. The absolute stereochemistry at C-11a of the natural products was determined to be S by comparison of the optical rotation of the natural products with synthetic counterparts derived from L-proline. This report is the first total synthesis of optically active fuligocandin B.
- Published
- 2010
67. New Flavanol Dimers from the Bark of Celtis tetrandra and Their TRAIL Resistance-Overcoming Activity
- Author
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Thaworn Kowithayakorn, Prapairat Seephonkai, Masami Ishibashi, Ryusho Ishikawa, Midori A. Arai, and Takashi Koyano
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Pharmacology ,Traditional medicine ,010405 organic chemistry ,Chemistry ,Celtis tetrandra ,Catechin ,Plant Science ,General Medicine ,01 natural sciences ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Complementary and alternative medicine ,visual_art ,Drug Discovery ,visual_art.visual_art_medium ,Bark ,Trail resistance - Abstract
In the courses of our search for bioactive natural products on TRAIL resistance-overcoming activity, the active EtOAc extract from the bark of Celtis tetrandra was chemically investigated. The fractionation of the extract resulted in the isolation of flavanols; (+)-afzelechin (1), (-)- epiafzelechin (2), (-)-catechin (3), and two new flavanol dimers; (-)- epiafzelechin-(4α→8)-(-)-catechin (4) and (-)- epiafzelechin-(4α→8)-(-)- epicatechin (5). All isolated compounds 1-5 were tested for their TRAIL resistance-overcoming activity against AGS cells at the concentrations from 5–20 μM. It is likely that the flavanol dimers 4 and 5 exhibited weak activity in the range of the concentration of 10–20 μM as compared with the standard.
- Published
- 2018
68. A Method for the Rapid Discovery of Naturally Occurring Products by Proteins Immobilized on Magnetic Beads and Reverse Affinity Chromatography
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Eiji Kobatake, Shigeaki Kato, Thaworn Kowithayakorn, Midori A. Arai, Takashi Koyano, and Masami Ishibashi
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Specific protein ,Biological Products ,Chromatography ,Drug discovery ,Chemistry ,Organic Chemistry ,General Chemistry ,Ligand (biochemistry) ,Biochemistry ,Combinatorial chemistry ,High-performance liquid chromatography ,Chromatography, Affinity ,Magnetics ,Immobilized Proteins ,Affinity chromatography ,Screening method ,Immobilized proteins ,Target protein - Abstract
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 1alpha,25(OH)2 VD3 (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.
- Published
- 2009
69. The first Hes1 dimer inhibitors from natural products
- Author
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Masami Ishibashi, Ryoichiro Kageyama, Ayako Masada, Midori A. Arai, and Toshiyuki Ohtsuka
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Stereochemistry ,Dimer ,High-throughput screening ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Cell Line ,Mice ,chemistry.chemical_compound ,Drug Discovery ,Gene expression ,Basic Helix-Loop-Helix Transcription Factors ,Slime mold ,Animals ,Dicarboxylic Acids ,Myxomycetes ,Pyrroles ,Molecular Biology ,Homeodomain Proteins ,Biological Products ,biology ,Organic Chemistry ,Biological activity ,Mycetozoa ,biology.organism_classification ,Recombinant Proteins ,In vitro ,Quinone ,Immobilized Proteins ,chemistry ,embryonic structures ,Transcription Factor HES-1 ,Molecular Medicine ,Dimerization ,Naphthoquinones - Abstract
In the present study, we developed a high-throughput screening system for small molecule-inhibitors of the basic helix-loop-helix (bHLH) transcriptional repressor factor Hes1. Successful dimerization of Hes1 immobilized on a microplate and fluorophore (Cy3)-labelled Hes1 was confirmed. Using this system, several natural products were identified as the first Hes1 dimer inhibitors. Of these, two compounds which were isolated from myxomycetes (true slime molds) inhibited Hes1 from N box-dependent suppression of the gene expression in C3H10T1/2 cells.
- Published
- 2009
70. Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: interaction with a mutant vitamin D receptor Arg274Leu
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Shigeaki Kato, Shinobu Honzawa, Takayuki Sugiura, Naoyuki Takahashi, Atsushi Yamashita, Midori A. Arai, Masaaki Kurihara, and Atsushi Kittaka
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Vitamin ,Stereochemistry ,medicine.medical_treatment ,Organic Chemistry ,Mutant ,Ligand (biochemistry) ,Biochemistry ,Chemical synthesis ,Calcitriol receptor ,Steroid ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,polycyclic compounds ,Vitamin D and neurology ,medicine ,lipids (amino acids, peptides, and proteins) ,Stereoselectivity - Abstract
Vitamin D3 analogues have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D3 to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analogue, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 (4), from d -galactose was accomplished with the key steps of the introduction of the methyl and allyl groups to the chiral building blocks. The new analogue 4 is ca. 7.3-fold more active than the natural hormone 1α,25-dihydroxyvitamin D3 (1).
- Published
- 2009
71. Development of Chiral Spiro Ligands for Metal-Catalyzed Asymmetric Reactions
- Author
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Priti S. Koranne, Shinobu Takizawa, Takeyuki Suzuki, Gan B. Bajracharya, Hiroaki Sasai, and Midori A. Arai
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Metal ,Chemistry ,visual_art ,visual_art.visual_art_medium ,Organic chemistry ,General Chemistry ,Combinatorial chemistry ,Catalysis - Abstract
This account focuses our works on the development of chiral spiro ligands bearing N-heterocycles as metal-coordinating units and their applications in the metal-catalyzed asymmetric reactions. The ...
- Published
- 2009
72. Search for Bioactive Natural Products Targeting Cancer-Related Signaling Pathways
- Author
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Midori A. Arai and Masami Ishibashi
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Biological pathway ,Cell signaling ,Chemistry ,Organic Chemistry ,Wnt signaling pathway ,Screening programs ,medicine ,Cancer ,Computational biology ,Signal transduction ,medicine.disease ,Hedgehog ,Natural (archaeology) - Abstract
During our studies related to the search for bioactive natural products, we recently examined extracts of various natural resources including unexplored myxomycetes, marine organisms, as well as several medicinal plants collected in the north–eastern part of Thailand and Bangladesh. Here we describe our recent results from our screening programs targeting signaling molecules in cancer–related biological pathways such as TRAIL, Wnt, and Hedgehog signalings.
- Published
- 2009
73. The 2α-(3-hydroxypropyl) group as an active motif in vitamin D3 analogues as agonists of the mutant vitamin D receptor (Arg274Leu)
- Author
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Atsushi Yamashita, Masaaki Kurihara, Shigeaki Kato, Midori A. Arai, Yasuhiro Yamamoto, Shinobu Honzawa, Takayuki Sugiura, and Atsushi Kittaka
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Agonist ,Vitamin ,Transcription, Genetic ,medicine.drug_class ,Stereochemistry ,medicine.medical_treatment ,Clinical Biochemistry ,Mutant ,Mutation, Missense ,Pharmaceutical Science ,Biochemistry ,Calcitriol receptor ,Steroid ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Vitamin D and neurology ,Humans ,Moiety ,Molecular Biology ,Cholecalciferol ,Chemistry ,Organic Chemistry ,Nuclear receptor ,Drug Design ,Receptors, Calcitriol ,Molecular Medicine ,Mutant Proteins - Abstract
We designed and synthesized 1alpha- and 1beta-hydroxymethyl-2alpha-(3-hydroxypropyl)-25-hydroxyvitamin D(3) (2a,b) and related analogues 2alpha-(3-hydroxypropyl)-25-hydroxyvitamin D(3) (3), Posner's analogues of 1alpha- and 1beta-hydroxymethyl-25-hydroxyvitamin D(3) (4a,b), as well as 2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D(3) (5), to confirm the effect of the 1alpha-hydroxy group and/or 2alpha-(3-hydroxypropyl) group of vitamin D(3) analogues with the modified A-ring moiety on the mutant vitamin D receptor, VDR(Arg274Leu). The 2alpha-(3-hydroxypropyl) group showed better effect on enhancement of the transcriptional activity through the mutant VDR than the 1alpha- and 1beta-hydroxymethyl groups.
- Published
- 2008
74. Determination of absolute stereochemistry, total synthesis, and evaluation of peptides from the myxomycete Physarum melleum
- Author
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Shuwa Hanazawa, Xiaofan Li, Masami Ishibashi, and Midori A. Arai
- Subjects
Protein Conformation ,Stereochemistry ,Clinical Biochemistry ,Protozoan Proteins ,Pharmaceutical Science ,Peptide ,Biochemistry ,Physarum ,chemistry.chemical_compound ,Depsipeptides ,Drug Discovery ,Animals ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,Chromatography, High Pressure Liquid ,chemistry.chemical_classification ,Chemistry ,Organic Chemistry ,Wnt signaling pathway ,Absolute configuration ,Total synthesis ,Stereoisomerism ,Biological activity ,Wnt Proteins ,Lactam ,Molecular Medicine ,Stereoselectivity ,Lactone ,Signal Transduction - Abstract
The absolute stereochemistry of melleumin A (1) and B (2), novel peptide compounds isolated from the myxomycete Physarum melleum, was determined by synthesis of their segments and by a modified Mosher's method. Total synthesis of melleumin B (2) was achieved by a stereoselective method, which provided further evidence for all the absolute stereochemistries of melleumin B (2). The Wnt signal inhibitory activities of 2 and its 10R-epimer 19 were evaluated. Compound 19 showed moderate inhibition of Wnt signal transcription, which suggests that melleumin analogues might be useful as Wnt signal inhibitors.
- Published
- 2008
75. Synthesis, determination of stereochemistry, and evaluation of new bisindole alkaloids from the myxomycete Arcyria ferruginea: An approach for Wnt signal inhibitor
- Author
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Xiaofan Li, Midori A. Arai, Kouken Kaniwa, and Masami Ishibashi
- Subjects
Arcyria ferruginea ,Arcyria ,Stereochemistry ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Stereoisomerism ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Alkaloids ,Arcyriaflavin C ,Transcription (biology) ,Drug Discovery ,Animals ,Myxomycetes ,Molecular Biology ,Natural product ,biology ,Alkaloid ,Organic Chemistry ,Wnt signaling pathway ,Biological activity ,General Medicine ,biology.organism_classification ,Small molecule ,Wnt Proteins ,chemistry ,Molecular Medicine ,Signal Transduction - Abstract
To determine the stereochemistry of dihydroarcyriarubin C (1), new bisindole alkaloid isolated from the myxomycete Arcyria ferruginea, cis- (2) and trans-dihydroarcyriarubin C (3) were synthesized. Comparison of their NMR characteristics allowed the trans stereochemistry of the natural product to be confirmed. Moreover, the Wnt signal inhibitory activities of 2 and 3 were compared with that of arcyriaflavin C (4), which is a natural product containing a bond between C-2 and C-2'. The cis-dihydroarcyriarubin C (2) showed moderate inhibition of Wnt signal transcription, which suggests that bisindole frameworks might be useful as small-molecule Wnt signal inhibitors.
- Published
- 2007
76. Kinetic Studies of 25-Hydroxy-19-nor-vitamin D3 and 1α,25-Dihydroxy-19-nor-vitamin D3 Hydroxylation by CYP27B1 and CYP24A1
- Author
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Midori A. Arai, Naoko Urushino, Keiko Yamamoto, Masaki Kamakura, Sachie Nakabayashi, Shinichi Ikushiro, Miho Ohta, Toshiyuki Sakaki, Keiko Hayashi, Atsushi Kittaka, Tai C. Chen, and Shigeaki Kato
- Subjects
Male ,Models, Molecular ,Vitamin ,Stereochemistry ,Metabolite ,Kinetics ,Pharmaceutical Science ,Alpha (ethology) ,Thymus Gland ,Hydroxylation ,Calcitriol receptor ,Cell Line ,chemistry.chemical_compound ,Calcitriol ,Cytochrome P-450 Enzyme System ,CYP24A1 ,Escherichia coli ,Animals ,Humans ,Vitamin D3 24-Hydroxylase ,Chromatography, High Pressure Liquid ,Cell Proliferation ,Cholecalciferol ,25-Hydroxyvitamin D3 1-alpha-Hydroxylase ,Pharmacology ,Carbon Monoxide ,Prostate ,In vitro ,chemistry ,Steroid Hydroxylases ,Cattle ,Plasmids - Abstract
Our previous study demonstrated that 25-hydroxy-19-nor-vitamin D(3) [25(OH)-19-nor-D(3)] inhibited the proliferation of immortalized noncancerous PZ-HPV-7 prostate cells similar to 1 alpha,25-dihydroxyvitamin D(3) [1 alpha,25(OH)(2)D(3)], suggesting that 25(OH)-19-nor-D(3) might be converted to 1 alpha,25-dihydroxy-19-nor-vitamin D(3) [1 alpha,25(OH)(2)-19-nor-D(3)] by CYP27B1 before exerting its antiproliferative activity. Using an in vitro cell-free model to study the kinetics of CYP27B1-dependent 1 alpha-hydroxylation of 25(OH)-19-nor-D(3) and 25-hydroxyvitamin D(3) [25(OH)D(3)] and CYP24A1-dependent hydroxylation of 1 alpha,25(OH)-19-nor-D(3) and 1 alpha,25(OH)(2)D(3), we found that k(cat)/K(m) for 1 alpha-hydroxylation of 25(OH)-19-nor-D(3) was less than 0.1% of that for 25(OH)D(3), and the k(cat)/K(m) value for 24-hydroxylation was not significantly different between 1 alpha,25(OH)(2)-19-nor-D(3) and 1 alpha,25(OH)(2)D(3). The data suggest a much slower formation and a similar rate of degradation of 1 alpha,25(OH)(2)-19-nor-D(3) compared with 1 alpha,25(OH)(2)D(3). We then analyzed the metabolites of 25(OH)D(3) and 25(OH)-19-nor-D(3) in PZ-HPV-7 cells by high-performance liquid chromatography. We found that a peak that comigrated with 1 alpha,25(OH)(2)D(3) was detected in cells incubated with 25(OH)D(3), whereas no 1 alpha,25(OH)(2)-19-nor-D(3) was detected in cells incubated with 25(OH)-19-nor-D(3). Thus, the present results do not support our previous hypothesis that 25(OH)-19-nor-D(3) is converted to 1 alpha,25(OH)(2)-19-nor-D(3) by CYP27B1 in prostate cells to inhibit cell proliferation. We hypothesize that 25(OH)-19-nor-D(3) by itself may have a novel mechanism to activate vitamin D receptor or it is metabolized in prostate cells to an unknown metabolite with antiproliferative activity without 1 alpha-hydroxylation. Thus, the results suggest that 25(OH)-19-nor-D(3) has potential as an attractive agent for prostate cancer therapy.
- Published
- 2007
77. Design and synthesis of chiral hybrid spiro (isoxazole–isoxazoline) ligands
- Author
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Kiyotaka Onitsuka, Takeyuki Suzuki, Priti S. Koranne, Tetsuya Tsujihara, Hiroaki Sasai, Gan B. Bajracharya, and Midori A. Arai
- Subjects
Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Tandem ,Stereochemistry ,Organic Chemistry ,Enantioselective synthesis ,Alcohol ,Decane ,Physical and Theoretical Chemistry ,Isoxazole ,Catalysis - Abstract
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.
- Published
- 2007
78. High-Throughput System for Analyzing Ligand-Induced Cofactor Recruitment by Vitamin D Receptor
- Author
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Ken-ichi Takeyama, Midori A. Arai, Shigeaki Kato, Tai C. Chen, Atsushi Kittaka, and Saya Ito
- Subjects
Vitamin ,VDR binding ,Drug Evaluation, Preclinical ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Ligands ,Calcitriol receptor ,Cofactor ,Nuclear Receptor Coactivator 2 ,chemistry.chemical_compound ,Nuclear Receptor Coactivator 1 ,Cell Line, Tumor ,Formaldehyde ,Coactivator ,Vitamin D and neurology ,Humans ,Coenzyme A ,Vitamin D ,Histone Acetyltransferases ,Pharmacology ,biology ,Chemistry ,Organic Chemistry ,Biological activity ,Carbocyanines ,Ligand (biochemistry) ,Biochemistry ,biology.protein ,Receptors, Calcitriol ,Transcription Factors ,Biotechnology - Abstract
A high-throughput screening system for analyzing small molecule-induced coactivator (CoA) recruitment by the vitamin D receptor (VDR) has been developed. The vitamin D-induced protein-protein interactions between VDR and fluorophore (Cy3 or Cy5)-labeled TIF2 or SRC-1 were successfully detected by using a new HCHO fixing method of the protein complex on microplates. The results obtained from this screening of our synthetic vitamin D analogues suggest that the CoA-recruiting activities play an important role in determining the biological activity of various vitamin D analogues and explain the discrepancies between the VDR binding affinity and their biological activity.
- Published
- 2007
79. Natural compounds with Wnt signal modulating activity
- Author
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Midori A. Arai, Masami Ishibashi, and Rolly G. Fuentes
- Subjects
Biological Products ,Molecular Structure ,Organic Chemistry ,Wnt signaling pathway ,LRP6 ,Wnt signalling ,Neurodegenerative Diseases ,Biology ,biology.organism_classification ,Biochemistry ,Signal ,Cell biology ,Wnt Proteins ,Mechanism of action ,Neoplasms ,Drug Discovery ,medicine ,Animals ,Humans ,medicine.symptom ,Signal transduction ,Zebrafish ,Wnt Signaling Pathway ,Signal Transduction - Abstract
Covering: up to 2015 The Wnt signalling pathway is essential in many biological processes. The Wnt signal is associated with several diseases, particularly cancer and neurodegenerative diseases. Recently, high-throughput screening systems have been developed to rapidly identify compounds, including natural compounds, that target the Wnt signal. Some studies on natural modulators of the Wnt signal have also suggested their possible target. This review highlights some important natural compounds reported to regulate Wnt activity and describes their possible mechanism of action.
- Published
- 2015
80. Hedgehog inhibitors from Artocarpus communis and Hyptis suaveolens
- Author
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Masami Ishibashi, Takashi Koyano, Samir Kumar Sadhu, Thaworn Kowithayakorn, Firoj Ahmed, Midori A. Arai, and Kyoko Uchida
- Subjects
Magnetic Resonance Spectroscopy ,Clinical Biochemistry ,Cell ,Pharmaceutical Science ,Electrophoretic Mobility Shift Assay ,Biochemistry ,Zinc Finger Protein GLI1 ,Artocarpus ,Inhibitory Concentration 50 ,GLI1 ,Cell Line, Tumor ,Drug Discovery ,Hyptis suaveolens ,medicine ,Humans ,Hedgehog Proteins ,Cytotoxicity ,Molecular Biology ,Hedgehog ,Biological Products ,biology ,Molecular Structure ,Chemistry ,Organic Chemistry ,Embryogenesis ,DNA ,biology.organism_classification ,Antineoplastic Agents, Phytogenic ,medicine.anatomical_structure ,biology.protein ,Molecular Medicine ,Hyptis ,Signal transduction ,Drug Screening Assays, Antitumor ,Signal Transduction ,Transcription Factors - Abstract
The hedgehog (Hh) signaling pathway plays crucial roles in cell maintenance and proliferation during embryonic development. Naturally occurring Hh inhibitors were isolated from Artocarpus communis and Hyptis suaveolens using our previously constructed cell-based assay system. Bioactivity guided fractionation led to the isolation of 15 compounds, including seven new compounds ( 4 , 5 , 6 , 7 , and 9 – 11 ). The isolated compounds showed cytotoxicity against a cancer cell line (PANC1) in which Hh signaling was abnormally activated. Several compounds ( 12 – 14 ; GLI1 transcriptional inhibition IC 50 = 7.6, 4.7, and 4.0 μM, respectively) inhibited Hh related protein (BCL2) expression. Moreover, compounds 1 , 12 , and 13 disrupted GLI1 and DNA complex formation.
- Published
- 2015
81. Phenolic compounds from the bark of Oroxylum indicum activate the Ngn2 promoter
- Author
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Midori A. Arai, Rolly G. Fuentes, Samir Kumar Sadhu, Firoj Ahmed, and Masami Ishibashi
- Subjects
biology ,Molecular Structure ,Plant Extracts ,Nerve Tissue Proteins ,biology.organism_classification ,Oroxylum indicum ,Molecular biology ,Baicalein ,chemistry.chemical_compound ,chemistry ,Phenols ,Apigenin ,Basic Helix-Loop-Helix Transcription Factors ,Molecular Medicine ,Oroxylin A ,Hispidulin ,Chrysin ,Transcription factor ,Baicalin ,Transcription Factors - Abstract
A reporter gene assay that detects neurogenin 2 (Ngn2) promoter activity was utilized to identify compounds that induce neuronal differentiation. Ngn2 is a basic helix-loop-helix transcription factor that activates transcription of pro-neural genes. Using this assay system and an activity-guided approach, seven phenolic compounds were isolated from the methanol extract of Oroxylum indicum: 1 oroxylin A, 2 chrysin, 3 hispidulin, 4 baicalein, 5 apigenin, 6 baicalin, and 7 isoverbascoside. Compounds 1 and 2 induced an estimated 2.7-fold increase in Ngn2 promoter activity, whereas 3 increased the activity by 2.5-fold. Furthermore, 1 and 2 enhanced neuronal differentiation of C17.2 cells, which are multipotent stem cells.
- Published
- 2015
82. Prenylated flavonoids and resveratrol derivatives isolated from Artocarpus communis with the ability to overcome TRAIL resistance
- Author
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Takashi Koyano, Thaworn Kowithayakorn, Kazufumi Toume, Midori A. Arai, Masami Ishibashi, and Tadashi Habu
- Subjects
Flavonoid ,Pharmaceutical Science ,Caspase 3 ,Apoptosis ,Resveratrol ,Biology ,Analytical Chemistry ,TNF-Related Apoptosis-Inducing Ligand ,chemistry.chemical_compound ,Artocarpus ,Drug Discovery ,Stilbenes ,Humans ,Viability assay ,Nuclear Magnetic Resonance, Biomolecular ,Pharmacology ,chemistry.chemical_classification ,Flavonoids ,Reactive oxygen species ,Molecular Structure ,Organic Chemistry ,biology.organism_classification ,Molecular biology ,Complementary and alternative medicine ,Biochemistry ,chemistry ,Molecular Medicine ,Tumor necrosis factor alpha ,Tumor Suppressor Protein p53 ,Reactive Oxygen Species - Abstract
In a screening program on natural products that can abrogate tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance, four new prenylated flavonoid and resveratrol derivatives (1-4) were isolated from Artocarpus communis, together with eight known prenylflavonoids (5-12). The structures of 1-4 were elucidated spectroscopically. Pannokin D [corrected] (1) (2 μM) and artonin E (5) (3 μM) potently exhibited the ability to overcome TRAIL resistance. Artonin E (5) induced caspase-dependent apoptosis in combination with TRAIL, increased caspase 3/7 activity, and enhanced the protein levels of p53 and DR5. Moreover, this substance decreased cell viability in combination with TRAIL and enhanced the protein levels of DR5, and these effects were mediated by increases in the production of ROS (reactive oxygen species). Thus, artonin E (5) was found to induce extrinsic apoptotic cell death by the ROS- and p53-mediated up-regulation of DR5 expression in AGS cells.
- Published
- 2014
83. 3',6-dimethoxy-3',4'-methylenedioxy-2,5-epoxylignan-4'-ol Inhibited Glioma-Associated Oncogene
- Author
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Yusnita Rifai, Midori A. Arai, and Masami Ishibashi
- Subjects
animal structures ,Oncogene ,RNA ,Chromosomal translocation ,Biology ,Bioinformatics ,Molecular biology ,Methylenedioxy ,Hedgehog Signaling, GLI, Smo, PANC1, mRNA expression, Ptch ,chemistry.chemical_compound ,chemistry ,embryonic structures ,Signal transduction ,Smoothened ,Transcription factor ,Hedgehog - Abstract
Aberrant activation of Hedgehog (Hh) signaling pathway has been linked to the development of cancers. A naturally occurring Hedgehog inhibitor, 3',6-dimethoxy-3'',4''-(methylenedioxy)-2,5-epoxylignan-4'-ol (DMEO), isolated from Piper nigrum, exhibited selective cytotoxicity against human pancreatic (PANC1) with no toxic effect on normal cells. This compound blocked the translocation of GLI transcription factors into the nucleus in PANC1. RNA interferences of the Smoothened (Smo) function in PANC1 treated with the compound downregulated the mRNA expression of Ptch. Key Words : Hedgehog Signaling, GLI, Smo, PANC1, mRNA expression, Ptch
- Published
- 2014
84. Design and Synthesis of Oligosaccharides that Interfere with Glycoprotein Quality-control systems
- Author
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Shinya Hagihara, Katsuhiko Kitamoto, Kiichiro Totani, Jun-ichi Maruyama, Midori A. Arai, Yukishige Ito, and Ichiro Matsuo
- Subjects
Protein Folding ,Calnexin ,Oligosaccharides ,Endoplasmic Reticulum ,Biochemistry ,Malate dehydrogenase ,Humans ,Tetrasaccharide ,Molecular Biology ,Glycoproteins ,chemistry.chemical_classification ,biology ,Endoplasmic reticulum ,Organic Chemistry ,Isothermal titration calorimetry ,chemistry ,Drug Design ,Chaperone (protein) ,biology.protein ,Molecular Medicine ,Calreticulin ,Glycoprotein ,Molecular Chaperones - Abstract
Calnexin (CNX) and its soluble homologue calreticulin (CRT) are lectin-like molecular chaperones that help newly synthesized glycoproteins to fold correctly in the rough endoplasmic reticulum (ER). To investigate the mechanism of glycoprotein-quality control, we have synthesized structurally defined high-mannose-type oligosaccharides related to this system. This paper describes the synthesis of the non-natural undecasaccharide 2 and heptasaccharide 16, designed as potential inhibitors of the ER quality-control system. Each possesses the key tetrasaccharide element (Glc1Man3) critical for the CNX/CRT binding, while lacking the pentamannosyl branch required for glucosidase II recognition. These oligosaccharides were evaluated for their ability to bind CRT by isothermal titration calorimetry (ITC). As expected, each of them had a significant affinity towards CRT. In addition, these compounds were shown to be resistant to glucosidase II digestion. Their activities in blocking the chaperone function of CRT were next measured by using malate dehydrogenase (MDH) as a substrate. Their inhibitory effects were shown to correlate well with their CRT-binding affinities, both being critically dependent upon the presence of the terminal glucose (Glc) residue.
- Published
- 2005
85. Relationship of Stereochemical and Skeletal Diversity of Small Molecules to Cellular Measurement Space
- Author
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Takayoshi Arai, Midori A. Arai, Stuart L. Schreiber, Paul A. Clemons, Young Kwon Kim, Elton F. Dean, Julia O. Lamenzo, and Nick Patterson
- Subjects
Stereochemistry ,Ring number ,Drug Evaluation, Preclinical ,Stereoisomerism ,Metathesis ,Biochemistry ,Catalysis ,Membrane Potentials ,Structure-Activity Relationship ,Colloid and Surface Chemistry ,Animals ,Cluster Analysis ,Combinatorial Chemistry Techniques ,Structure–activity relationship ,Bicyclic molecule ,Chemistry ,Esterases ,Dominant factor ,Biological activity ,DNA ,Intracellular Membranes ,General Chemistry ,Bridged Bicyclo Compounds, Heterocyclic ,Small molecule ,Mitochondria - Abstract
Systematic and quantitative measurements of the roles of stereochemistry and skeleton-dependent conformational restriction were made using multidimensional screening. We first used diversity-oriented synthesis to synthesize the same number (122) of [10.4.0] bicyclic products (B) and their corresponding monocyclic precursors (M). We measured the ability of these compounds to modulate a broad swath of biology using 40 parallel cell-based assays. We analyzed the results using statistical methods that revealed illuminating relationships between stereochemistry, ring number, and assay outcomes. Conformational restriction by ring-closing metathesis increased the specificity of responses among active compounds and was the dominant factor in global activity patterns. Hierarchical clustering also revealed that stereochemistry was a second dominant factor; whereas the stereochemistry of macrocyclic appendages was a determinant for bicyclic compounds, the stereochemistry of the carbohydrates was a determinant for the monocyclic compounds of global activity patterns. These studies illustrate a quantitative method for measuring stereochemical and skeletal diversity of small molecules and their cellular consequences.
- Published
- 2004
86. Synthesis of fluorine substituted oligosaccharide analogues of monoglucosylated glycan chain, a proposed ligand of lectin-chaperone calreticulin and calnexin
- Author
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Maki Takatani, Ichiro Matsuo, Midori A. Arai, Shinya Hagihara, and Yukishige Ito
- Subjects
Glycan ,Calnexin ,Recombinant Fusion Proteins ,Molecular Sequence Data ,Disaccharide ,Oligosaccharides ,Calorimetry ,Ligands ,Biochemistry ,chemistry.chemical_compound ,Lectins ,Humans ,Tetrasaccharide ,Molecular Biology ,chemistry.chemical_classification ,biology ,Endoplasmic reticulum ,Isothermal titration calorimetry ,Fluorine ,Cell Biology ,Oligosaccharide ,Carbohydrate Sequence ,chemistry ,biology.protein ,Calreticulin ,Molecular Chaperones - Abstract
As a part of a exploring the N-glycan-mediated glycoprotein quality control in endoplasmic reticulum, 2-fluorinated derivative Glcalpha1 --> 3Man(F) 1, Glcalpha1 --> 3Man(F)alpha1 --> 2Man2, and Glcalpha1 --> 3Man(F)alpha1 --> 2Manalpha1 --> 2Man 3 were synthesized in a concise manner. These oligosaccharides were subjected to binding studies with calreticulin by using isothermal titration calorimetry. It was revealed that disaccharide 1 was a poor ligand, while tri- (2) and tetrasaccharide (3) had observable affinity.
- Published
- 2004
87. Katorazone, a new yellow pigment with a 2-azaquinone-phenylhydrazone structure produced by Streptomyces sp. IFM 11299
- Author
-
Masami Ishibashi, Kazufumi Toume, Midori A. Arai, Hyuma Masu, and Mohamed S. Abdelfattah
- Subjects
biology ,Chemistry ,Stereochemistry ,Chemical structure ,Alkaloid ,Organic Chemistry ,Ethyl acetate ,biology.organism_classification ,Mass spectrometry ,Biochemistry ,Streptomyces ,Pigment ,chemistry.chemical_compound ,Gastric adenocarcinoma ,visual_art ,Drug Discovery ,visual_art.visual_art_medium ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
An unusual alkaloid with a 2-azaquinone-phenylhydrazone structure, katorazone ( 1 ), and other metabolites were isolated from the ethyl acetate extract of Streptomyces sp. IFM 11299. The chemical structure of katorazone ( 1 ) was elucidated by 1D and 2D NMR analyses together with HR-ESI mass spectrometry. Katorazone ( 1 ) showed a synergistic effect in combination with TRAIL and decreased the viability of human gastric adenocarcinoma (AGS) cells.
- Published
- 2012
88. Synthesis of new chiral bis(isoxazoline) ligands containing spiro[5.5]undecane skeleton
- Author
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Hiroaki Sasai, Minori Kuraishi, Midori A. Arai, and Takayoshi Arai
- Subjects
Pharmacology ,Stereochemistry ,Organic Chemistry ,Chiral ligand ,Catalysis ,Analytical Chemistry ,Diethyl malonate ,chemistry.chemical_compound ,chemistry ,Yield (chemistry) ,Drug Discovery ,Michael reaction ,Undecane ,Spectroscopy ,Conjugate - Abstract
New chiral bis(isoxazoline) ligands bearing a spiro[5.5]undecane skeleton were designed and synthesized in five steps from diethyl malonate (3). These ligands showed a coordinating ability to Cu(II) as chiral ligands. A complex of (+)-(M*,S*,R*)-[5.5]-SPRIX 2b and Cu(OTf)(2) catalyzed the conjugate addition of diethyl-zinc to 2-cyclohexenone (8) to give (S)-3-ethyl-cyclohexanone (9) in 93% yield with 54% ee.
- Published
- 2002
89. Germacranolides from Enhydra fluctuans with TRAIL-resistance Abrogating Activity
- Author
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Masami Ishibashi, Naoki Ishikawa, Midori A. Arai, Samir Kumar Sadhu, Firoj Ahmed, and Utpal Kumar Karmakar
- Subjects
0301 basic medicine ,Pharmacology ,Plant Science ,General Medicine ,Biology ,Enhydra fluctuans ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Complementary and alternative medicine ,030220 oncology & carcinogenesis ,Drug Discovery ,Cancer cell ,Cancer research ,Trail resistance - Abstract
TRAIL selectively kills cancer cells without harming most normal cells. However, TRAIL resistance is a major problem for its therapeutic use. Developing a strategy to overcome resistance is crucial for the successful use of TRAIL as an antitumor agent. In our screening program of natural products that can abrogate TRAIL resistance, four germacranolides (1–4) were isolated from the aerial parts of Enhydra fluctuans. All compounds exhibited potent TRAIL-resistance overcoming activity against TRAIL-resistant human gastric adenocarcinoma (AGS) cells.
- Published
- 2017
90. Isolation and Evaluation of Hedgehog Inhibitors from Christmas Grass (Themeda arguens)
- Author
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Thaworn Kowithayakorn, Takashi Koyano, Midori A. Arai, Masami Ishibashi, and Tatsuro Yoneyama
- Subjects
Pharmacology ,Isolation (health care) ,Themeda ,biology ,Chemistry ,Organic Chemistry ,Botany ,biology.organism_classification ,Hedgehog ,Analytical Chemistry - Published
- 2017
91. ChemInform Abstract: Calotropin: A Cardenolide from Calotropis gigantea that Inhibits Wnt Signaling by Increasing Casein Kinase 1α in Colon Cancer Cells
- Author
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Masami Ishibashi, Samir Kumar Sadhu, Hyun Young Park, Midori A. Arai, Firoj Ahmed, and Kazufumi Toume
- Subjects
biology ,Chemistry ,Colorectal cancer ,Wnt signaling pathway ,General Medicine ,biology.organism_classification ,medicine.disease ,Calotropin ,Cell biology ,chemistry.chemical_compound ,medicine ,Cardenolide ,Casein kinase 1 ,Calotropis gigantea - Abstract
Calotropin exhibits the highest inhibition of the Wnt signaling pathway in comparison to five other isolated cardenolides.
- Published
- 2014
92. 2-Methoxy-1,4-naphthoquinone isolated from Impatiens balsamina in a screening program for activity to inhibit Wnt signaling
- Author
-
Naomi Mori, Masami Ishibashi, Takashi Koyano, Kazufumi Toume, Midori A. Arai, and Thaworn Kowithayakorn
- Subjects
Magnetic Resonance Spectroscopy ,Beta-catenin ,Stereochemistry ,1,4-Naphthoquinone ,Cell Line ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Humans ,Luciferase ,beta Catenin ,Molecular Structure ,biology ,Wnt signaling pathway ,biology.organism_classification ,Molecular biology ,Naphthoquinone ,Wnt Proteins ,chemistry ,Cell culture ,biology.protein ,Molecular Medicine ,Impatiens ,Signal transduction ,Naphthoquinones ,Signal Transduction - Abstract
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/β-catenin (TOP) transcriptional activity (IC(50) 2.9 µM), while it decreased the transcriptional activity of FOP (mutated TCF-binding site)-transfected cells at >5 µM.
- Published
- 2010
93. Terpenoids and a Flavonoid Glycoside from Acacia pennata Leaves as Hedgehog/GLI-Mediated Transcriptional Inhibitors
- Author
-
Midori A. Arai, Masami Ishibashi, Yusnita Rifai, Takashi Koyano, and Thaworn Kowithayakorn
- Subjects
Male ,Patched ,Molecular Sequence Data ,Pharmaceutical Science ,Zinc Finger Protein GLI1 ,Analytical Chemistry ,DU145 ,GLI1 ,Drug Discovery ,Gene expression ,Humans ,Hedgehog Proteins ,Glycosides ,Hedgehog ,Pharmacology ,Base Sequence ,integumentary system ,biology ,Oncogene ,Terpenes ,Organic Chemistry ,Acacia ,Thailand ,Antineoplastic Agents, Phytogenic ,Molecular biology ,Plant Leaves ,HaCaT ,Complementary and alternative medicine ,Biochemistry ,Cancer cell ,biology.protein ,Molecular Medicine ,Quercetin ,Drug Screening Assays, Antitumor ,Signal Transduction ,Transcription Factors - Abstract
Overexpression of glioma-associated oncogene 1 (GLI1), which has been characterized as a terminal effector and a target gene of the Hedgehog (Hh) signaling pathway, is associated with the development of cancer. A cellular screen was applied utilizing of a GLI-dependent luciferase reporter in human keratinocyte cells (HaCaT) and identified two terpenoids (1 and 2) and a flavonoid glycoside (5) from Acacia pennata as Hh/GLI inhibitors. Compounds 1, 2, and 5 exhibited selective cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells with no toxic effect on normal cells. This result was consistent with a dose-dependent reduction of the protein levels of antiapoptotic BCL-2 and the tumor suppressor patched 1 protein (PTCH). Additionally, treatment of 1 downregulated mRNA expression of Ptch in PANC1, suggesting that the compound has an inhibitory effect on the transcription of Hh/GLI.
- Published
- 2010
94. Xylogranin B: a potent Wnt signal inhibitory limonoid from Xylocarpus granatum
- Author
-
Kentaro Kamiya, Samir Kumar Sadhu, Naomi Mori, Midori A. Arai, Masami Ishibashi, Firoj Ahmed, and Kazufumi Toume
- Subjects
Limonins ,Stereochemistry ,Cell ,Limonoid ,Biochemistry ,Xylocarpus granatum ,medicine ,Humans ,Luciferase ,Physical and Theoretical Chemistry ,Meliaceae ,Cytotoxicity ,Furans ,Luciferases ,IC50 ,Wnt Signaling Pathway ,beta Catenin ,biology ,Molecular Structure ,Chemistry ,Organic Chemistry ,Wnt signaling pathway ,biology.organism_classification ,HCT116 Cells ,Molecular biology ,Triterpenes ,Plant Leaves ,Cytosol ,medicine.anatomical_structure ,Colonic Neoplasms ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
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.
- Published
- 2013
95. Physalin H from Solanum nigrum as an Hh signaling inhibitor blocks GLI1-DNA-complex formation
- Author
-
Kyoko Uchida, Midori A. Arai, Firoj Ahmed, Masami Ishibashi, and Samir Kumar Sadhu
- Subjects
Patched ,genetic structures ,natural products ,Hedgehog signal ,Cell ,behavioral disciplines and activities ,Full Research Paper ,lcsh:QD241-441 ,lcsh:Organic chemistry ,GLI1 ,Hedgehog inhibitor ,medicine ,lcsh:Science ,Cytotoxicity ,Hedgehog ,physalins ,Solanum nigrum ,biology ,Cell growth ,Chemistry ,business.industry ,Organic Chemistry ,DNA-binding domain ,Cell biology ,Biotechnology ,medicine.anatomical_structure ,nervous system ,Cancer cell ,biology.protein ,lcsh:Q ,business ,psychological phenomena and processes - Abstract
Hedgehog (Hh) signaling plays an important role in embryonic development, cell maintenance and cell proliferation. Moreover, Hh signaling contributes to the growth of cancer cells. Physalins are highly oxidized natural products with a complex structure. Physalins (1–7) were isolated from Solanum nigrum (Solanaceae) collected in Bangladesh by using our cell-based assay. The isolated physalins included the previously reported Hh inhibitors 5 and 6. Compounds 1 and 4 showed strong inhibition of GLI1 transcriptional activity, and exhibited cytotoxicity against cancer cell lines with an aberrant activation of Hh signaling. Compound 1 inhibited the production of the Hh-related proteins patched (PTCH) and BCL2. Analysis of the structures of different physalins showed that the left part of the physalins was important for Hh inhibitory activity. Interestingly, physalin H (1) disrupted GLI1 binding to its DNA binding domain, while the weak inhibitor physalin G (2) did not show inhibition of GLI1-DNA complex formation.
- Published
- 2013
96. ChemInform Abstract: Catalytic Asymmetric Synthesis of Mixed 3,3′-Bisindoles and Their Evaluation as Wnt Signaling Inhibitors
- Author
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Kentaro Kamiya, Masami Ishibashi, Takayoshi Arai, Yushi Yamamoto, Atsuko Awata, and Midori A. Arai
- Subjects
Indole test ,Stereochemistry ,Chemistry ,Enantioselective synthesis ,Wnt signaling pathway ,General Medicine ,Catalysis - Abstract
Friedel—Crafts reaction of isatin-derived nitroalkenes with indoles in the presence of either Cu(O-Tf)2 [conditions A)] or CuOTf [conditions B)] yields 3,3′-bisindoles which represent the skeleton of various indole alkaloids.
- Published
- 2013
97. β-Sitosterol and flavonoids isolated from Bauhinia malabarica found during screening for Wnt signaling inhibitory activity
- Author
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Hyun Young Park, Midori A. Arai, Thaworn Kowithayakorn, Masami Ishibashi, Kazufumi Toume, and Takashi Koyano
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Cell Survival ,Cell ,Flavonoid ,Ether ,Biology ,Inhibitory postsynaptic potential ,Transfection ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Genes, Reporter ,medicine ,Humans ,Luciferase ,Kaempferols ,Luciferases ,Wnt Signaling Pathway ,chemistry.chemical_classification ,Flavonoids ,Plants, Medicinal ,Dose-Response Relationship, Drug ,Plant Extracts ,Methanol ,Wnt signaling pathway ,HCT116 Cells ,Sitosterols ,Plant Leaves ,medicine.anatomical_structure ,HEK293 Cells ,chemistry ,Biochemistry ,Bauhinia malabarica ,Bauhinia ,Solvents ,Molecular Medicine ,Quercetin ,Phytotherapy - Abstract
Screening with a cell-based luciferase assay was conducted to identify bioactive natural products which inhibit Wnt signaling activity-guided separation of an MeOH extract of Bauhinia malabarica (Caesalpiniaceae) leaves yielded five compounds, which were identified as β-sitosterol (1), quercetin (2), 6,8-C-dimethyl kaempferol-3-O-rhamnopyranoside (3), hyperin (4), and 6,8-C-dimethyl kaempferol-3-methyl ether (5). The tested compounds 1, 3, and 5 exhibited Wnt signaling inhibitory activity, with IC50 values of 0.77, 0.74, and 16.6 μM, respectively.
- Published
- 2013
98. Novel C5-Substituted 2′-Deoxyuridine Derivatives Bearing Amino-Linker Arms: Synthesis, Incorporation into Oligodeoxyribonucleotides, and Their Hybridization Properties
- Author
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Masakazu Endo, Midori A. Arai, Akiko Nakamura, Hiroaki Sawai, and Hiroaki Ozaki
- Subjects
Tris ,Nuclease ,biology ,Chemistry ,Stereochemistry ,Ethylenediamine ,General Chemistry ,Deoxyuridine ,chemistry.chemical_compound ,Phosphodiester bond ,biology.protein ,Amine gas treating ,Thermal stability ,Linker - Abstract
2′-Deoxyuridine derivatives bearing several kinds of amino-linker arms at C5 position were synthesized from 5-(methoxycarbonylmethyl)-2′-deoxyuridine and ethylenediamine, 1,6-hexanediamine, or tris(2-aminoethyl)amine. The modified nucleosides were incorporated into oligodeoxyribonucleotides at one or three positions in place of thymidine residues. The thermal stability of the duplexes was investigated. Three incorporations of ethylenediamine or tris(2-aminoethyl)amine at the C5-position increase the duplex stability. The amino-linker arm affected the stability of the duplexes depending on the number of amino groups in the linker arm and the length of the arm. The linker arm improved the nuclease resistance at 5′-side phosphodiester linkage of the modified nucleoside in oligodeoxyribonucleotides.
- Published
- 1995
99. Bioassay-Guided Isolation of Compounds from Datura Stramonium with TRAIL-Resistance Overcoming Activity
- Author
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Masami Ishibashi, Utpal Kumar Karmakar, Naoki Ishikawa, Firoj Ahmed, Kazufumi Toume, Midori A. Arai, and Samir Kumar Sadhu
- Subjects
0301 basic medicine ,Pharmacology ,Datura stramonium ,Traditional medicine ,Stereochemistry ,Plant Science ,General Medicine ,Drug resistance ,Biology ,Tyramine ,biology.organism_classification ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Complementary and alternative medicine ,chemistry ,Cell culture ,Trigonelline ,Apoptosis ,Drug Discovery ,Cancer cell ,Bioassay - Abstract
TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids – scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 μM, respectively in TRAIL-resistant AGS cells.
- Published
- 2016
100. ChemInform Abstract: Katorazone, a New Yellow Pigment with a 2-Azaquinone-phenylhydrazone Structure Produced by Streptomyces sp. IFM 11299
- Author
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Masami Ishibashi, Kazufumi Toume, Mohamed S. Abdelfattah, Midori A. Arai, and Hyuma Masu
- Subjects
biology ,Stereochemistry ,Chemical structure ,Alkaloid ,Ethyl acetate ,General Medicine ,biology.organism_classification ,Mass spectrometry ,Streptomyces ,chemistry.chemical_compound ,Gastric adenocarcinoma ,Pigment ,chemistry ,visual_art ,visual_art.visual_art_medium ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
An unusual alkaloid with a 2-azaquinone-phenylhydrazone structure, katorazone ( 1 ), and other metabolites were isolated from the ethyl acetate extract of Streptomyces sp. IFM 11299. The chemical structure of katorazone ( 1 ) was elucidated by 1D and 2D NMR analyses together with HR-ESI mass spectrometry. Katorazone ( 1 ) showed a synergistic effect in combination with TRAIL and decreased the viability of human gastric adenocarcinoma (AGS) cells.
- Published
- 2012
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