研究者詳細 - 井本　正哉

論文 - 井本　正哉

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Development of a luminescence-controllable firefly luciferin analogue using selective enzymatic cyclization

Ioka S., Saitoh T., Maki S., Imoto M., Nishiyama S.

Tetrahedron （Tetrahedron） 72 （ 47 ） 7505 - 7508 2016年

研究論文（学術雑誌）, 査読有り, ISSN 00404020

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Screening and target identification of bioactive compounds that modulate cell migration and autophagy

Tashiro E., Imoto M.

Bioorganic and Medicinal Chemistry （Bioorganic and Medicinal Chemistry） 24 （ 15 ） 3283 - 3290 2016年

研究論文（学術雑誌）, 査読有り, ISSN 09680896

© 2016 Elsevier Ltd Cell migration is a fundamental step for embryonic development, wound repair, immune responses, and tumor cell invasion and metastasis. It is well known that protrusive structures, namely filopodia and lamellipodia, can be observed at the leading edge of migrating cells. The formation of these structures is necessary for cell migration; however, the molecular mechanisms behind the formation of these structures remain largely unclear. Therefore, bioactive compounds that modulate protrusive structures are extremely powerful tools for studying the mechanisms behind the formation of these structures and subsequent cell migration. Therefore, we have screened for bioactive compounds that inhibit the formation of filopodia, lamellipodia, or cell migration from natural products, and attempted to identify the target molecules of our isolated compounds. Additionally, autophagy is a bulk, non-specific protein degradation system that is involved in the pathogenesis of cancer and neurodegenerative disorders. Recent extensive studies have revealed the molecular mechanisms of autophagy, however, they also remain largely unclear. Thus, we also have screened for bioactive compounds that modulate autophagy, and identified the target molecules. In the present article, we introduce the phenotypic screening system and target identification of four bioactive compounds.

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Synthesis of Firefly Luciferin Analogues and Evaluation of the Luminescent Properties

Ioka S., Saitoh T., Iwano S., Suzuki K., Maki S., Miyawaki A., Imoto M., Nishiyama S.

Chemistry - A European Journal （Chemistry - A European Journal） 22 （ 27 ） 9330 - 9337 2016年

研究論文（学術雑誌）, 査読有り, ISSN 09476539

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Five new firefly luciferin (1) analogues were synthesized and their light emission properties were examined. Modifications of the thiazoline moiety in 1 were employed to produce analogues containing acyclic amino acid side chains (2–4) and heterocyclic rings derived from amino acids (5 and 6) linked to the benzothiazole moiety. Although methyl esters of all of the synthetic derivatives exhibited chemiluminescence activity, only carboluciferin (6), possessing a pyrroline-substituted benzothiazole structure, had bioluminescence (BL) activity (λmax=547 nm). Results of bioluminescence studies with AMP-carboluciferin (AMP=adenosine monophosphate) and AMP-firefly luciferin showed that the nature of the thiazoline mimicking moiety affected the adenylation step of the luciferin–luciferase reaction required for production of potent BL. In addition, BL of 6 in living mice differed from that of 1 in that its luminescence decay rate was slower.

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Chemical biology of compounds obtained from screening using disease models

Tashiro E., Imoto M.

Archives of Pharmacal Research （Archives of Pharmacal Research） 38 （ 9 ） 1651 - 1660 2015年09月

研究論文（学術雑誌）, 査読有り, ISSN 02536269

© 2015 The Pharmaceutical Society of Korea. Bioactive compounds are extremely powerful tools for studying biological systems because they can rapidly, conditionally, often reversibly, and dose-dependently modulate the biological function of living cells. Moreover, they are expected to be drug seeds for chemotherapy of several diseases. Two approaches are used to find and obtain bioactive compounds, namely, molecular-target-based screening and phenotypic screening. Through phenotypic screening that mimics tumor metastasis, multi-drug resistance, and Parkinson's disease, we identified several compounds that inhibit cancer cell migration, anti-apoptotic function of Bcl-2/Bcl-xL, and neuronal cell death. By using MEK inhibitor that was developed by target-based screening, we discovered that MEK inhibitor selectively induces apoptosis in tumor cells with β-catenin mutation. Using target-based screening, we identified arabilin, a novel androgen antagonist. In this review, we introduce our recent studies on the identification of bioactive compounds by phenotypic screening and by target-based screening for drug-seed discovery.

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Metabolomics and molecular targeted therapy of cancer

Tashiro E., Imoto M.

Nihon rinsho. Japanese journal of clinical medicine （Nihon rinsho. Japanese journal of clinical medicine） 73 （ 8 ） 1268 - 1272 2015年08月

研究論文（学術雑誌）, 査読有り, ISSN 00471852

Metabolomics is defined as the quantitative measurement of the dynamic multiparametric metabolites. Recent technological advances in the quantification of cellular metabolites, such as capillary electrophoresis (CE) -TOFMS, have prompted the comprehensive analysis of the global metabolism. Now, metabolomics has been used in the identification of new biomarker for toxicology and disease diagnosis, and the elucidation of fermentation processes. Moreover, it is considered that metabolomics would be a powerful tool for the target identification of small molecular bioactive compounds. Here we introduce our recent study that metabolomics was applied to identify the molecular target of glucopiericidin A, which was isolated through a screening of natural products for an inhibitor of cellular filopodia protrusion in carcinoma cells.

[Metabolomics and molecular targeted therapy of cancer].

Tashiro E, Imoto M

Nihon rinsho. Japanese journal of clinical medicine 73 （ 8 ） 1268 - 72 2015年08月

研究論文（学術雑誌）, 査読有り, ISSN 0047-1852

Evaluation of drug toxicity profiles based on the phenotypes of ascidian Ciona intestinalis

Mizotani Y., Itoh S., Hotta K., Tashiro E., Oka K., Imoto M.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 463 （ 4 ） 656 - 660 2015年07月

研究論文（学術雑誌）, 査読有り, ISSN 0006291X

© 2015 Elsevier Inc. All rights reserved. In vivo toxicity evaluation using model organisms is an important step for the development of new drugs. Here, we report that Ciona intestinalis, a chordate invertebrate, is beneficial to drug toxicity evaluation for the following reasons: rapid embryonic and larval development, resemblance to vertebrates, ease of management, low cost, transparent body, and low risk of ethical issues. The dynamic phenotypic change of Ciona larvae during metamorphosis prompted us to examine the effect of cytotoxic drugs on its development by quantifying six toxicity endpoints: degenerated tail size, ampulla length, rotation of body axis, stomach size, heart rate, and body size. As a result, mitochondrial respiratory inhibitors, tubulin polymerization/depolymerization inhibitors, or DNA/RNA synthesis inhibitors showed distinct toxicity profiles against these six endpoints, but drugs with the same targets showed a similar toxicity profile in Ciona. Our results suggest Ciona is an effective animal model for profiling drug toxicity and exploring the mechanisms of drugs with unknown targets.

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Apoptosis induction associated with the ER stress response through up-regulation of JNK in HeLa cells by gambogic acid

Krajarng A., Imoto M., Tashiro E., Fujimaki T., Shinjo S., Watanapokasin R.

BMC Complementary and Alternative Medicine （BMC Complementary and Alternative Medicine） 15 （ 1 ） 26 2015年02月

研究論文（学術雑誌）, 査読有り

© 2015 Krajarng et al. Background: Gambogic acid (GA) was extracted from the dried yellow resin of gamboge (Garcinia hanburyi) which is traditionally used as a coloring material for painting and cloth dying. Gamboge has been also used as a folk medicine for an internal purgative and externally infected wound. We focused on the mechanisms of apoptosis induction by GA through the unfold protein response (ER stress) in HeLa cells. Methods: The cytotoxic effect of GA against HeLa cells was determined by trypan blue exclusion assay. Markers of ER stress such as XBP-1, GRP78, CHOP, GADD34 and ERdj4 were analyzed by RT-PCR and Real-time RT-PCR. Cell morphological changes and apoptotic proteins were performed by Hoechst33342 staining and Western blotting technique. Results: Our results indicated a time- and dose-dependent decrease of cell viability by GA. The ER stress induction is determined by the up-regulation of spliced XBP1 mRNA and activated GRP78, CHOP, GADD34 and ERdj4 expression. GA also induced cell morphological changes such as nuclear condensation, membrane blebbing and apoptotic body in Hela cells. Apoptosis cell death detected by increased DR5, caspase-8, -9, and -3 expression as well as increased cleaved-PARP, while decreased Bcl-2 upon GA treatment. In addition, phosphorylated JNK was up-regulated but phosphorylated ERK was down-regulated after exposure to GA. Conclusions: These results suggest that GA induce apoptosis associated with the ER stress response through up-regulation of p-JNK and down-regulation of p-ERK in HeLa cells.

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SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in β-catenin-mutated tumors

Kiga M., Nakayama A., Shikata Y., Sasazawa Y., Murakami R., Nakanishi T., Tashiro E., Imoto M.

Scientific Reports （Scientific Reports） 5 8155 2015年02月

研究論文（学術雑誌）, 査読有り

Although clinical studies have evaluated several MEK1/2 inhibitors, it is unlikely that MEK1/2 inhibitors will be studied clinically. BRAF mutations have been proposed as a responder marker of MEK1/2 inhibitors in a preclinical study. However, current clinical approaches focusing on BRAF mutations have shown only moderate sensitivity of MEK1/2 inhibitors. This has led to insufficient support for their promoted clinical adoption. Further characterization of tumors sensitive to MEK inhibitors holds great promise for optimizing drug therapy for patients with these tumors. Here, we report that β-catenin mutations accelerate apoptosis induced by MEK1/2 inhibitor. SMK-17, a selective MEK1/2 inhibitor, induced apoptosis in tumor cell lines harboring β-catenin mutations at its effective concentration. To confirm that β-catenin mutations and mutant β-catenin-mediated TCF7L2 (also known as TCF4) transcriptional activity is a predictive marker of MEK inhibitors, we evaluated the effects of dominant-negative TCF7L2 and of active, mutated β-catenin on apoptosis induced by MEK inhibitor. Indeed, dominant-negative TCF7L2 reduced apoptosis induced by MEK inhibitor, whereas active, mutated β-catenin accelerated it. Our findings show that β-catenin mutations are an important responder biomarker for MEK1/2 inhibitors.

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Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions

Yoshimaru T., Komatsu M., Tashiro E., Imoto M., Osada H., Miyoshi Y., Honda J., Sasa M., Katagiri T.

Scientific Reports （Scientific Reports） 4 7355 2014年12月

研究論文（学術雑誌）, 査読有り

© 2014, Nature Publishing Group. All rights reserved. Xanthohumol (XN) is a natural anticancer compound that inhibits the proliferation of oestrogen receptor-α (ERα)-positive breast cancer cells. However, the precise mechanism of the antitumour effects of XN on oestrogen (E2)-dependent cell growth, and especially its direct target molecule(s), remain(s) largely unknown. Here, we focus on whether XN directly binds to the tumour suppressor protein prohibitin 2 (PHB2), forming a novel natural antitumour compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2/ERα signalling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERα. This event led to the complete suppression of the E2-signalling pathways and ERα-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancer.

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Identification of licopyranocoumarin and glycyrurol from herbal medicines as neuroprotective compounds for Parkinson's disease

Fujimaki T., Saiki S., Tashiro E., Yamada D., Kitagawa M., Hattori N., Imoto M.

PLoS ONE （PLoS ONE） 9 （ 6 ） e100395 2014年06月

研究論文（学術雑誌）, 査読有り

In the course of screening for the anti-Parkinsonian drugs from a library of traditional herbal medicines, we found that the extracts of choi-joki-to and daio-kanzo-to protected cells from MPP+-induced cell death. Because choi-joki-to and daio-kanzo-to commonly contain the genus Glycyrrhiza, we isolated licopyranocoumarin (LPC) and glycyrurol (GCR) as potent neuroprotective principals from Glycyrrhiza. LPC and GCR markedly blocked MPP +-induced neuronal PC12D cell death and disappearance of mitochondrial membrane potential, which were mediated by JNK. LPC and GCR inhibited MPP+-induced JNK activation through the suppression of reactive oxygen species (ROS) generation, thereby inhibiting MPP +-induced neuronal PC12D cell death. These results indicated that LPC and GCR derived from choi-joki-to and daio-kanzo-to would be promising drug leads for PD treatment in the future. © 2014 Fujimaki et al.

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Chemical genomic-based pathway analyses for epidermal growth factor-mediated signaling in migrating cancer cells

Magi S., Saeki Y., Kasamatsu M., Tashiro E., Imoto M.

PLoS ONE （PLoS ONE） 9 （ 5 ） e96776 2014年05月

研究論文（学術雑誌）, 査読有り

To explore the diversity and consistency of the signaling pathways that regulate tumor cell migration, we chose three human tumor cell lines that migrated after treatment with EGF. We then quantified the effect of fifteen inhibitors on the levels of expression or the phosphorylation levels of nine proteins that were induced by EGF stimulation in each of these cell lines. Based on the data obtained in this study and chemical-biological assumptions, we deduced cell migration pathways in each tumor cell line, and then compared them. As a result, we found that both the MEK/ERK and JNK/c-Jun pathways were activated in all three migrating cell lines. Moreover, GSK-3 and p38 were found to regulate PI3K/Akt pathway in only EC109 cells, and JNK was found to crosstalk with p38 and Fos related pathway in only TT cells. Taken together, our analytical system could easily distinguish between the common and cell type-specific pathways responsible for tumor cell migration. © 2014 Magi et al.

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5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation

Magi S., Takemoto Y., Kobayashi H., Kasamatsu M., Akita T., Tanaka A., Takano K., Tashiro E., Igarashi Y., Imoto M.

Cancer Science （Cancer Science） 105 （ 3 ） 290 - 296 2014年03月

研究論文（学術雑誌）, 査読有り, ISSN 13479032

Cell migration is an essential step for tumor metastasis. The small GTPase Rac1 plays an important role in cell migration. Previously, we reported that epidermal growth factor (EGF) induced two waves of Rac1 activation; namely, at 5 min and 12 h after stimulation. A second wave of EGF-induced Rac1 activation was required for EGF-induced cell migration, however, the spatiotemporal regulation of the second wave of EGF-induced Rac1 activation remains largely unclear. In this study, we found that 5-lipoxygenase (5-LOX) is activated in the process of EGF-induced cell migration, and that leukotriene C4 (LTC4) produced by 5-LOX mediated the second wave of Rac1 activation, as well as cell migration. Furthermore, these effects caused by LTC4 were found to be blocked in the presence of the antagonist of cysteinyl leukotriene receptor 1 (CysLT1). This blockage indicates that LTC4-mediated CysLT1 signaling regulates the second EGF-induced wave of Rac1 activation. We also found that 5-LOX inhibitors, CysLT1 antagonists and the knockdown of CysLT1 inhibited EGF-induced T cell lymphoma invasion and metastasis-inducing protein 1 (Tiam1) expression. Tiam1 expression is required for the second wave of EGF-induced Rac1 activation in A431 cells. Therefore, our results indicate that the 5-LOX/LTC4/CysLT1 signaling pathway regulates EGF-induced cell migration by increasing Tiam1 expression, leading to a second wave of Rac1 activation. Thus, CysLT1 may serve as a new molecular target for antimetastatic therapy. In addition, the CysLT1 antagonist, montelukast, which is used clinically for allergy treatment, might have great potential as a novel type of antimetastatic agent. 5-lipoxygenase (5-LOX) is activated in the process of EGF-induced cell migration, and that leukotriene C4 (LTC4) produced by 5-LOX mediated Rac1 activation and cell migration. LTC4-mediated CysLT1 signaling regulates Tiam1 expression which is required for Rac1 activation. © 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-β

Sakata K., Eda S., Lee E., Hara M., Imoto M., Kojima S.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 443 （ 3 ） 950 - 956 2014年01月

研究論文（学術雑誌）, 査読有り, ISSN 0006291X

Aim Hepatic fibrosis and angiogenesis occur in parallel during the progression of liver disease. Fibrosis promotes angiogenesis via inducing vascular endothelial growth factor (VEGF) from the activated hepatic stellate cells (HSCs). In turn, increased neovessel formation causes fibrosis, although the underlying molecular mechanism remains undetermined. In the current study, we aimed to address a role of endothelial cells (ECs) as a source of latent transforming growth factor (TGF)-β, the precursor of the most fibrogenic cytokine TGF-β. Methods After recombinant VEGF was administered to mice via the tail vein, hepatic angiogenesis and fibrogenesis were evaluated using immunohistochemical and biochemical analyses in addition to investigation of TGF-β activation using primary cultured HSCs and liver sinusoidal ECs (LSECs). Results In addition to increased hepatic levels of CD31 expression, VEGF-treated mice showed increased α-smooth muscle actin (α-SMA) expression, hepatic contents of hydroxyproline, and latency associated protein degradation products, which reflects cell surface activation of TGF-β via plasma kallikrein (PLK). Liberating the PLK-urokinase plasminogen activator receptor complex from the HSC surface by cleaving a tethering phosphatidylinositol linker with its specific phospholipase C inhibited the activating latent TGF-β present in LSEC conditioned medium and subsequent HSC activation. Conclusion Neovessel formation (angiogenesis) accelerates liver fibrosis at least in part via provision of latent TGF-β that activated on the surface of HSCs by PLK, thereby resultant active TGF-β stimulates the activation of HSCs. © 2013 Elsevier Inc. All rights reserved.

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HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type i receptor

Sakata K., Hara M., Terada T., Watanabe N., Takaya D., Yaguchi S., Matsumoto T., Matsuura T., Shirouzu M., Yokoyama S., Yamaguchi T., Miyazawa K., Aizaki H., Suzuki T., Wakita T., Imoto M., Kojima S.

Scientific Reports （Scientific Reports） 3 3243 2013年12月

研究論文（学術雑誌）, 査読有り

Viruses sometimes mimic host proteins and hijack the host cell machinery. Hepatitis C virus (HCV) causes liver fibrosis, a process largely mediated by the overexpression of transforming growth factor (TGF)-β and collagen, although the precise underlying mechanism is unknown. Here, we report that HCV non-structural protein 3 (NS3) protease affects the antigenicity and bioactivity of TGF-β2 in (CAGA) 9 -Luc CCL64 cells and in human hepatic cell lines via binding to TGF-β type I receptor (TβRI). Tumor necrosis factor (TNF)-α facilitates this mechanism by increasing the colocalization of TβRI with NS3 protease on the surface of HCV-infected cells. An anti-NS3 antibody against computationally predicted binding sites for TβRI blocked the TGF-β mimetic activities of NS3 in vitro and attenuated liver fibrosis in HCV-infected chimeric mice. These data suggest that HCV NS3 protease mimics TGF-β2 and functions, at least in part, via directly binding to and activating TβRI, thereby enhancing liver fibrosis.

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Establishment of a new detection system for the dimerization of IRE1α by BiFC assay

Shinjo S., Tashiro E., Imoto M.

Bioscience, Biotechnology and Biochemistry （Bioscience, Biotechnology and Biochemistry） 77 （ 6 ） 1333 - 1336 2013年07月

研究論文（学術雑誌）, 査読有り, ISSN 09168451

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Comparative analysis of the expression patterns of UPR-target genes caused by upr-inducing compounds

Shinjo S., Mizotani Y., Tashiro E., Imoto M.

Bioscience, Biotechnology and Biochemistry （Bioscience, Biotechnology and Biochemistry） 77 （ 4 ） 729 - 735 2013年06月

研究論文（学術雑誌）, 査読有り, ISSN 09168451

Endoplasmic reticulum (ER) stress, due to an accumulation of unfolded proteins in the ER, leads to a process known as the unfolded protein response (UPR). Since the several compounds used to induce UPR have different modes of action, their mechanisms of protein accumulation are thought to be different, but it is unclear whether these compounds can upregulate UPR target genes with similar kinetics. Hence, we sought to compare the expression patterns of nine UPR target genes induced by seven UPR-inducing compounds. Hierarchical clustering analysis revealed that the expression patterns of the UPR target genes induced by the seven compounds were classified into two clusters; cluster A (thapsigargin, tunicamycin, 2-deoxyglucose, and dithiothreitol) and cluster B (brefeldin A, monensin, and eeyarestatin I). Thus, this study suggests the existence of at least two types of UPR target gene expression profiles, which depend on the mode of action of the compounds.

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[The 14th result of screening for antineoplastic agents].

Yamori T., Uehara Y., Fukazawa H., Yoshida M., Imoto M., Kiyomiya H., Minakami T., Kawata M., Nagata H., Matsuura M.

Gan to kagaku ryoho. Cancer & chemotherapy （Gan to kagaku ryoho. Cancer & chemotherapy） 40 Suppl 1 18 - 114 2013年04月

研究論文（学術雑誌）, 査読有り, ISSN 03850684

[The 15th result of screening for antineoplastic agents].

Yamori T., Uehara Y., Fukazawa H., Yoshida M., Imoto M., Kiyomiya H., Mashima T., Manakami T., Kawata M., Nagata H., Dan S., Matsuura M., Kakeya H., Tomita A.

Gan to kagaku ryoho. Cancer & chemotherapy （Gan to kagaku ryoho. Cancer & chemotherapy） 40 Suppl 1 116 - 147 2013年04月

研究論文（学術雑誌）, 査読有り, ISSN 03850684

Novel isoflavone glucosides in groundnut (Apios americana medik) and their antiandrogenic activities

Ichige M., Fukuda E., Miida S., Hattan J., Misawa N., Saito S., Fujimaki T., Imoto M., Shindo K.

Journal of Agricultural and Food Chemistry （Journal of Agricultural and Food Chemistry） 61 （ 9 ） 2183 - 2187 2013年03月

研究論文（学術雑誌）, 査読有り, ISSN 00218561

Isoflavone glucosides (2′-hydroxy,5-methoxy genistein-7-O-glucoside (1), 2′-hydroxy genistein-7-O-gentibioside (2), 5-methoxy genistein-7-O-glucoside (3), 3′,5-dimethoxy genistein-7-O-glucoside (4), 2′-hydroxy genistein-7-O-glucoside (5), genistein-7-O-gentibioside (6), 2′-hydroxy,5-methoxy genistein-4′,7-O-diglucoside (7), and 2′-hydroxy genistein-4′,7-O-diglucoside (8)) were isolated from the groundnut of Apios americana Medik. Their structures were elucidated on the basis of HR-ESI-MS and 1D- and 2D-NMR analyses. Compounds 1, 2, 4, and 7 are new compounds presented here for the first time. Compounds 2 and 5 were proven to be androgen receptor antagonists due to their binding activities for androgen receptors (IC50 280 and 160 μM, respectively) and the inhibitory activity of androgen-induced expression of prostate-specific antigen (PSA) mRNA in LNCaP (prostate adenocarcinoma) cells (IC50 20 and 18 μM, respectively). © 2013 American Chemical Society.

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