Details of a Researcher - Kikuchi, Haruhisa

Papers - Kikuchi, Haruhisa

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Dictyopyrones, novel alpha-pyronoids isolated from Dictyostelium spp., promote stalk cell differentiation in Dictyostelium discoideum

A Arai, Y Goto, A Hasegawa, K Hosaka, H Kikuchi, Y Oshima, S Tanaka, Y Kubohara

DIFFERENTIATION (BLACKWELL PUBLISHING) 73 ( 7 ) 377 - 384 2005.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0301-4681

Dictyopyrones A and B (DpnA and B), whose function(s) is not known, were isolated from fruiting bodies of Dictyostelium discoideum. In the present study, to assess their function(s), we examined the effects of Dpns on in vitro cell differentiation in D. discoideum monolayer cultures with cAMP. Dpns at 1-20 mu M promoted stalk cell formation to some extent in the wild-type strain V12M2. Although Dpns by themselves could hardly induce stalk cell formation in a differentiation-inducing factor (DIF)-deficient strain HM44, both of them dose-dependently promoted DIF-1-dependent stalk cell formation in the strain. In the sporogenous strain HM18, Dpns at 1-20 mu M suppressed spore formation and promoted stalk cell formation in a dose-dependent manner. Analogs of Dpns were less effective in affecting cell differentiation in both HM44 and HM18 cells, indicating that the activity of Dpns should be chemical structure specific. It was also shown that DpnA at 2-20 mu M dose-dependently suppressed spore formation induced with 8-bromo cAMP and promoted stalk cell formation in V12M2 cells. Interestingly, it was shown by the use of RT-PCR that DpnA at 10 mu M slightly promoted both prespore- and prestalk-specific gene expressions in an early phase of V12M2 and HM18 in vitro differentiation. The present results suggest that Dpns may have functions (1) to promote both prespore and prestalk cell differentiation in an early stage of development and (2) to suppress spore formation and promote stalk cell formation in a later stage of development in D. discoideum.

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Involvement of reactive oxygen species and stress-activated MAPKs in satratoxin H-induced apoptosis

P Nusuetrong, M Yoshida, MA Tanitsu, H Kikuchi, M Mizugaki, K Shimazu, T Pengsuparp, D Meksuniyen, Y Oshima, N Nakahata

EUROPEAN JOURNAL OF PHARMACOLOGY (ELSEVIER SCIENCE BV) 507 ( 1-3 ) 239 - 246 2005.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0014-2999

Satratoxins, members of the trichothecene mycotoxin family, have been known to be harmful to health. However, the mechanisms underlying the toxicity still remain unclear. The present study is undertaken to elucidate the mechanisms of the satratoxin H-induced cytotoxicity in PC12 cells. Satratoxin H caused cytotoxicity, which was reflected from apoptosis determined by chromatin staining and flow cytometry. Satratoxin H stimulated the phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Pre-incubation with SB203580, a p38 MAPK inhibitor, or SP600125, a JNK inhibitor, but not PD98059, an ERK inhibitor, reduced satratoxin-induced cytotoxicity. Co-incubation of cells with slutatbione. N-acetyl-L-cysteine or glutathione reductase inhibited cytotoxicity and the phosphorylation of p38 MAPK induced by satratoxin H. Our data suggest that satratoxin H-induced apoptosis in PC12 cells is dependent on the activation of p38 MAPK/JNK and the increase in reactive oxygen species. (C) 2004 Elsevier B.V. All rights reserved.

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A novel carbon skeletal trichothecane, tenuipesine A, isolated from an entomopathogenic fungus, Paecilomyces tenuipes

H Kikuchi, Y Miyagawa, K Nakamura, Y Sahashi, S Inatomi, Y Oshima

ORGANIC LETTERS (AMER CHEMICAL SOC) 6 ( 24 ) 4531 - 4533 2004.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1523-7060

Tenuipesine A (1), a novel trichothecane with an unprecedented carbon-migrated skeleton that embodies of a cyclopropane ring, was isolated from cultivated fruiting bodies of Paecilomyces tenuipes (Isaria japonica), a popular e ntomo pathogenic fungi employed in folk medicine and health foods in China, Korea, and Japan. The structure was determined on the basis of two-dimensional NMR data. Its stereochemistry was elucidated by spectroscopic data and the chemical transformation of the coexisting trichothecene, 4beta-acetoxy-12,13-epoxytrichothec-g-ene3cc,15-diol (2).

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Novel trichothecanes, paecilomycine A, B, and C, isolated from entomopathogenic fungus, Paecilomyces tenuipes

H Kikuchi, Y Miyagawa, Y Sahashi, S Inatomi, A Haganuma, N Nakahata, Y Oshima

TETRAHEDRON LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 45 ( 33 ) 6225 - 6228 2004.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0040-4039

Paecilomycine A (1), B (2), and C (3) were isolated from cultivated fruiting bodies of Paecilomyces tenuipes (Isaria japonica), which is a popular entomopathogenic fungus used in folk medicine and health foods in China, Korea, and Japan. The structures of 1 3 were deduced from their spectroscopic data and their absolute configurations were elucidated by preparing their MPA esters. Compound I showed activity in the neurotrophic factor biosynthesis in glial cells. (C) 2004 Elsevier Ltd. All rights reserved.

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Structural requirements of dictyopyrones isolated from Dictyostelium spp. in the regulation of Dictyostelium development and in anti-leukemic activity

H Kikuchi, K Sasaki, J Sekiya, Y Maeda, A Amagai, Y Kubohara, Y Oshima

BIOORGANIC & MEDICINAL CHEMISTRY (PERGAMON-ELSEVIER SCIENCE LTD) 12 ( 12 ) 3203 - 3214 2004.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0968-0896

Cellular slime molds are fascinating to the field of developmental biology, and have long been used as excellent model organisms for the study of various aspects of multicellular development. We have recently isolated alpha-pyronoids, named dictyopyrones A-D (1-4), from various species of Dictyostelium cellular slime molds, and it was shown that compound 3 may regulate Dictyostelium development. In this study, we synthesized dictyopyrones A-D (1-4) and their analogues, investigated the physiological role of the molecules in cell growth and morphogenesis in D. discoideum, and further verified their effects on human leukemia K562 cells. Nitrogen-containing compounds 22 and 37 strongly inhibited cell growth in K562 leukemia cells, indicating that these compounds may be utilized as novel lead compounds for anti-leukemic agents. (C) 2004 Elsevier Ltd. All rights reserved.

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Novel spirocyclic trichothecanes, spirotenuipesine A and B, isolated from entomopathogenic fungus, Paecilomyces tenuipes

H Kikuchi, Y Miyagawa, Y Sahashi, S Inatomi, A Haganuma, N Nakahata, Y Oshima

JOURNAL OF ORGANIC CHEMISTRY (AMER CHEMICAL SOC) 69 ( 2 ) 352 - 356 2004.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3263

Entomopathogenic fungi forming fruiting bodies have been employed as tonics and antitussives from ancient times. Paecilomyces tenuipes, which is also called Isaria japonica, is a very popular entomopathogenic fungus and is often considered a health food in northeast Asian countries such as China, Korea, and Japan. We cultivated the fruiting bodies of Paecilomyces tenuipes. Among the large-scale cultivations, fruiting body grown in barley grain contained two novel spirocyclic trichothecane derivatives, spirotenuipesine A (1) and B (2), and known trichothecane mycotoxins. Compounds 1 and 2 showed potent activity in neurotrophic factor biosynthesis in glial cells. The isolation of these compounds indicated that P. tenuipes is a promising source for producing various biologically active substances including trichothecanes. It is noteworthy that trichothecane mycotoxins are present in Paecilomyces tenuipes, which is typically used in medicinal health food.

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Novel aromatics bearing 4-O-methylglucose unit isolated from the oriental crude drug Bombyx Batryticatus

H Kikuchi, N Takahashi, Y Oshima

TETRAHEDRON LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 45 ( 2 ) 367 - 370 2004.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0040-4039

Oriental crude drug, Bombyx Batryticatus, is dried silkworm larva, Bombyx mori L., which are dead and stiffened due to a Beauveria bassiana infection. In traditional Japanese, Korean, and Chinese medicine, it is employed as analgesic and anticonvulsant. We investigated the constituents of Bombyx Batryticatus and isolated four novel aromatics bearing 4-O-methylglucose moiety, BB-1, 2, 3, and 4 (1-4). It is speculated that these compounds are produced by an interaction between plants, insects, and microorganisms. (C) 2003 Elsevier Ltd. All rights reserved.

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Adenosine as an active constituent of Auricularia auricula for the inhibition of rabbit platelet aggregation

Murata A, Oka N, Ohkubo S, Sato Y, Funamori M, Kikuchi H, Tanitsu M.-A, Kogi K, Sato S, Tadano T, Oshima Y, Nakahata N

Pharmacometrics 67 ( 3-4 ) 359 - 364 2004

Research paper (scientific journal), Joint Work, Accepted

CiNii Research

Metabolites of febrifugine and its synthetic analogue by mouse liver S9 and their antimalarial activity against Plasmodium malaria parasite

S Hirai, H Kikuchi, HS Kim, K Begum, Y Wataya, H Tasaka, Y Miyazawa, K Yamamoto, Y Oshima

JOURNAL OF MEDICINAL CHEMISTRY (AMER CHEMICAL SOC) 46 ( 20 ) 4351 - 4359 2003.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-2623

Quinazolinone type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use for malaria. Because of their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from I and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and -B (4 and 5) were isolated as the major metabolites of 1. In addition to 4 and 5, feb-C and -D (6 and 7) were also purified from the metabolic mixture of 3. Compounds 4 and 5 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 6 and 7, derived from 3, also bear febrifugine type structures in which the 4"- and 6"-positions of the piperidine ring of 1 were oxidized. In vitro antimalarial. and cytotoxic tests using synthetically obtained racemic 4-6 and enantiomerically pure 7 demonstrated that 4 and 6 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. The antimalarial. activity of 5 and 7, however, was dramatically decreased in the test. The in vitro antimalarial activity of analogues 22 and 43, which are stereoisomers of 4 and 6, was also evaluated, showing that 22 is active. The results suggest that basicity of both the 1- and the 1"-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 4 and 6 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially, no serious side effects were observed with 4. Thus, the metabolite 4 appears to be a promising lead compound for the development of new types of antimalarial drugs.

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A newly established in vitro culture using transgenic Drosophila reveals functional coupling between the phospholipase A(2)-generated fatty acid cascade and lipopolysaccharide-dependent activation of the immune deficiency (imd) pathway in insect immunity

M Yajima, M Takada, N Takahashi, H Kikuchi, S Natori, Y Oshima, S Kurata

BIOCHEMICAL JOURNAL (PORTLAND PRESS) 371 ( 1 ) 205 - 210 2003.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 0264-6021

Innate immunity is the first line of defence against infectious micro-organisms, and the basic mechanisms of pathogen recognition and response activation are evolutionarily conserved. In mammals, the innate immune response in combination with antigen-specific recognition is required for the activation of adaptive immunity. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Here, for the purpose of pharmaceutical screening, we established an in vitro culture based on the innate immune response of Drosophila. The in vitro system is capable of measuring lipopolysaccharide (LPS)-dependent activation of the immune deficiency (imd) pathway, which is similar to the tumour necrosis factor signalling pathway in mammals. Screening revealed that well-known inhibitors of phospholipase A(2) (PLA(2)), dexamethasone (Dex) and p-bromophenacyl bromide (BPB) inhibit LPS-dependent activation of the imd pathway. The inhibitory effects of Dex and BPB were suppressed by the addition of an excess of three (arachidonic acid, eicosapentaenoic acid and gamma-linolenic acid) of the fatty acids so far tested. Arachidonic acid, however, did not activate the imd pathway when used as the sole agonist. These findings indicate that PLA, participates in LPS-dependent activation of the imd pathway via the generation of arachidonic acid and other mediators, but requires additional signalling from LPS stimulation. Moreover, PLA(2) was activated in response to bacterial infection in Sareophaga. These results suggest a functional link between the PLA(2)-generated fatty acid cascade and the LPS-stimulated imd pathway in insect immunity.

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Multiple activities of a novel substance, dictyopyrone C isolated from Dictyostelium discoideum, in cellular growth and differentiation

Y Maeda, H Kikuchi, K Sasaki, A Amagai, J Sekiya, Y Takaya, Y Oshima

PROTOPLASMA (SPRINGER-VERLAG WIEN) 221 ( 3-4 ) 185 - 192 2003

Research paper (scientific journal), Joint Work, Accepted, ISSN 0033-183X

We report that a novel substance named dictyopyrone C (DPC) has remarkable effects on growth and differentiation of Dictyostelium discoideum Ax-2 cells, in a dose-dependent manner. In the presence of 3-15 muM DPC, differentiation of starving Ax-2 (clone MS) cells was greatly enhanced in submerged culture, when vegetative MS cells were harvested at the mid-late-exponential growth phase (>3 x 10(6) cells per ml) and starved. In contrast, DPC above 30 muM markedly impaired the progression of differentiation including cell aggregation, most of starved cells being round after 3-4 h of DPC application and then lysed during further incubation. In the presence of 30 muM DPC however, MS cells that had been harvested at the early exponential growth phase (<5 x 10(5) cells per ml) and starved became neither round nor lysed and exhibited rather enhanced differentiation. Essentially the same results were obtained in cultures of starved cells on nonnutrient agar. With respect to the DPC effect on MS cells growing in axenic medium, cell lysis and growth inhibition by DPC at concentrations higher than 15 muM were realized in the mid-late-exponential-growth-phase cells (>3 x 10(6) cells per ml) but not in the early-exponential-growth-phase cells (<5 x 10(5) cells per ml). Moreover, analysis using synchronized MS cells has demonstrated that the DPC effect changes in a cell-cycle-dependent manner. In contrast to such unique DPC actions, the pyrone ring of DPC had no effects on growth and differentiation within the range of 3-120 muM tested. These findings strongly suggested the importance of the combined structure of the pyrone ring and the linear carbon chain in revelation of the DPC activities.

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Potent antimalarial febrifugine analogues against the Plasmodium malaria parasite

H Kikuchi, H Tasaka, S Hirai, Y Takaya, Y Iwabuchi, H Ooi, S Hatakeyama, HS Kim, Y Wataya, Y Oshima

JOURNAL OF MEDICINAL CHEMISTRY (AMER CHEMICAL SOC) 45 ( 12 ) 2563 - 2570 2002.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-2623

Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical use against malaria. However, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. Thus, we have evaluated the in vitro antimalarial activity of the analogues of febrifugine (1) and isofebrifugine (2). The activities of the analogues derived from Df-1 (3) and Df-2 (4), condensation products of 1 and 2 with acetone, respectively, were also obtained. The 3"-keto derivative (7, EC50 = 2.0 x 10(-8) M) of 1 was found to exhibit potential antimalarial activity with high selectivity against P. falciparum in vitro. The in vitro activities of the reduction product (8, EC50 = 2.0 x 10-8 M) of 1 at C-2' and its cyclic derivatives 9 and 10 (EC50 = 3.7 x 10(-9) and 8.6 x 10(-9) M, respectively) were found to be strongly active and selective. Additionally, the Dess-Martin oxidation product of 3 was found to be strongly active with high selectivity against P. falciparum. A structure-activity relationship study (SAR) demonstrates that the essential role played by the 4-quinazolinone ring in the appearance of activity and the presence of a 1"-amino group and C-2', C-3" O-functionalities are crucial in the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been conducted.

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The isolation and synthesis of two novel N-acetyl glucosamine derivatives from Dictyostelium cellular slime molds which exhibit neurite outgrowth activity

H Kikuchi, J Komiya, Y Saito, JI Sekiya, S Honma, N Nakahata, Y Oshima

TETRAHEDRON LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 43 ( 8 ) 1477 - 1480 2002.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 0040-4039

To clarify the diversity of secondary metabolites of Dictyostelium cellular slime molds and explore any biologically active substances which they may hold, constituents of two species were investigated. From a methanol extract or their fruit bodies, two novel acylated amino sugar were isolated, dictyoglucosamine A (1) from D. purpureum and dictyoglucosamine B (2) from D. discoideum. For further analysis, these compounds were then synthesized from N-aceyl-D-glucosamine. Biological evaluation of 1 and 2 shocked the induce neuronal differentiation of rat pheochromocytoma (PC-12) cells. (C) Elsevier Science Ltd. All rights reserved.

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Furanodictine A and B: Amino sugar analogues produced by cellular slime mold Dictyostelium discoideum showing neuronal differentiation activity

H Kikuchi, Y Saito, J Komiya, Y Takaya, S Honma, N Nakahata, A Ito, Y Oshima

JOURNAL OF ORGANIC CHEMISTRY (AMER CHEMICAL SOC) 66 ( 21 ) 6982 - 6987 2001.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3263

We investigated the constituents of Dictyostelium discoideum to clarify the diversity of secondary metabolites of Dictyostelium cellular slime molds and to explore biologically active substances that could be useful in the development of novel drugs. From a methanol extract of the multicellular fruit body of D. discoideum, we isolated two novel amino sugar analogues, furanodictine A (1) and B (2). They are the first 3,6-anhydrosugars to be isolated from natural sources. Their relative structures were elucidated by spectral means, and the absolute configurations were confirmed by asymmetric syntheses of 1 and 2. These furanodictines potently induce neuronal differentiation of rat pheochromocytoma (PC-12) cells.

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Novel aromatic substances, dictyomedin A and B, from Dictyostelium cellular slime molds and their inhibitory effects on Dictyostelium development

Y Takaya, H Kikuchi, Y Terui, J Komiya, Y Maeda, A Ito, Y Oshima

TETRAHEDRON LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 42 ( 1 ) 61 - 63 2001.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0040-4039

To elucidate the diversity of secondary metabolites of Dictyostelium cellular slime molds and search for physiologically active substances affecting their development, we investigated the constituents of D, medium. From the methanol extract of its fruit body, we obtained two novel aromatic compounds named dictyomedin A (1) and B (2), and their structures were elucidated by means of physicochemical data. Biological evaluation of the compounds showed that they delayed the differentiation of D. discoideum cells. (C) 2000 Elsevier Science Ltd. All rights reserved.

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Novel acyl alpha-pyronoids, dictyopyrone A, B, and C, from Dictyostelium cellular slime molds

Y Takaya, H Kikuchi, Y Terui, J Komiya, KI Furukawa, K Seya, S Motomura, A Ito, Y Oshima

JOURNAL OF ORGANIC CHEMISTRY (AMER CHEMICAL SOC) 65 ( 4 ) 985 - 989 2000.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3263

For the elucidation of the diversity of secondary metabolites of Dictyostelium cellular slime molds, we investigate the constituent of three species of slime molds. From the methanol extract of their fruit bodies, we obtained three novel compounds, dictyopyrone A (1) and B (2) from D. discoideum and D, rhizoposium and dictyopyrone C (3) from D, longosporum. They possess a unique cr-pyrone moiety with a side chain at the C-3 position. Their relative structures were elucidated by spectral means, and the absolute configuration was confirmed by asymmetric synthesis of 1. Since these compounds were obtained from different species of Dictyostelium slime molds, they may be a type of compound common to this genus.

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