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Reviews, Commentaries, etc. - Arai, Midori

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Synthesis and development of compounds for nervous system regeneration after spinal cord injury

A.Arai Midori, Sawada Keisuke, Kubo Takekazu, Yamashita Toshihide, Sugimoto Hachiro, Ishibashi Masami

Proceedings of the Symposium on Progress in Organic Reactions and Syntheses (Division of Organic Chemistry, The Pharmaceutical Society of Japan) 35 ( 0 ) 138 - 138 2009

We are interested in a diverse compound library based on diversity oriented synthesis and searching for useful small molecules. Blebbistatin accelerates extension of axonal growth. We planned to synthesize various Blebbistatin derivatives with plural anthranilic acid units and pyrrolidone units for improvement of chemical properties and bioactivity of Blebbistatin. Four derivatives were synthesized in solution phase. Moreover, solid-phase synthesis was examined to obtain a lot of number of derivatives. For the solid phase library synthesis, pyrrolidone unit was attached to Merrifield resin. Solid-phase arylation of amide was examined by using arylboronic acid and Cu(OAc)2.

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天然物を基盤とするWntおよびHedgehogシグナル阻害剤の探索

荒井緑, 石橋正己

ファルマシア 45 121 - 125 2009

2-II-21 ヒト前立腺由来PZ-HPV-7細胞におけるビタミンD_3誘導体の細胞増殖抑制作用および代謝(一般研究発表,新世紀ビタミン学の展望と先進的展開を目指して,日本ビタミン学会第60回大会発表要旨)

中林佐知栄, 榊利之, 鎌倉昌樹, 池田進之介, 荒井緑, 橘高敦史, 楠堂達也, 山下均, 太田美穂, 生城真一

ビタミン (公益社団法人日本ビタミン学会) 82 ( 4 ) 275 - 275 2008

ISSN 0006-386X

28 Search the Wnt Signaling Inhibitor with Frameworks Trusted in Nature(Oral Presentation)

Arai Midori A, Hanazawa Shuwa, Uchino Yujiro, Li Xiaofan, Numata Terumi, Sugimitsu Noriko, Ishibashi Masami

Symposium on the Chemistry of Natural Products, symposium papers (Symposium on the Chemistry of Natural Products Steering Committee) 50 ( 0 ) 191 - 196 2008

Natural products have their important meanings in biological systems. Isolation of new natural products and synthesis of small molecules based on their scaffolds would be of chemical relevance to living cells and organs. In this study, we focused on the Wnt signaling, which pathways show aberrant activation in many cancer cells. We synthesized natural products melleumin A (1) and B (2), and trans-dihydroarcyriarubin C, which were isolated by us from myxomycetes (true slime molds), and also synthesized their isomers. Melleumin A (1) and B (2) are novel peptide compounds isolated from the myxomycete Physarum melleum. Their syntheses have been achieved by coupling procedures of their components, L-threonine, glycine, and an unusual amino acid, a tyrosine-attached acetic acid. We found cis-dihydroarcyriarubin C (12), and isomers of melleumin B are moderate inhibitors of Wnt signal transcription. We also developed a high-throughput system for analyzing of inhibition of making a complex between TCF and β-catenin by using microplates. The regulation of transcription by TCF/β-catenin complex is a final step of the Wnt signal pathway. In this assay, cis-dihydroarcyriarubin C (12) showed inhibition, which indicates that a cell-based Wnt signal inhibition would be caused by disruption of TCF/β-catenin complex. We also found several natural products from our natural products library that show a cell-based Wnt signal inhibition and a protein-based TCF/β-catenin complex inhibition.

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Library Construction Study of Chromone, Flavonoid Derivatives with Diverse Heterocyclic Units

Arai Midori.A, Sawada Keisuke, Sato Mina, Morizane Takeo, Hosoya Takahiro, Ishibashi Masami

Proceedings of the Symposium on Progress in Organic Reactions and Syntheses (Division of Organic Chemistry, The Pharmaceutical Society of Japan) 34 ( 0 ) 143 - 143 2008

We are interested in a diverse compounds library based on natural products and searching for useful small molecules. Heterocyclic-substituted chromones and flavonoids would be expected to have important bioactivity related with some disease.4'-Benzyloxy-2'-hydroxyacetophenone reacted with various pyridinecarboxaldehydes or benzaldehydes to give intermediate chalcone derivatives, which underwent intramolecular cyclization followed by aldol reaction with another aldehyde to give various heterocyclic substituted chromones or flavonoids.On solid-phase synthesis, we can achieve these reactions under similar conditions of liquid-phase.For more diversity, Suzuki-Miyaura cross coupling progressed on both aromatic units.Some of synthesized compounds showed the inhibition of GLI-mediated transcription, cytotoxicity against some cancer cells and promoted differentiation of neural stem cell.

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Synthesis and Evaluation of Melleumin Derivatives from the Myxomycete; an Approach for Wnt Signal Inhibitors Trusted in Nature

Arai Midori A, Uchino Yujiro, Hanazawa Shuwa, Li Xiaofan, Ishibashi Masami

Proceedings of the Symposium on Progress in Organic Reactions and Syntheses (Division of Organic Chemistry, The Pharmaceutical Society of Japan) 34 ( 0 ) 61 - 61 2008

During our studies in a search for natural products from myxomycetes, we have isolated a novel peptide lactone, melleumin A , and its seco acid methyl ester, melleumin B , from the cultured plasmodium of the myxomycete Physarum melleum. We studied the total synthesis of melleumin A, B and their diastereomers. Melleumin A and B consist of four residues, p-methoxybenzoic acid, L-threonine, glycine, and an unusual amino acid, a tyrosine-attached acetic acid. Total synthesis of melleumin A, B and their diastereomers were achieved by a stereoselective method. The Wnt signal inhibitory activities of melleumin A, B and their diastereomers were evaluated. The 3R-epimer, 10R-epimer and (3R, 4S, 10R, 11R)-isomer of melleumin B showed moderate inhibition of the Wnt signaling pathway.

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16 Search for Natural Products Targeting Hedgehog Signaling Pathway

Hosoya Takahiro, Arai Midori A, Tateno Chikashi, Koyano Takashi, Kowithayakom Thaworn, Ishibashi Masami

Symposium on the Chemistry of Natural Products, symposium papers (Symposium on the Chemistry of Natural Products Steering Committee) 49 ( 0 ) 91 - 96 2007

The hedgehog (Hh)/GLI signaling pathway has been implicated not only in a variety of developmental processes in wide range of organisms, but also in the formation and development of different tumors including skin, brain, prostate, upper gastrointestinal tract, pancreas and lung. Targeting Hh/GLI signaling has been expected as an effective cancer therapeutic strategy. To find the specific inhibitors of Hh/GLI signaling pathway from natural resources, a cell-based screening assay system targeting transcriptional activator GLI1, which constitutes the final step in the Hh signaling pathway, was constructed. A pGL4-Luc reporter vector inserted with 12×GLI binding sites was stably transfected into HaCaT cell line expressing GLI1 under tetracycline repressor control. A suitable protocol for the screening was then established. The screening of our natural products library with the above constructed system identified six active compounds; staurosporinone (1), 6-hydroxystaurosporinone (2), arcyriaflavin C (3), 5,6-dihydroxyarcyriaflavin A (4), zerumbone (5), and zerumbone epoxide (6). Their IC_<50> values of GLI1 transcriptional inhibitory activity were 1.8, 3.6, 11.3, 6.9, 3.0 and 55μM, respectively. The next screening of our natural plants extracts library gave 15 hit plants. Repeated chromatography separations of the MeOH extracts of Physalis minima and Zizyphus cambodiana gave active compounds. P minima gave two compounds; physalin F (10) and physalin B (11), and Z. combodiana a compound; colubrinic acid (13). Their IC_<50> values were 0.66, 0.62 and 29μM, respectively. It was reported that glil, ptchl, bcl2 are the Hh/GLI-mediated transcriptional targets. The influences of these inhibitors (1, 5, 10 and 11) on these protein expressions were investigated with western blotting analysis. These inhibitors decreased the expression of GLI1 and PTCH1, which are related Hh signaling pathway. Moreover, BCL2, which is related with apoptosis, was also decreased.

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Efficient Synthesis of Chromone and Flavonoid Derivatives by Michael-aldol Reaction

Arai Midori.A, Sato Mina, Sawada Keisuke, Hosoya Takahiro, Ishibashi Masami

Proceedings of the Symposium on Progress in Organic Reactions and Syntheses (Division of Organic Chemistry, The Pharmaceutical Society of Japan) 33 ( 0 ) 18 - 18 2007

We describe the one-pot synthesis by Michael-aldol reaction of chromone and flavonoid derivatives bearing pyridine units. 4'-Benzyloxy-2'-hydroxyacetophenone (1) reacted with various pyridinecarboxaldehyde (2) to give intermediate chalcone derivatives, which underwent intramolecular cyclization followed by aldol reaction with another aldehyde. The endo 2,3-disubstituted chromones were obtained in one step as the only or major product. Furthermore, use of substituted benzaldehydes (Aldehyde A) and subsequent addition of 2 (Aldehyde B) gave 3-pyridyl-substituted flavones. Some of synthesized compounds showed the inhibition of GLI-mediated transcription, and cell growth inhibitory activity against HeLa cells.

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Synthesis study of Melleumin A and B

Hanazawa Shuwa, Arai Midori, Uchino Yujiro, Ishibashi Masami

Proceedings of the Symposium on Progress in Organic Reactions and Syntheses (Division of Organic Chemistry, The Pharmaceutical Society of Japan) 33 ( 0 ) 56 - 56 2007

A novel peptide lactone, melleumin A, and its seco acid methyl ester, melleumin B, were isolated from cultured plasmodium of the myxomycete Physarum melleum. We studied the total synthesis of melleumin A and B. Melleumin A and B consist of four residues, p-methoxybenzoic acid, L-threonine, glycine, and an unusual amino acid, a tyrosine-attached acetic acid. Total synthesis of melleumin B was achieved by a stereoselective method, which provided further evidence for the all absolute stereochemistry of melleumin B. The Wnt signal inhibitory actives of melleumin B and its 10-epimer were evaluated. 10-epimer of melleumin B showed moderate inhibition of Wnt signal transcription.

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2-I-21 14-epi-25-hydroxy-19-norvitamin D_3誘導体の分子設計と合成(一般研究発表,日本ビタミン学会第58回大会研究発表要旨)

荒井緑, 原英己, 堤龍司, Chen Tai C, 橘高敦史

ビタミン (日本ビタミン学会) 80 ( 4 ) 2006.04

ISSN 0006-386X

シトクロムP450による25(OH)-19-ノルおよび1α,25(OH)2-19-ノルビタミンD3の代謝(一般研究発表,日本ビタミン学会第58回大会研究発表要旨)

漆野奈穂子, 生城真一, 中林佐知栄, 鎌倉昌樹, 荒井緑, 堤龍司, 橘高敦史, 太田美穂, 井上國世, 榊利之

ビタミン (日本ビタミン学会) 80 ( 4 ) 224 - 224 2006.04

ISSN 0006-386X

2-C-4 前立腺がんを標的としたプロホルモン型25(OH)-19-ノルビタミンD_3誘導体(第57回大会一般研究発表)(第57回大会研究発表要旨)

荒井緑, 堤龍司, Chen Tai C, Holick Michael F, 榊利之, 漆野奈穂子, 井上國世, 橘高敦史

ビタミン (日本ビタミン学会) 79 ( 4 ) 2005.04

ISSN 0006-386X

Design of the Vitamin D Analogs Aiming at the Recovery of the Affinity for Mutant Vitamin D Receptor

Honzawa Shinobu, Takahashi Naoyuki, Yamashita Atsushi, Sugiura Takayuki, Kurihara Masaaki, Arai Midori A, Kato Shigeaki, Kittaka Atsushi

Proceedings of the Symposium on Progress in Organic Reactions and Syntheses (Division of Organic Chemistry, The Pharmaceutical Society of Japan) 31 ( 0 ) 80 - 80 2005

1&alpha;,25-Dihydroxyvitamin D3(1) has a wide range of biological activities, for example, calcium and phosphorus homeostasis, cell growth and differentiation. The actions of 1 are mediated by a specific nuclear receptor, vitamin D receptor (VDR). Hydrogen bonds between three hydroxyl groups of 1 and hydrophilic amino acids in the ligand-binding domain (LBD) of VDR are essential for its actions. Arginine 274 is known to form hydrogen bond with 1&alpha;-OH of 1, and its mutation lead to loss of the affinity and its actions. For the mutant VDR we designed the analogs having a CH3 or HOCH2 group on its 1&alpha;-position to effect hydrophobic interaction. A coupling reaction of CD ring bromoolefin and A ring enyne was carried out by the method developed by Trost. A ring enynes for 1&alpha;-CH3 and 1&alpha;-HOCH2 analogs were prepared from D-galactose and D-glucose, respectively.

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Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space

YK Kim, MA Arai, T Arai, JO Lamenzo, EF Dean, N Patterson, PA Clemons, SL Schreiber

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (AMER CHEMICAL SOC) 126 ( 45 ) 14740 - 14745 2004.11

ISSN 0002-7863

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.

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Accelerated glycosylation under frozen conditions

M Takatani, J Nakano, MA Arai, A Ishiwata, H Ohta, Y Ito

TETRAHEDRON LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 45 ( 20 ) 3929 - 3932 2004.05

ISSN 0040-4039

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Development of the first spiro bis(is oxazoline)ligands (SPRIXs) and their applications to catalytic enantioselective reactions

MA Arai, T Shinohara, T Arai, H Sasai

JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN (SOC SYNTHETIC ORGANIC CHEM JPN) 62 ( 1 ) 59 - 69 2004.01

ISSN 0037-9980

The first chiral isoxazoline ligands bearing spiro skeleton are developed. The spiro bis(isoxazoline) ligands (SPRIXs) are readily synthesized from diethyl malonate via double intramolecular nitrile oxide cycloaddition as a key step. The complex of (M, S, S)-R-SPRIX and Pd(OCOCF3)(2) promoted the catalytic asymmetric Wacker-type cyclization of alkenyl alcohols to give optically active cyclic ethers for the first time. Furthermore, starting from dialkenyl alcohol, the enantioselective tandem cyclization via oxy-palladation was achieved with up to 95% ee. Asymmetric ligands other than SPRIXs promote neither the Wacker-type reaction nor the tandem reaction.

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Spiro bis(isoxazole) as a new chiral ligand

K Wakita, MA Arai, T Kato, T Shinohara, H Sasai

HETEROCYCLES (PERGAMON-ELSEVIER SCIENCE LTD) 62 831 - 838 2004.01

ISSN 0385-5414

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Synthesis of fluorine substituted oligosaccharide analogues of monoglucosylated glycan chain, a proposed ligand of lectin-chaperone calreticulin and calnexin

Y Ito, S Hagihara, MA Arai, Matsuo, I, M Takatani

GLYCOCONJUGATE JOURNAL (KLUWER ACADEMIC PUBL) 21 ( 5 ) 257 - 266 2004

ISSN 0282-0080

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.

Synthesis of glycoprotein molecular probes for the analyses of protein quality control system

K Totani, Matsuo, I, M Takatani, MA Arai, S Hagihara, Y Ito

GLYCOCONJUGATE JOURNAL (KLUWER ACADEMIC PUBL) 21 ( 1-2 ) 69 - 74 2004

ISSN 0282-0080

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Synthesis of novel chiral spiro bis(pyrazole) ligands

S Takizawa, Y Honda, MA Arai, T Kato, H Sasai

HETEROCYCLES (PERGAMON-ELSEVIER SCIENCE LTD) 60 ( 11 ) 2551 - 2556 2003.11

ISSN 0385-5414

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