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Papers - Arai, Midori

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Development of Chiral Spiro Ligands for Metal-Catalyzed Asymmetric Reactions

Gan B. Bajracharya, Midori A. Arai, Priti S. Koranne, Takeyuki Suzuki, Shinobu Takizawa, Hiroaki Sasai

BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN (CHEMICAL SOC JAPAN) 82 ( 3 ) 285 - 302 2009.03

Accepted, ISSN 0009-2673

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 spiro bis(isoxazoline) ligands (SPRIXs), spiro bis(isoxazole) ligands, and spiro (isoxazole-isoxazoline) ligands were readily synthesized through intramolecular double nitrile oxide cycloaddition of the corresponding dioximes as a key step. An unprecedented activation of olefins was displayed by the Pd-11 complexes of these chiral spiro ligands in the enantioselective oxidative cyclizations, for example; the asymmetric tandem cyclization of dialkenyl alcohol via oxy-palladation produced a bicyclic ether in excellent enantioselectivity and enantioselective version of the aminocarbonylation proceeded for the first time. Other hitherto known chiral ligands we examined failed to promote these reactions.

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A Method for the Rapid Discovery of Naturally Occurring Products by Proteins Immobilized on Magnetic Beads and Reverse Affinity Chromatography

Midori A. Arai, Eiji Kobatake, Takashi Koyano, Thaworn Kowithayakorn, Shigeaki Kato, Masami Ishibashi

CHEMISTRY-AN ASIAN JOURNAL (WILEY-V C H VERLAG GMBH) 4 ( 12 ) 1802 - 1808 2009

Accepted, ISSN 1861-4728

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

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Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana

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

BIOORGANIC & MEDICINAL CHEMISTRY (PERGAMON-ELSEVIER SCIENCE LTD) 16 ( 21 ) 9420 - 9424 2008.11

Accepted, ISSN 0968-0896

The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. By screening tropical plant extracts by using our screening system, Zizyphus cambodiana was found to include Hh/GLI signaling inhibitors. Bioassay-guided fractionation of this plant extract led to the isolation of three active pentacyclic triterpenes, colubrinic acid (1), betulinic acid (2) and alphitolic acid (3), as potent inhibitors. The inhibition of GLI-related protein expression with 1 or 2 was observed in HaCaT cells with exogenous GLI1, or human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited by 1 or 2. We also examined the cytotoxicity of these active compounds against PANC1, human prostate cancer cells (DU145) and mouse embryo fibroblast cells (C3H10T1/2). The cytotoxicity against cancer cells (PANC1 and DU145) by 1 or 2 would be caused by inhibition of the expression of the anti-apoptosis protein BCL2. These pentacyclic triterpene inhibitors showed an important relationship between Hh/GLI signaling inhibition, the decrease of BCL2, and cytotoxicity against cancer cells. (C) 2008 Elsevier Ltd. All rights reserved.

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SYNTHESIS AND EVALUATION OF ISOMERS OF MELLEUMIN B FROM THE MYXOMYCETE PHYSARUM MELLEUM; AN APPROACH FOR WNT SIGNAL INHIBITOR TRUSTED IN NATURE

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

HETEROCYCLES (PERGAMON-ELSEVIER SCIENCE LTD) 76 ( 2 ) 1425 - 1438 2008.11

Accepted, ISSN 0385-5414

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Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription

Takahiro Hosoya, Midori A. Arai, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

CHEMBIOCHEM (WILEY-V C H VERLAG GMBH) 9 ( 7 ) 1082 - 1092 2008.05

Accepted, ISSN 1439-4227

The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystourosporinone (10), orcyriaflavin C (71) and 5,6-dihydroxyarcyrioflovin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physolins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis BcI2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.

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Vitamin D hormone: Structural refinement of the seco-steroidal skeleton and the nuclear receptor mediated biological activity

Atsushi Kittaka, Daisuke Sawada, Masashi Takano, Nozomi Saito, Tomoyuki Katayama, Kanako Shindo, Yuya Tsukuda, Shinobu Honzawa, Midori A. Arai, Hiroshi Saito, Ken-ichiro Takagi, Kazuya Takenouchi, Seiichi Ishizuka, Toshiyuki Sakaki, Tai C. Chen

ANTICANCER RESEARCH (INT INST ANTICANCER RESEARCH) 28 ( 3A ) 1618 - 1619 2008.05

Accepted, ISSN 0250-7005

The 2 alpha-(3-hydroxypropyl) group as an active motif in vitamin D-3 analogues as agonists of the mutant vitamin D receptor (Arg274Leu)

Honzawa Shinobu, Yamamoto Yasuhiro, Yamashita Atsushi, Sugiura Takayuki, Kurihara Masaaki, Arai Midori A, Kato Shigeaki, Kittaka Atsushi

BIOORGANIC & MEDICINAL CHEMISTRY 16 ( 6 ) 3002 - 3024 2008.03

Accepted, ISSN 0968-0896

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Determination of absolute stereochemistry, total synthesis, and evaluation of peptides from the myxomycete Physarum melleum

Shuwa Hanazawa, Midori A. Arai, Xiaofan Li, Masarni Ishibashi

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 18 ( 1 ) 95 - 98 2008.01

Accepted, ISSN 0960-894X

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. (C) 2007 Elsevier Ltd. All rights reserved.

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Hedgehog signaling inhibitors isolated from myxomycetes and a Solanaceae plant

Ishibashi, M., Hosoya, T., Tateno, C., Arai, M. A.

Planta Medica 74 ( 9 ) 909 - 909 2008

Accepted

Efficient Synthesis of Chromone and Flavonoid Derivatives with Diverse Heterocyclic Units

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

CHEMISTRY-AN ASIAN JOURNAL (WILEY-V C H VERLAG GMBH) 3 ( 12 ) 2056 - 2064 2008

Accepted, ISSN 1861-4728

Chromones and flavonoids are important bioactive compounds. We envisioned that new heterocyclic-substituted chromones or flavonoids might act as new bioactive compounds. To obtain diverse molecules, we developed an efficient one-pot synthesis by Michael aldol reaction of chromone and flavonoid derivatives bearing heterocyclic units. The 2,3-heterocyclic-substituted chromones were obtained in one step. Moreover, the use of substituted benzaldehydes and subsequent addition of heterocyclic aldehydes gave 3-pyridyl-substituted flavones. We also examined these one-pot reactions in the solid phase. To introduce an additional point of diversity into the molecules, Suzuki-Miyaura coupling was performed. Furthermore, we identified the cytotoxicity of the synthesized compounds against cancer cells (PANC1 and HeLa cells). Several compounds were cytotoxic to these cancer cells.

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Total synthesis of melleumins A and B and their analogs: Determination of stereochemistry and Wnt signal inhibitory activity

Ishibashi, M., Hanazawa, S., Uchino, Y., Li, X., Arai, M. A.

Planta Medica 74 ( 9 ) 2008

Accepted

Kinetic studies of 25-hydroxy-19-nor-vitamin D-3 and 1 alpha,25-dihydroxy-19-nor-vitamin D-3 hydroxylation by CYP27B1 and CYP24A1

Naoko Urushino, Sachie Nakabayashi, Midori A. Arai, Atsushi Kittaka, Tai C. Chen, Keiko Yamamoto, Keiko Hayashi, Shigeaki Kato, Miho Ohta, Masaki Kamakura, Shinichi Ikushiro, Toshiyuki Sakaki

DRUG METABOLISM AND DISPOSITION (AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS) 35 ( 9 ) 1482 - 1488 2007.09

Accepted, ISSN 0090-9556

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) D3] and CYP24A1-dependent hydroxylation of 1 alpha,25(OH)-19-nor-D3 and 1 alpha, 25(OH)(2)D-3, we found that k(cat)/ Km 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 kcat/ Km value for 24-hydroxylation was not significantly different between 1 alpha,25(OH)219- 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.

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Synthesis, determination of stereochemistry, and evaluation of new bisindole alkaloida from the myxomycete Arcyria ferruginea: An approach for Wnt signal inhibitor

Kouken Kaniwa, Midori A. Arai, Xiaofan Li, Masami Ishibashi

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 17 ( 15 ) 4254 - 4257 2007.08

Accepted, ISSN 0960-894X

To determine the stereochemistry of dihydroarcyriarubin C (1), new bisindole alkaloid isolated from the myxomycete Arcyriajerruginea, 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 Writ 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-T. The cis-dihydroar-cyriarubin C (2) showed moderate inhibition of Wnt signal transcription, which suggests that bisindole frameworks might be useful as small-molecule Writ signal inhibitors. (c) 2007 Elsevier Ltd. All rights reserved.

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Design and synthesis of chiral hybrid spiro (isoxazole-isoxazoline) ligands

Priti S. Koranne, Tetsuya Tsujihara, Midori A. Arai, Gan B. Bajracharya, Takeyuki Suzuki, Kiyotaka Onitsuka, Hiroaki Sasai

TETRAHEDRON-ASYMMETRY (PERGAMON-ELSEVIER SCIENCE LTD) 18 ( 8 ) 919 - 923 2007.05

Accepted, ISSN 0957-4166

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High-throughput system for analyzing ligand-induced cofactor recruitment by vitamin D receptor

Midori A. Arai, Ken-ichi Takeyama, Saya Ito, Shigeaki Kato, Tai C. Chen, Atsushi Kittaka

BIOCONJUGATE CHEMISTRY (AMER CHEMICAL SOC) 18 ( 3 ) 614 - 620 2007.05

Accepted, ISSN 1043-1802

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.

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Creative synthesis of novel vitamin D analogs for health and disease

Atsushi Kittaka, Nozomi Saito, Shinobu Honzawa, Kazuya Takenouchi, Seiichi Ishizuka, Tai C. Chen, Sara Peleg, Shigeaki Kato, Midori A. Arai

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY (PERGAMON-ELSEVIER SCIENCE LTD) 103 ( 3-5 ) 269 - 276 2007.03

Accepted, ISSN 0960-0760

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

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Evaluation of C-2-substituted 19-nor-1α,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer

T. C. Chen, K. S. Persons, S. Zheng, J. Mathieu, M. F. Holick, Y. F. Lee, B. Bao, M. A. Arai, A. Kittaka

Journal of Steroid Biochemistry and Molecular Biology 103 ( 3-5 ) 717 - 720 2007.03

ISSN 0960-0760

1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1α,25(OH)2D3 can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized 3H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1α,25(OH)2D3 analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2α- or 2β-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1α,25(OH)2D3. The 3H-thymidine incorporation data were supported by the cell counting data after cells were treated with 1α,25(OH)2D3, 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3 or 19-nor-2β-(3-hydroxypropyl)-1α,25(OH)2D3 for 7 days. 19-Nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3 and 19-nor-2β-(3-hydroxypropyl)-1α,25(OH)2D3 were also shown to be about 10-fold more active than 1α,25(OH)2D3 in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1α,25(OH)2D3 molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer. © 2006 Elsevier Ltd. All rights reserved.

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Enantioselective glyoxylate-ene reaction using a novel spiro bis(isoxazoline) ligand in copper catalysis

Kazuhiko Wakita, Gan B. Bajracharya, Midori A. Arai, Shinobu Takizawa, Takeyuki Suzuki, Hiroaki Sasai

TETRAHEDRON-ASYMMETRY (PERGAMON-ELSEVIER SCIENCE LTD) 18 ( 3 ) 372 - 376 2007.02

Accepted, ISSN 0957-4166

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Novel 2-alkyl-1 alpha,25-dihydroxy-19-norvitamin D-3: Efficient synthesis with Julia olefination, evaluation of biological activity and development of new analyzing system for co-activator recruitment

Midori A. Arai, Atsushi Kittaka

ANTICANCER RESEARCH (INT INST ANTICANCER RESEARCH) 26 ( 4A ) 2621 - 2631 2006.07

Accepted, ISSN 0250-7005

New 2-alkyl-1a,25-dihydroxy-19-norvitamin D-3 analogs were efficiently synthesized. The C2-alkyl-A-ring precursors were prepared as (3R,5R)-4-alkyl-3,5-dihydroxycyclohexanones from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The novel CD-ring coupling partner, with the elongated two carbon unit, was synthesized from 25-hydroxy Grundmann's ketone, and applied to modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were moderate (47-62%). After the separation of the diastereomers based on C2 stereochemistry using HPLC, the structure (2 alpha or 2 beta) was determined by H-1 NMR studies including NOE (nuclear Overhauser effect) experiments. It was also found that 1H NMR chemical shifts on the A-ring showed good correlation with DeLuca's 2-methyl- and 2-ethyl-1 alpha,25-dihydroxy-19-norvitamin D-3 analogs. Among the synthesized 19-norvitamin D-3 analogs, 2 alpha-(3-hydroxypropyl)-1a,25-dihydroxy-19-norvitamin D-3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone (1), while its beta-isomer had only a 3% affinity. Both 2 alpha-allyl- and 2 alpha-propyl-1 alpha, 25-dihydroxy-19-norvitamin D-3 and their 2 beta-analogs possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1 and, interestingly, even the weaker ligand, 2 beta-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitamin D-3 (8b), showed a 67-fold higherpotency in cell differentiation activity than that of 1. Next, a novel rapid analyzing system of ligand-induced co-factor recruitment on VDR was developed using fluorophore labelled CoA and HCHO fixing of the complex. The efficiency of recruitment of co-activators would explain the discrepancy between the biological activity and the VDR affinity of the ligand.

Design and synthesis of oligosaccharides that interfere with glycoprotein quality-control systems

MA Arai, Matsuo, I, S Hagihara, K Totani, J Maruyama, K Kitamoto, Y Ito

CHEMBIOCHEM (WILEY-V C H VERLAG GMBH) 6 ( 12 ) 2281 - 2289 2005.12

Accepted, ISSN 1439-4227

Calnexin (CNX) and its soluable 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. The paper describes the synthesis of the non-natural undecsaccharide 2 and heptasaccharide 16, designed as potential inhibitors of the ER quality-control system. Each possesses the key tetrasaccharide element (Glc(1)Man(3)) 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 colorimetry (ITC). As expected, each of them had a significant affinity towards CRT In addition, these compounds were shown to be resistant to glucosidose II digestion. Their activities in blocking the chaperone function of CRT wet I e next measured by using malate dehydrogenose (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.

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