2005 Fiscal Year Final Research Report Summary
Synthesis and Anti-Tumor Activity of TDCM
| Project/Area Number |
14208075
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | Tokushima Bunri University |
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Principal Investigator |
NISHIZAWA Mugio Tokushima Bunri University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (40137188)
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| Co-Investigator(Kenkyū-buntansha) |
IMAGAWA Hiroshi Tokushima Bunri University, Faculty of Pharmaceutical Sciences, Lecturer, 薬学部, 講師 (80279116)
TAKAO Hiroko Tokushima Bunri University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (00279118)
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| Project Period (FY) |
2002 – 2005
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| Keywords | activation of immune system / anti-tumor activity / trehalose derivative / glycolipid / mercuric triflate-catalyzed reaction / hydration of alkyne / enyne cyclization / sterol biosynthesis |
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| Research Abstract |
Cell surface glycolipids of Mycobacterium tuberculosis with more the 60 carbons fatty acid residue exhibits anti-tumor activity based on the activation of immune systems, however significant toxicity retards its medical applications even though a significant research have been carried out for many years particularly by Yamamura school of Osaka University. We have interested in a shorter fatty acid analogues, TDCM, obtained from cell surface of diphteriae, and achieved the synthesis of four stereoisomers (RR, RS, SR and SS) based upon the stereogenic centers of its fatty acid residue. First, we identified that the natural product is the RR isomer, and then synthetic SS isomer showed significant anti-tumor activity by activating macrophages without showing toxicity (neither in vivo nor cytotoxicity). Then we achieved the synthesis of a large numbers of analogues after establishing the in vitro assay systems. We are currently applying the patent by developing anti-tumor active compounds t
… More
hat shows activation of IL-6.
On the other hand we have been working on the development of new synthetic methodologies. In 1983, we developed highly efficient olefin cyclization agent, Hg(OTf)_2. In 2002, the year this research project started, we hound that Hg(OTf)_2 shows powerful catalytic activity for the hydration of terminal alkynes leading to methyl ketones. The process is clean catalytic reaction and dose not produce methylmercuric chloride that induced Minamata decease in 1952. We have further demonstrated that Hg(OTf)_2-catalyzed hydroxylative 1,6-enyne cyclization to give exomethylene five-membered ring products, cyclization of 1-alkyn-5-ones leading to 2-methylfurans, arylalkyne cyclization leading to dihydronaphthalene derivatives, biomimetic tandem cyclization of alkynyl alkenyl aryl derivative to give polycarbocycles, and the reaction of propargyl acetate with water affording vinyl ketones. These reactions likely involve a protodemercuration step of the vinylmercury intermediate, which is induced by in situ-generated TfOH.
We have also been investigating the area of sterol biosynthesis after elucidation of stepwise mechanism for oxidosqualene cyclization. Recently we found that the energetically disfavored ring enlargement of pre-C-ring tert-cation to six-membered ring sec-cation is overcome by conformation change controlled by counteranions. This is the first example of the anti-Markovnikov rearrangement observed in cation chemistry, and this is the first example that the cation conformational calculation in the presence of counteranion. Less
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[Journal Article] Mercuric Triflate-(TMU)_3-Catalyzed Cyclization of w-Alkynoic Acid Leading w-Methylene-w-lactones and Application to the Synthesis of Naturally Occurring g-Methylene-g-lactone.2006
Author(s)
Imagawa, H., Fujikawa.Y., Tsuchihiro, A., Kinoshita, A., Yoshinaga, T., Takao, H., Nishizawa, M.
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Journal Title
Synlett (4)
Pages: 639-641
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] An Unusual Twist Conformation of 2-O-Methyl-1,3,4,5-tetrakis-O-tert-butylsilyl-myo-inositol.2004
Author(s)
Yamada, H., Okajima, K., Imagawa, H., Nagata, Y., Nishizawa, M.
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Journal Title
Tetrahedron Lett. 45(22)
Pages: 4349-4351
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Stable Axial-Rich Chair Conformer of myo-Inositol Derivatives due to Introduction of Two Adjacent Bulky Silyl Protections.2004
Author(s)
Yamada, H., Okajima, K., Imagawa, H., Mukae, T., Kawamura, Y., Nishizawa, M.
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Journal Title
Tetrahedron Lett. 45(15)
Pages: 3157-3160
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Cyclization of Dienols, Polyenes, and Dienyne Mediated by Mercuric Salts : Course of Cyclizations Controlled by Stability of Cationic Intermediates.2004
Author(s)
Takao, H., Wakabayashi, A., Takahashi, K., Imagawa, H., Sugihara, T., Nishizawa, M.
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Journal Title
Tetrahedron Lett. 45(5)
Pages: 1079-1082
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] An Efficient Chemical Fixation of Nitric Oxide : Convenient and Practical Synthesis of 1,2,3-Oxadiazole 3-Oxide.2004
Author(s)
Sugihara, T., Kuwahara, K., Wakabayashi, A., Takao, H., Imagawa, H., Nishizawa, M.
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Journal Title
Chem.Commun. (2)
Pages: 216-217
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Mercuric Triflate Catalyzed Hydroxylative Cyclization of 1,6-Enynes.2003
Author(s)
Nishizawa, M., Yadav, V.K., Skwarczynski, M., Takao, H., Imagawa, H., Sugihara, T.
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Journal Title
Org.Lett. 5(10)
Pages: 1609-1611
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Triethyl- (or Trimethyl-) silyl Triflate-Catalyzed Reductive Cleavage of Triphenylmethyl (Trityl) Ethers with Triethylsilane.2003
Author(s)
Imagawa, H., Tsuchihashi, T., Singh, R.K., Yamamoto, H., Sugihara T., Nishizawa, M.
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Journal Title
Org.Lett. 5(2)
Pages: 153-155
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Methylidynetricobalt Nonacarbonyl Catalyzed Cyclotrimerization of Alkynes.2002
Author(s)
Sugihara, T., Wakabayashi, A., Nagai, Y., Takao, H., Imagawa, H., Nishizawa, M.
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Journal Title
Chem.Comm. (6)
Pages: 576-577
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Inhibitory Effect of Trehalose Dimycolate (TDM) and Its Stereoisomeric Derivatives, Trehalose Dicorynomycolates (TDCMs), with Low Toxicity on Lung Metastasis of Tumor Cell in Mice.1999
Author(s)
Watanabe, R., Yoo, Y.C., Hata, K., Mitobe, M., Koike, Y., Nishizawa, M., Garcia, D.M., Noguehi, Y., Imagawa, H., Yamada, H., Azuma, I.
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Journal Title
Vaccine 17
Pages: 1484-1492
Description
「研究成果報告書概要(欧文)」より
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