Research
Team Leader Mikiko Sodeoka, Ph.D.
This Team focuses on the development of novel types of ligand molecules, which can activate or inhibit the functions of their target proteins, based on synthetic organic chemistry. In particular, the ligand molecules, which interact with proteins involved in post-translational modification such as protein phosphorylation, glycosylation, methylation, acetylation will be designed and synthesized. We plan to design the ligand molecules based on the structure of physiological ligands and substrates of target molecules, the information on the ligand molecules found by Molecular Ligand Discovery Research Team and the structural information on target molecules found by Molecular Ligand Target Research Team. This Team also expects to contribute to identification of target molecules by optimizing ligand molecules and developing the probe molecules. In addition, we do innovate in the novel synthetic methodologies for synthesizing ligand molecules.
Research Projects
1. Development of molecular ligands controlling protein modification
2. Synthesis of molecular ligand derivatives for analysis of target proteins
3. Development of synthetic methodology for molecular ligands
Specific Research Areas
1. Synthesis of ginkgolic acid derivatives and fluorescent-labeled probe
Ginkgolic acid (1) was identified as a small molecule inhibitor of protein SUMOylation by Molecular Ligand Discovery Team. To elucidate the inhibition mechanism of SUMOylation by ginkgolic acid, this year we synthesized methyl ester 2, acetyl derivative 3, and fluorescent-labeled probe 4 based on ginkgolic acid. Although 3 showed weak inhibition of SUMOylation, methyl ester 2 did not inhibit it even at 10 μM. This result indicated that carboxylic acid on benzene ring of 1 is essential for inhibition of SUMOylation. Furthermore, we found that BODIPY-labeled compound 4 also showed SUMOylation inhibition. By using this probe molecule 4, Molecular Ligand Target Research Team found that it bound to SUMO-activating enzyme E1 directly.
2. Structure-activity relationship study of chaetocin, a novel lysine-specific histone methyltransferases inhibitor
Chaetocin, which belongs to a family of mycotoxins isolated from chaetomium minutum, is a potent inhibitor of lysine-specific histone methyltransferases. To examine the structure–activity relationship, the synthetic study of (+)-chaetocin was carried out. Finally, the total syntheses of (+)-chaetocin and its enantiomer (-)-chaetocin starting from amino acids were achieved recently. Inhibitory activities of these synthetic chaetocin and its derivatives to histone methyltransferase G9a were evaluated in collaboration with Molecular Ligand Discovery Team.
3. Synthesis of difluoromethylene-linked disaccharide unit
To clarify the precise function of glycoconjugates, we focus on the development of CF2-glycosides analogues as nonhydrolyzable glycoside mimics. Although they are expected to be useful molecular probes due to their chemical and biological stability, there are actually few synthetic reports of CF2-glycoside analogue of biologically important saccharides, because the methodologies for the construction of CF2-glycoside bond were limited. This year, we achieved the construction of CF2-glycoside linkage by the reaction of galactose derivative possessing gem-CF2-methylene group at C3. Synthesis of GM1 analogue by using this method was also examined.
4. Analysis of glycoprotein quality control in the endoplasmic reticulum
Glycoprotein glycans play critical roles in a wide variety of biological events. A majority of eukaryotic proteins carry N-linked glycans. In the endoplasmic reticulum, so-called calnexin/calreticulin cycle plays a key role in glycoprotein folding. We studied properties of glucosidase II, a key enzyme in this cycle. Our study revealed that the presence of the β-subunit was essential for its glycan processing activity. In addition, its specificity was studied by using non-natural substrates. Further study was extended to clarify the specificity of malectin, a recently discovered ER lectin.
5. Development of a general approach for synthesis of polyfunctionalized p-terphenyls and its application to total synthesis of vialinin B and related compounds
We have been engaged in synthetic studies on the natural p-terphenyls with potent inhibitory activity of TNF-α production and had accomplished the total synthesis of vialinin A (3). As a part of our continuing studies in this field, we synthesized thelephantin G isolated from the Chinese mushroom, Thelephora aurantiotincta, and revised the originally proposed p-hydroquinone structure 1 of thelephantin G to the catechol 2. In order to clarify the target molecule of vialinins, we also conducted design and synthesis of a fluorescent-labeled probe based on the molecular structure of 3. Furthermore, the first total synthesis of vialinin B (4), a powerful inhibitor of TNF-α production, was achieved. The key reactions include a double Suzuki-Miyaura coupling of electron-rich aryl bromide with a couple of phenylboronic acids, and a Cu-mediated Ullmann reaction.
6. Development of a new methodology for the preparation of organofluorine compounds
The synthesis of organofluorine compounds has attracted considerable interests and attention in pharmaceutical science and material chemistry. However, the perfluoroalkyl metal reagents have been generally regarded as unstable species since they undergo a facile α- or β-metal fluoride (M-F) elimination. We have screened various organometallics for the preparation of thermally stable perfluoroalkyl metal species and disclosed monoanion- and dianion-type zincate complexes that promotes highly chemoselective metalation of perfluoroalkyl iodides without any transition metal catalyst.
Members
Mikiko Sodeoka, Ph.D. (Team Leader, concurrently Chief Scientist of Synthetic Organic Chemistry Laboratory)
Yukishige Ito, Ph.D. (concurrently Chief Scientist of Synthetic Cellular Chemistry Laboratory)
Hou Zhaomin, Ph.D. (concurrently Chief Scientist of Organometallic Chemistry Laboratory)
Hiroyuki Koshino, Ph.D. (concurrently Team Head of Molecular Characterization Team, Chemical Biology Core Facility）
Hiroyuki Koshino, Ph.D. (concurrently Team Head of Molecular Characterization Team, Chemical Biology Core Facility）
Go Hirai, Ph.D. (concurrently Senior Research Scientist of Synthetic Organic Chemistry Laboratory)
Shunya Takahashi, Ph.D. (concurrently Senior Research Scientist of Molecular Characterization Team, Chemical Biology Core Facility）
Takemichi Nakamura, Ph.D. (concurrently Senior Research Scientist of Molecular Characterization Team, Chemical Biology Core Facility）
Publications
Fukuda, I., Ito, A., Hirai, G., Nishimura, S., Kawasaki, H., Saitoh, H., Kimura, K., Sodeoka, M., and Yoshida, M.: "Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate." Chem. Biol., 16: 133-140, 2009. PMID: 19246003
Ohkubo, M., Hirai, G., and Sodeoka, M.: "Synthesis of the DFGH ring system of type B physalins: highly oxygenated, cage-shaped molecules." Angew. Chem. Int. Ed., 48: 3862-3866, 2009. PMID: 19378305
Watanabe, T., Totani, K., Matsuo, I., Maruyama, J., Kitamoto, K., and Ito, Y.: "Genetic analysis of glucosidase II β-subunit in trimming of high-mannose-type glycans." Glycobiology, 19: 834-840, 2009. PMID: 19395677
Muranaka, A., Yasuike, S., Liu, C. Y., Kurita, J., Kakusawa, N., Tsuchiya, T., Okuda, M., Kobayashi, N., Matsumoto, Y., Yoshida, K., Hashizume, D., and Uchiyama, M.: "Effect of periodic replacement of the heteroatom on the spectroscopic properties of indole and benzofuran derivatives." J. Phys. Chem., 113: 464-473, 2009. PMID: 19099440
Ye, Y. Q., Koshino, H., Onose, J., Negishi, C., Yoshikawa, K., Abe, N., and Takahashi, S.: "Structural revision of thelephantin G by total synthesis and the inhibitory activity against TNF-α production." J. Org. Chem., 74: 4642-4645, 2009. PMID: 19453155
Discovery Team
