In a living cell, the cascade mechanism of signal transduction is functioning through the molecular recognition of chemical substances. The signal transduction is initiated by the formation of a complex between a bioactive natural product and its targeted protein. This project aims at clarifying the molecular mechanism how a protein recognizes a bioactive molecule by using organic synthesis. Specifically, the interaction between the strongly active natural products and its targeting proteins will be investigated as model systems. On the basis of the demonstrated molecular mechanism, the innovative bioactive molecules will be ultimately synthesized through the rational molecular design for applying our methodology to medicinal chemistry.

[Bioluminescence] Molecular mechanism of Symplectoteuthis bioluminescence, Molecular mechanism of dioxetanone chemiluminescence, Research on novel bioluminescent systems.

[Diapose of silk worm] Molecular mechanism of diapose of silk worm, which caused EA4 protein.

[Protein phosphatase] Molecular mechanism of inhibition of tautomycin against protein phosphatase 1A.

[Total synthesis] Synthetic studies of neurotoxic Ciguatoxin, tetrodotoxin and its derivatives.

• Synthesis of ¹³C-Dehydrocoelenterazxine and NMR Studies on Bioluminescence of Symplectoteuthis model.  Kuse, M.; Isobe, M. Tetrahedron 2000, 56, 2629-2639.

• Effects of modification of the hydrophobic C1-C16 segment of tautomycin on its affinity to  type 1 and type 2A protein phosphatases.  Takai, A.; Tsuboi, K.; Koyasu, M.; Isobe, M.  Biochemical Journal 2000, 350, 81-88.

• Stereocontrolled Synthesis of (-)-5,11-Dideoxytetrodotoxin.  Asai, M.; Nishikawa, T.; Ohyabu, N.; Yamamoto N.; Isobe, M.  Tetrahedron, 2001, 57, 4543-4558.

• Extensive Investigations on Oxidized Amino Acid Residues in H2O2-Treated Cu,Zn-SOD Protein with LC-ESI-Q-TOF-MS,MS/MS for the Determination of the Copper-Binding Site  Kurahashi, T.;  Miyazaki, A.; Suwan, S.; Isobe, M.  J. Am. Chem. Soc., 2001, 123, 9268-9278.

• Synthesis of the BCD-ring of Ciguatoxin 1B using an acetylene cobalt complex and vinylsilane strategy   Kira, K.; Hamajima, A.; Isobe, M.     Tetrahedron, 2002,  58, 1875-1888.

• Determination of a Sugar Chain and its Linkage Site on a Glycoprotein TIME-EA4 from Silkworm Diapause Eggs by means of LC-ESI-Q-TOF-MS and MS/MS   Kurahashi, T.; Miyazaki, A.; Murakami, Y.; Suwan, S.; Franz, T.; Isobe, M.; Tani, N.; Kai, H.  Bioorganic and Medicinal Chemistry, 2002, 10, 1703-1710.

• Asymmetric Total Synthesis of 11-Deoxytetrodotoxin, a Naturally Occurring Congener.  Nishikawa, T.; Asai, M.; Isobe, M.  J. Am. Chem. Soc., 2002. 124, 7847-7852.

• Synthesis of JKLM Ring Fragment of Ciguatoxin 1B via Acetylene-Cobalt Strategy.  Baba, T.; Isobe, M.  Synlett,  2003, 547-551.

• Convergent Synthesis of the E’FGH Ring Fragment of Ciguatoxin 1B via an Acetylene Cobalt Complex Strategy, Takai, S.; Sawada, N.; Isobe, M.  J. Org. Chem., 2003, 68, 3225-3231.

• The First Total Synthesis of (-)-Tetrodotoxin.  Ohyabu, N.; Nishikawa, T.; Isobe, M.   J. Am. Chem. Soc., 2003, 125, 8798-8805..
  

• Molecular Diversity of Cereulide and valinomycin detected by means of nano-HPLC-ESI-Q-TOF-MS.   Pitchayawasin, S.; Isobe, M.; Kuse, M.; Franz, T.; Agata,N.; Ohta, M.  Int. J. Mass Spectrometry, 2004, 235, 123-129.
  

• Kanakubo, A.; Koga, K.; Yoza, K.; Isobe, M. Tetrabromohydroquinone and Riboflavin are Responsible for Green luminescence in the Luminous Acorn Worm, Ptychodera flava. Luminescence 2005, 20, 397-400.

• Tojo, S.; Isobe, M. Stereocontrolled Synthesis of Oxabicyclo[2.2.1]heptane Segment on Solanoeclepin A. Synthesis 2005, 8, 1237-1244.

• Kondo, N.; Kuse M.; Mutarapata, T,; Thasana, N.; Isobe, M. Novel Synthetic Route of Coelenterazines-2-synthesis of Various Dehydrocoelenterazine Analogs. J. Heterocyclic Chem. 2005, 65, 843-856.

• Kuse, M.; Doi, I.; Kondo, N.; Kageyama, Y.; Isobe, M. Synthesis of Azide-Fluoro-Dehydrocoelenterazine Analog as a Photoaffinity-Labeling Probe and Photolysis of Azide-Fluoro-Coelenterazine. Tetrahedron 2005, 61, 5754-5762.

• Ichikawa, Y.; Yamauchi, E.; Isobe, M. Allyl Cyanate-to-isocyanate Rearrangement for the Synthesis of Quaternary Stereocenter with Nitrogen Substituent. Biosci. Biotech. Biochem. 2005, 69, 939-943.

• Lin, C.; Yu, Y.; Kadono, T.; Iwata, M.; Umemura, K.; Furuichi, T.; Kuse, M.; Isobe, M.; Yamamoto, Y.; Matsumoto, H.; Yoshizuka, K.; Kawano, T. Action of Aluminum, Novel TPC1-type Channel Inhibitor, Against Salicylate-induced and Cold-shock-induced Calcium Influx in Tobacco BY-2 Cells. Biochem. Biphys. Res. Commun. 2005, 332, 823-830. 

• Suntornchashwej, S.; Chaichit, N.; Isobe, M.; Suwanborirux, K. Hectochlorin and Morpholine Derivatives from the Thai Sea Hare, Bursatella leachii. J. Nat. Prod. 2005, 68, 951-955.

• Nishiyama, T.; Ichikawa, Y.; Isobe, M. Total Synthesis of Glycosinnamoylsperimidin D. Angew. Chem., Int. Ed. 2005, 44, 4372-4375.

• Matsukawa, Y.; Isobe, M.; Kotsuki, H.; Ichikawa, Y. Synthesis of (+)-Conagenin. J. Org. Chem. 2005, 70, 5339-5341.

• Ichikawa, Y.; Ito, T.; Isobe, M. Stereoselective Allyl Amine Synthesis via Enantioselective Addition of Diethylzinc and [1,3]-Chirality Transfer. Synthesis of Lentiginosine and Polyoxamic Acid Derivative. Chem. Eur. J., 2005, 1949-1957.

• Ti, X.; Tuzuki, N.; Tani, N.; Isobe, M.; Kai, H. The Peptide PIN Changes the Timing of Transitory Burst Activity of Timer-ATPase TIME in Accordance with Diapause Development in Eggs of the Silkworm, Bombyx mori. J. Insect. Physiol. 2005, 51, 1025-1032.

• Hamajima, A.; Isobe, M. Convergent Synthesis of the Right-Hand Segment of Ciguatoxin. Org. Lett. 2006, 8, 1205-1208.

• Nishikawa, T.; Koide, Y.; Kanakubo, A.; Yoshimura, H.; Isobe, M. Synthesis of β-Analogues of C-Mannosyltryptophan, a Novel C-Glycosylamino Acid Found in Proteins. Org. Biol. Chem. 2006, 4, 1268-1277.

• Ichikawa, Y.; Matsukawa, Y.; Isobe, M. Urea Glycoside Synthesis in Water. J. Am. Chem. Soc. 2006, 128, 3934-3938.

• Hamajima, A.; Nakata, H.; Goto, M.; Isobe, M. Novel Functional Group Transformation from Acetylene Cobalt Complex to Ketone via Ligand Exchange. Chem. Lett. 2006, 35, 464-465.

• Urabe, D.; Nishikawa, T.; Isobe, M. An Efficient Total Synthesis of Optically Active Tetrodotoxin from Levoglucosenone. Chem. Asian J. 2006, 1, 125-135.

• Isobe, M.; Kai, H.; Kurahashi, T.; Suwan, S.; Pitchayawasin-T. S.; Franz, T.; Tani, N.; Higashi, K.; Nishida, H. A Molecular Mechanism of the Termination of Insect Diapause-----a Timer Protein, TIME-EA4 in the Diapause Eggs of the Silkworm, Bombyx mori. ChemBioChem. 2006, 7, 1590-1598.

• Hokama, Y.; Chun, K. E.; Campora, C. E.; Higa, N.; Suma, C.; Hamajima, A.; Isobe, M. Biological Activity of the Functional Epitope of Ciguatoxin Fragment AB on the Neuroblastoma Sodium Channel in Tissue Culture. J. Clinical Laboratory Analysis. 2006, 20, 126-132.

• Pitchayawasin-Thapphasaraphong, S.; Isobe, M. Molecular Diversity of Valinomycin, A 36-Membered Cyclic Depsipeptide. Which was Detected by Means of HPLC-Q-TOF-MS on Hydrolysate Dipeptides. ITE Letters on Batteries, New Technologies & Medicine 2006, 7, 465-471.

• Ti, X.; Tani, N.; Isobe, M.; Kai, H. Time-measurement-regulating Peptide PIN May Alter a Timer Conformation of Time Interval Measuring Enzyme (TIME). J. Insect Physiology 2006, 52, 461-467.

• Saeeng, R.; Isobe, M. Stereoselective C-Alkynylation, Allenylation and Propargylation Leading to Sugar Glycosides. Chem. Lett. Highlight Review. 2006, 35, 552-557.

• Kanokmedhakul, S.; Kanokmedhakul, K.; Nasomjai, P.; Louangsysouphanh, S.; Soytong, K.; Isobe, M.; Kongsaeree, P.; Prabpai, S.; Suksamrarnr, A. Antifungal Azaphilones from the Fungus Chaetomium cupreum CC3003. J. Nat. Prod. 2006, 69, 891-895.

• Nishikawa, T.; Urabe, D.; Tomita, M.; Tsujimoto, T.; Iwabuchi, T.; Isobe, M. One-pot Transformation of Trichloroacetamide into Readily Deprotectable Carbamates. Org. Lett. 2006, 8, 3263-3265.

• Ichikawa, Y.; Matsukawa, Y.; Tamura, M.; Ohara, F.; Isobe, M.; Kotsuki, H. Synthesis of Urea-Tethered Disaccharides in Water. Chem. Asian J. 2006, 1, 717-723.

• Ichikawa, Y.; Egawa, H.; Ito, T.; Isobe, M.; Nakano, K.; Kotsuki, H. Stereocontrolled Route to Vicinal Diamines by [3,3] Sigmatropic Rearrangement of Allyl Cyanate: Asymmetric Synthesis of Anti-(2R,3R)- and Syn-(2R,3S)-2,3-diaminobutanoic Acids. Org. Lett. 2006, 8, 5737-5740.

• Sawayama, Y.; Tsujimoto, T.; Sugino, K.; Nishikawa, T.; Isobe, M.; Kawagishi, H. Syntheses of Naturally Occurring Terphenyls and Its Related Compounds. Biosci. Biotech. Biochem. 2006, 70, 2998-3003.

• Suntornchashwej, M.; Suwanborirux, K.; Koga, K.; Isobe, M. Malyngamide X, the First 7R-Lyngbic Acid Connecting to A New Tripeptide Backbone from the Thai Sea Hare Bursatella leachii. Chem. Asian J. 2007, 2, 114-122.

• Isobe, M.; Kurono, M.; Tsuboi, K.; Takai, A. Synthesis of [18,19,21,22-¹³C₄]-Labeled Tautomycin as NMR Probe of Protein Phosphatase Inhibitor. Chem. Asia J. 2007, 2, 377-385.

• Sydnes, M. O.; Isobe, M. Synthesis of the Second Generation Photoaffinity Probes of Tautomycin. Tetrahedron 2007, 63, 2593-2603.

• Suntornchashwej, S.; Suwanborirux, K.; Isobe, M. Total Synthesis of Malyngamide X and Its 7’S-Epi-isomer. Tetrahedron 2007, 63, 3217-3226.

• Sarin Tadtong, S.; Meksuriyen, D.; Tanasupawat, S.; Isobe, M.; Suwanborirux. K. Geldanamycin Derivatives and Neuroprotective Effect on Cultured P19-derived Neurons. Bioorg. Med. Chem. Lett. 2007, 17, 2939-2943.

• Nonomiya, A.; Hamajima, A.; Isobe, M. Synthesis of Symmetric HIJ-ring Model of Ciguatoxin. Tetrahedron 2007, 63, 5886-5894.

• Minoru Isobe and Pauline Chiu: The 1^st International Conference on Cutting-Edge Organic Chemistry in Asia - Asian Core Program (ACP) and IUPAC East Asian Networking Project. Chem. Asian. J. 2007, 2(#3), 452-454.

• Sydnes, M. O.; Doi, I.; Ohishi, A.; Kuse, M.; Isobe, M. Determination of Solvent-Trapped Products Obtained by Photolysis of Aryl Azides in 2,2,2-Trifluoroethanol. Chem. Asian J. 2008, 3, 102-112.

• Kajii, S.; Nishikawa, T.; Isobe, M. Synthesis of N-Hydroxyenamide, a Potential Precursor of Chartelline. Tetrahedron Lett. 2008, 49, 594-597.

• Sydnes, M.O.; Isobe, M. One-pot reductive monoalkylation of nitro aryls with hydrogen over Pd/C. Tetrahedron Lett. 2008, 49, 1199-1202.

• Masayama, A.; Takahashi, T.; Tsukada, K.; Nishikawa, S.; Takahashi, R.; Adachi, M.; Koga, K.; Suzuki, A.; Yamane, T.; Nakano, H.; Iwasaki, Y. Streptomyces Phospholipase D Mutants with Altered Substrate Specificity Capable of Phosphatidylinositol Synthesis. ChemBioChem 2008, in press.

• Sydnes, M.O.; Kuse, M.; Kurono, M.; Shimomura, A.; Ohinata, H.; Takai, A.; Isobe, M. Protein Phosphatase Inhibitory Activity of Tautomycin Photoaffinity Probes Evaluated at Femto-molar Level. Bioorg. Med. Chem. 2008, 16, 1747-1755.

• Nishikawa, T.; Adachi, M.; Isobe, M. C-Glycosylation, Chemical Glycosylation Reactions, In Glycoscience, 2^nd edition, Springer Verlag 2008, in press.