研究概要

Ubiquitin-targeting chimeras (UbTACs) is an approach to catalyze the ubiquitination of substrate proteins to trigger various cellular outcomes. The UbTACs comprise of a novel E3 ubiquitin ligase ligand conjugated via a linker to a neo-substrate protein ligand. To develop a potent UbTACs we need to examine the structure activity relationship of these bispecific molecules. Herein, we decide to utilize the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, which arguably is one of the most reliable bonds forming reaction, to couple azide-linker derivative of novel E3 ubiquitin ligase ligands and alkyne-linker derivative of neo-substrate protein ligands. The CuAAC reaction of azides and alkynes to form 1,2,3-triazole ring, which commonly referred to as “click chemistry”, is easy to use, high yielding, boasts excellent functional group compatibility, and can be performed under mild reaction condition. We will prepare the azide-linker and alkyne-linker derivatives, and then conjugate them by using “click chemistry”. This approach would allow for the parallel synthesis of UbTACs library.

研究概要を示す模式図

本領域での研究成果

1. Nakamoto Y, Pradipta AR, Mukai H, Zouda M, Watanabe Y, Kurbangalieva A, Ahmadi P, Manabe Y, Fukase K, Tanaka K.
   Expanding the applicability of the metal labeling of biomolecules by the RIKEN click reaction: A case study with Gallium-68 positron emission tomography.
   ChemBioChem. 19, 2055-2060 (2018)
   PMID: 30066425
2. Tanei T, Pradipta AR, Morimoto K, Fujii M, Arata M, Ito A, Yoshida M, Saigitbatalova E, Kurbangalieva A, Ikeda J-I, Morii E, Noguchi S, *Tanaka K.
   Cascade reaction in human live tissue allows clinically applicable diagnosis of breast cancer morphology.
   Adv. Sci. 6, 1801479 (2018)
   PMID: 30693189
   プレスリリース
3. Qi Y, Zhao X, Chen J, Pradipta AR, Wei J, Ruan H, Zhou L, Hsung RP, Tanaka K.
   In vitro and in vivo cancer cell apoptosis triggered by competitive binding of Cinchona alkaloids to the RING domain of TRAF6.
   Biosci. Biotechnol. Biochem. 83, 1011-1026 (2019)
   PMID: 31074699
4. Pradipta AR, Fujii M, Tanei T, Morimoto K, Shimazu K, Noguchi S, *Tanaka K.
   Tetramethylrhodamine is an essential scaffold of azide probe in detecting cellular acrolein.
   Bioorg. Med. Chem. 27, 2228-2234 (2019)
   PMID: 31023557
5. Chulakova DR, *Pradipta AR, Lodochnikova OA, Kuznetsov DR, Bulygina KS, Smirnov IS, Usachev KS, Latypova LZ, Kurbangalieva AR, *Tanaka K.
   Facile access to optically active 2,6-dialkyl-1,5-diazacyclooctanes.
   Chem. Asian J. 14, 4048-4054 (2019)
   PMID: 31381243
6. Lodochnikova OA, Chulakova DR, Gerasimova DP, Litvinov IA, Pradipta AR, *Tanaka K, *Kurbangalieva AR.
   Stereochemical features of the crystallization of eight-membered 1,5-diazaheterocycles with chiral aminoindanol fragments at nitrogen atoms.
   J. Struct. Chem. 61, 119-125 (2020)
7. *Pradipta AR, Tanei T, Morimoto K, Shimazu K, Noguchi S, *Tanaka K.
   Emerging technologies for real-time intraoperative margin assessment in future breast-conserving surgery.
   Adv. Sci. 7, 1901519 (2020)
   PMID: 32382473
8. *Pradipta AR, Chang TC, *Tanaka K.
   Enantioselective synthesis of cyclic and linear diamines by iminocycloaddition.
   Chirality 32, 1160-1168 (2020)
   PMID: 32621328
9. Smirnov I, Sibgatullina R, Urano S, Tahara T, Ahmadi P, Watanabe Y, Pradipta AR, Kurbangalieva A, *Tanaka K.
   A Strategy for Tumor Targeting by Higher-Order Glycan Pattern Recognition: Synthesis and In Vitro and In Vivo Properties of Glycoalbumins Conjugated with Four Different N-Glycan Molecules.
   Small 16, 2004831 (2020)
   PMID: 33079456
10. Muguruma K, Pradipta AR, Ode Y, Terashima K, Michiba H, Fujii M, *Tanaka K.
    Disease-associated acrolein: A possible diagnostic and therapeutic substrate for in vivo synthetic chemistry.
    Bioorg. Med. Chem. 28, 115831 (2020)
    PMID: 33199202
11. *Pradipta A R, Ahmadi P, Terashima K, Muguruma K, Fujii M, Ichino T, Maeda S, *Tanaka K.
    Targeted 1,3-dipolar cycloaddition with acrolein for cancer prodrug activation.
    Chem. Sci. 12, 5438-5449 (2021)
    プレスリリース
12. Pradipta A R, *Tanaka K.
    Application of acrolein imines to organic synthesis, biofunctional studies, and clinical practice.
    Chem. Rec. 21, 646-662 (2021)
    PMID: 33769681
13. *Pradipta A R, *Tanaka K.
    Biofunctional chemistry and reactivity of biogenic acrolein for cancer diagnosis and therapy.
    Chem. Commun. 57, 9798-9806 (2021)
    PMID: 34581321
14. *Pradipta A R, Michiba H, Kubo A, Fujii M, Tanei T, Morimoto K, Shimazu K, *Tanaka K.
    The secon-generation click-to-sense probe for intraoperative diagnosis of breast cancer tissues based on acrolein targeting.
    Bull. Chem. Soc. Jpn. (2022)

代表的な論文

1. Pradipta AR, *Tanaka K.
   Unexplored reactivity of N-alkyl unsaturated imines: A simple procedure for producing optically active 1,3-diamines via a stereocontrolled formal [4 + 2] and [4 + 2 + 2] iminocycloaddition. 
   Bull. Chem. Soc. Jpn. 89, 337-345 (2016)
2. Pradipta AR, Taichi M, *Nakase I, Saigitbatalova E, Kurbangalieva A, Kitazume S, Taniguchi N, *Tanaka K.
   Uncatalyzed click reaction between phenyl azides and acrolein: 4-Formyl-1,2,3-triazolines as “clicked” markers for visualizations of extracellular acrolein released from oxidatively stressed cells.
   ACS Sens. 1, 623-632 (2016)
3. Tsubokura K, Vong K K H, Pradipta AR, Ogura A, Urano S, Tahara T, Nozaki S, Onoe H, Nakao Y, Sibgatullina R, Kurbangalieva A, Watanabe Y, *Tanaka K.
   In vivo gold complex catalysis within live mice.
   Angew. Chem. Int. Ed. 56, 3579-3584 (2017)
   PMID: 28198119
4. Nakamoto Y, Pradipta AR, Mukai H, Zouda M, Watanabe Y, Kurbangalieva A, Ahmadi P, Manabe Y, Fukase K, *Tanaka K.
   Expanding the applicability of the metal labeling of biomolecules by the RIKEN click reaction: A case study with Gallium-68 positron emission tomography.
   ChemBioChem 19, 2055-2060 (2018)
   PMID: 30066425
5. Tanei T, Pradipta AR, Morimoto K, Fujii M, Arata M, Ito A, Yoshida M, Saigitbatalova E, Kurbangalieva A, Ikeda J-I, Morii E, *Noguchi S, *Tanaka K.
   Cascade reaction in human live tissue allows clinically applicable diagnosis of breast cancer morphology.
   Adv. Sci. 6, 1801479 (2019)
   PMID: 30693189
6. Pradipta AR, Latypova L, Chulakova D, Smirnov I, Kurbangalieva A, Tanaka K.
   Cycloaddition reactions of N-alkyl-α,β-unsaturated imines: Facile preparation of azaheterocycles for synthesis and biological applications.
   Heterocycles 97, 668-685 (2018)