Hydroxamic Acid Derivatives of Mycophenolic Acid Inhibit Histone Deacetylase at the Cellular Level

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  • BATOVSKA Daniela I.
    Research Faculty of Agriculture, Hokkaido University
  • KIM Dong Hoon
    Chemical Genomics Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University
  • MITSUHASHI Shinya
    Research Faculty of Agriculture, Hokkaido University
  • CHO Yoon Sun
    Chemical Genomics Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University
  • KWON Ho Jeong
    Chemical Genomics Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University
  • UBUKATA Makoto
    Research Faculty of Agriculture, Hokkaido University

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Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARγ agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 μM, and cell proliferation at concentrations of 2, 1.5 and 1 μM, respectively.

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