Hydroxamic acid derivatives of mycophenolic acid inhibit histone deacetylase at the cellular level

Daniela I. Batovska, Dong Hoon Kim, Shinya Mitsuhashi, Yoon Sun Cho, Ho Jeong Kwon, Makoto Ubukata

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2623-2631
Number of pages9
JournalBioscience, Biotechnology and Biochemistry
Volume72
Issue number10
DOIs
Publication statusPublished - 2008

Bibliographical note

Funding Information:
We are grateful to Dr. Stuart Schreiber for presenting histacin and tubacin. This study was supported in part by grant-in-aid for Scientific Research (A) (no. 19208011), and for Scientific Research on Priority Area ‘‘Creation of Biologically Functional Molecules’’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MU), and by grant-in-aid for the National R & D Program for Cancer Control from the Ministry of Health & Welfare (0620360-1) and for the Brain Korea 21 Project, Republic of Korea (HJK). DIB and SM were supported by postdoctoral fellowships from the Japan Society for the Promotion of Science.

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Analytical Chemistry
  • Biochemistry
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Organic Chemistry

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