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

• Published in: Bioscience, biotechnology, and biochemistry Vol. 72; no. 10; pp. 2623 - 2631
• Main Authors: Batovska, D.I.(Hokkaido Univ., Sapporo (Japan)), Kim, D.H, Mitsuhashi, S, Cho, Y.S, Kwon, H.J, Ubukata, M
• Format: Journal Article
• Language: English
• Published: Tokyo Japan Society for Bioscience, Biotechnology, and Agrochemistry 01.10.2008; Japan Society for Bioscience Biotechnology and Agrochemistry; Oxford University Press
• Subjects: BETAIL; Biological and medical sciences; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; ENZYME INHIBITORS; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; GANADO; Gene Expression Regulation, Enzymologic - drug effects; HDAC inhibitors synthesis; histone deacetylase (HDAC); Histone Deacetylase Inhibitors; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - chemistry; IMMUNODEPRESSEUR; IMMUNOSUPPRESSANTS; INHIBIDORES DE ENZIMAS; INHIBITEUR D'ENZYME; INMUNODEPRESORES; inosine monophosphate dehydrogenase (IMPDH); LINFOMA; LIVESTOCK; LYMPHOMA; LYMPHOME; MICOTOXINAS; MIELOMA; Molecular Structure; mycophenolic acid (MPA); Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - chemistry; Mycophenolic Acid - pharmacology; MYCOTOXINE; MYCOTOXINS; MYELOMA; MYELOME; OXIDOREDUCTASES; OXIDORREDUCTASAS; OXYDOREDUCTASE; α-tubulin deacetylase (TDAC); Mycophenolic acid; HDAC inhibitors synthesis; Enzyme; histone deacetylase (HDAC); inosine monophosphate dehydrogenase (IMPDH); mycophenolic acid (MPA); Dehydrogenase; α-tubulin deacetylase (TDAC); Tubulin; Inosine; Inhibitor; Oxidoreductases; Inhibition; Histone
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1271/bbb.80303

Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma 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 nonspecific 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 ICsub(50) values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively.