Chlamydocin-hydroxamic acid analogues as histone deacetylase inhibitors.
Chlamydocin-hydroxamic acid analogues were designed and synthesized as histone deacetylase (HDAC) inhibitors based on the structure and HDAC inhibitory activity of chlamydocin and trichostatin A. Chlamydocin is a cyclic tetrapeptide containing an epoxyketone moiety in the side chain that makes it an irreversible inhibitor of HDAC. We replaced the epoxyketone moiety of chlamydocin with hydroxamic acid to design potent and reversible inhibitors of HDAC. In addition, a number of amino-cycloalkanecarboxylic acids (Acc) are introduced instead of the simple amino-isobutric acid (Aib) for a variety of the series of chlamydocin analogues. The compounds synthesized were tested for HDAC inhibitory activity and the results showed that many of them are potent inhibitors of HDAC. The replacement of Aib residue of chlamydocin with an aromatic amino acid enhances the in vivo and in vitro inhibitory activity. We have carried out circular dichroism and molecular modeling studies on chlamydocin-hydroxamic acid analogue and compared it with the solution structure of chlamydocin.
Nishino
Norikazu
N
Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan. nishino@life.kyutech.ac.jp
Jose
Binoy
B
Shinta
Ryuzo
R
Kato
Tamaki
T
Komatsu
Yasuhiko
Y
Yoshida
Minoru
M
D000818:Animals; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C555819:Ky-2 cyclic peptide; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; C006963:chlamydocin; D006655:Histone Deacetylases