title: Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition.
abstract: The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus Diheterospora chlamydosphoria, consists of α-aminoisobutyric acid, L-phenylalanine, D-proline and an unusual amino acid (S)-2-amino-8-((S)-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition.
authors.affiliation: Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu, 808-0196, Japan.
authors.forename: Md Shahidul
authors.initials: MS
authors.lastname: Islam
authors.forename: Mohammed P I
authors.initials: MP
authors.lastname: Bhuiyan
authors.forename: Md Nurul
authors.initials: MN
authors.lastname: Islam
authors.forename: Tienabe Kipassa
authors.initials: TK
authors.lastname: Nsiama
authors.forename: Naoto
authors.initials: N
authors.lastname: Oishi
authors.forename: Tamaki
authors.initials: T
authors.lastname: Kato
authors.forename: Norikazu
authors.initials: N
authors.lastname: Nishino
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000621:Aminoisobutyric Acids / Q000737:chemistry; D002210:Caprylates / Q000737:chemistry; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D007527:Isoenzymes; D007659:Ketones / Q000737:chemistry; D008024:Ligands; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000621:Aminoisobutyric Acids; D002210:Caprylates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D007659:Ketones; D008024:Ligands; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C100049:2-aminoisobutyric acid; D010649:Phenylalanine; C006963:chlamydocin; D011392:Proline; D006655:Histone Deacetylases