1. Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition
- Author
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Norikazu Nishino, Akihiro Ito, Tienabe K. Nsiama, Tamaki Kato, Mohammed Bhuiyan, Minoru Yoshida, Naoto Oishi, Md. Nurul Islam, and Md. Shahidul Islam
- Subjects
Aminoisobutyric Acids ,Proline ,medicine.drug_class ,Stereochemistry ,Phenylalanine ,Clinical Biochemistry ,Hydroxamic Acids ,Ligands ,Biochemistry ,Peptides, Cyclic ,Histone Deacetylases ,chemistry.chemical_compound ,Structure-Activity Relationship ,medicine ,Moiety ,Humans ,Amino Acids ,chemistry.chemical_classification ,Hydroxamic acid ,biology ,Tetrapeptide ,Molecular Structure ,Chemistry ,Organic Chemistry ,Histone deacetylase inhibitor ,Ketones ,Recombinant Proteins ,Amino acid ,Histone Deacetylase Inhibitors ,Isoenzymes ,Histone ,Enzyme ,HEK293 Cells ,biology.protein ,Histone deacetylase ,Caprylates - 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.
- Published
- 2011