title: Design and synthesis of mono and bicyclic tetrapeptides thioester as potent inhibitor of histone deacetylases.
abstract: Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that have an effect on gene regulation. The naturally occurring cyclic depsipeptide FK228 containing disulfide and Largazole possessing thioester functionalities act as pro-drugs and share the same HDAC inhibition mechanism in cell. Inspired from these facts, we have reported bicyclic tetrapeptide disulfide HDAC inhibitors resembling FK228 with potent activity and enhanced selectivity. In the present study, we report the design and synthesis of several mono and bicyclic tetrapeptide thioester HDAC inhibitors that share the inhibition mechanism similar to Largazole. Most of the compounds showed HDAC1 and HDAC4 inhibition and p21 promoting activity in nanomolar ranges. Among these the monocyclic peptides 1, 2 and bicyclic peptide, 4 are notable demanding more advanced research to be promising anticancer drug candidates.
authors.affiliation: Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, Serdang, Malaysia, ashraf_bio2003@yahoo.com.
authors.forename: Md Ashraful
authors.initials: MA
authors.lastname: Hoque
authors.forename: Md Shahidul
authors.initials: MS
authors.lastname: Islam
authors.forename: Md Nurul
authors.initials: MN
authors.lastname: Islam
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: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D017930:Genes, Reporter / Q000187:drug effects; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008907:Mink; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009994:Osmolar Concentration; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011355:Prodrugs; D011994:Recombinant Proteins; D012097:Repressor Proteins; C110550:HDAC1 protein, human; C400300:HDAC4 protein, human; C499033:Hdac6 protein, mouse; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D016283:Proto-Oncogene Proteins p21(ras)