title: Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification.
abstract: Chaetocin (1), a structurally complex epidithiodiketopiperazine (ETP) alkaloid produced by Chaetomium minutum, is a potent inhibitor of protein lysine methyltransferase G9a, which plays important roles in many biological processes. Here we present our synthetic investigations to identify a simple prototype G9a inhibitor structure based on structure-activity relationship (SAR) studies on chaetocin derivatives. The simple derivative PS-ETP-1 (14) was found to be a potent G9a inhibitor with greatly reduced cytotoxicity.
authors.affiliation: RIKEN Advanced Science Institute, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujishiro
authors.forename: Kosuke
authors.initials: K
authors.lastname: Dodo
authors.forename: Eriko
authors.initials: E
authors.lastname: Iwasa
authors.forename: Yuou
authors.initials: Y
authors.lastname: Teng
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sohtome
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hamashima
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Mikiko
authors.initials: M
authors.lastname: Sodeoka
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002597:Chaetomium / Q000737:chemistry*; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism
chemical_list: D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D010879:Piperazines; C002511:chaetocin; D013880:Thioredoxin-Disulfide Reductase; D011495:Histone-Lysine N-Methyltransferase