title: Novel non-peptide inhibitors targeting death receptor-mediated apoptosis.
abstract: We have previously reported that ECH, (2R, 3R, 4S)-2,3-epoxy-4-hydroxy-5-hydroxymethyl-6-(1E)-propenyl-cyclohex-5-en-1-one inhibits Fas-mediated apoptosis by blocking self-activation of pro-caspase-8 in the death-inducing signaling complex (DISC). A series of ECH derivatives were asymmetrically synthesized via key synthetic intermediates obtained from lipase-catalyzed kinetic resolution. Inhibitory activities of the derivatives towards death receptor-mediated apoptosis both in type I and type II cells were investigated, revealing that novel non-peptide inhibitors, RKTS-33 and RKTS-34, are effective as ECH.
authors.affiliation: Antibiotics Laboratory, RIKEN Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. hkakeya@riken.jp
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Miyake
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shoji
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishida
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Takao
authors.initials: T
authors.lastname: Kataoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D053222:Fas Ligand Protein; D006801:Humans; D007202:Indicators and Reagents; D019169:Jurkat Cells; D007700:Kinetics; D008049:Lipase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D019014:fas Receptor / Q000187:drug effects
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007202:Indicators and Reagents; D008562:Membrane Glycoproteins; D019014:fas Receptor; D008049:Lipase