Enantio- and diastereoselective total synthesis of EI-1941-1, -2, and -3, inhibitors of interleukin-1beta converting enzyme, and biological properties of their derivatives.
[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.
Shoji
Mitsuru
M
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
Uno
Takao
T
Kakeya
Hideaki
H
Onose
Rie
R
Shiina
Isamu
I
Osada
Hiroyuki
H
Hayashi
Yujiro
Y
D061945:Caspase Inhibitors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003512:Cyclohexanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D003512:Cyclohexanones; C476113:EI-1941-1; C476114:EI-1941-2; C511478:EI-1941-3; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D006574:Heterocyclic Compounds, 2-Ring