Novel non-peptide inhibitors targeting death receptor-mediated apoptosis |
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Authors: | Kakeya Hideaki Miyake Yasunobu Shoji Mitsuru Kishida Satoshi Hayashi Yujiro Kataoka Takao Osada Hiroyuki |
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Institution: | Antibiotics Laboratory, RIKEN Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. hkakeya@riken.jp |
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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. |
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