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Pure Appl. Chem., 2012, Vol. 84, No. 6, pp. 1369-1378

Published online 2012-04-02

Synthesis and biological activities of chaetocin and its derivatives

Mikiko Sodeoka1,2*, Kosuke Dodo1,2, Yuou Teng3,1,2, Katsuya Iuchi1,2, Yoshitaka Hamashima1,4, Eriko Iwasa1,2 and Shinya Fujishiro1

1 RIKEN Advanced Science Institute, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan
2 Sodeoka Live Cell Chemistry Project, ERATO, JST, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan
3 College of Biotechnology, Tianjin University of Science and Technology, No.29, 13th Street, Tianjin Economic-Technology Development Area, Tianjin, 300457, China
4 School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

Abstract: Chaetocin, a natural product isolated from fungi of Chaetomium species, is a member of the epipolythiodiketopiperazines (ETPs), which have various biological activities, including cytostatic and anticancer activities. Recently, the inhibitory activity toward histone methyltransferases (HMTs) was discovered for chaetocin. We previously reported the first total synthesis of chaetocin and various derivatives. During studies on the structure–activity relationship for HMT inhibition, we found that the enantiomer of chaetocin (ent-chaetocin) is a more potent apoptosis inducer than natural chaetocin in human leukemia HL-60 cells. Mechanistic studies showed that ent-chaetocin induces apoptosis through the caspase-8/caspase-3 pathway.