Synthesis and biological activities of chaetocin and its derivatives

Sodeoka, Mikiko; Dodo, Kosuke; Teng, Yuou; Iuchi, Katsuya; Hamashima, Yoshitaka; Iwasa, Eriko; Fujishiro, Shinya

doi:10.1351/PAC-CON-11-10-31

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

http://dx.doi.org/10.1351/PAC-CON-11-10-31

Published online 2012-04-02

Synthesis and biological activities of chaetocin and its derivatives

Mikiko Sodeoka^1,2*, Kosuke Dodo^1,2, Yuou Teng^3,1,2, Katsuya Iuchi^1,2, Yoshitaka Hamashima^1,4, Eriko Iwasa^1,2 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.