TY - JOUR
T1 - Structure-activity relationships of epolactaene derivatives
T2 - Structural requirements for inhibition of Hsp60 chaperone activity
AU - Nagumo, Yoko
AU - Kakeya, Hideaki
AU - Yamaguchi, Junichiro
AU - Uno, Takao
AU - Shoji, Mitsuru
AU - Hayashi, Yujiro
AU - Osada, Hiroyuki
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by the Chemical Biology project (RIKEN), and by funding from the Special Postdoctoral Researchers Program (to Y.N.).
PY - 2004/9/6
Y1 - 2004/9/6
N2 - Epolactaene derivatives were synthesized and their ability to inhibit the growth of human cancer cell lines was tested. These derivatives were further analyzed for their ability to affect human heat shock protein 60 (Hsp60). We discovered the structural characteristics important for the ability to bind to Hsp60 and the fundamental role of α,β-unsaturated ketone in inhibiting Hsp60 chaperone activity. Epolactaene is a microbial metabolite isolated from the fungal strain Penicillium sp. It arrests the cell cycle at the G 0/G 1 phase and induces the outgrowth of neurites in human neuroblastoma SH-SY5Y cells. In this communication, we report the structure-activity relationships (SARs) of new epolactaene derivatives, including those lacking the epoxylactam moiety and having various side chains. These derivatives were evaluated for their ability to inhibit the growth of human cancer cell lines. They were also analyzed for their ability to affect human heat shock protein 60 (Hsp60), which we have already identified as a protein that binds to epolactaene. We also identified the important structural framework of epolactaene/ETB (epolactaene tertiary butyl ester) for not only binding to Hsp60 but also inhibiting Hsp60 chaperone activity.
AB - Epolactaene derivatives were synthesized and their ability to inhibit the growth of human cancer cell lines was tested. These derivatives were further analyzed for their ability to affect human heat shock protein 60 (Hsp60). We discovered the structural characteristics important for the ability to bind to Hsp60 and the fundamental role of α,β-unsaturated ketone in inhibiting Hsp60 chaperone activity. Epolactaene is a microbial metabolite isolated from the fungal strain Penicillium sp. It arrests the cell cycle at the G 0/G 1 phase and induces the outgrowth of neurites in human neuroblastoma SH-SY5Y cells. In this communication, we report the structure-activity relationships (SARs) of new epolactaene derivatives, including those lacking the epoxylactam moiety and having various side chains. These derivatives were evaluated for their ability to inhibit the growth of human cancer cell lines. They were also analyzed for their ability to affect human heat shock protein 60 (Hsp60), which we have already identified as a protein that binds to epolactaene. We also identified the important structural framework of epolactaene/ETB (epolactaene tertiary butyl ester) for not only binding to Hsp60 but also inhibiting Hsp60 chaperone activity.
KW - Chaperone
KW - Epolactaene
KW - Heat shock protein 60
UR - http://www.scopus.com/inward/record.url?scp=3843120076&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3843120076&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2004.06.054
DO - 10.1016/j.bmcl.2004.06.054
M3 - Article
C2 - 15357965
AN - SCOPUS:3843120076
SN - 0960-894X
VL - 14
SP - 4425
EP - 4429
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 17
ER -
