Abstract
Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar K i values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.
| Original language | English |
|---|---|
| Pages (from-to) | 5614-5626 |
| Number of pages | 13 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 55 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2012 Jun 14 |
Fingerprint
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Structure-activity studies on the spiroketal moiety of a simplified analogue of debromoaplysiatoxin with antiproliferative activity. / Kikumori, Masayuki; Yanagita, Ryo C.; Tokuda, Harukuni; Suzuki, Nobutaka; Nagai, Hiroshi; Suenaga, Kiyotake; Irie, Kazuhiro.
In: Journal of Medicinal Chemistry, Vol. 55, No. 11, 14.06.2012, p. 5614-5626.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structure-activity studies on the spiroketal moiety of a simplified analogue of debromoaplysiatoxin with antiproliferative activity
AU - Kikumori, Masayuki
AU - Yanagita, Ryo C.
AU - Tokuda, Harukuni
AU - Suzuki, Nobutaka
AU - Nagai, Hiroshi
AU - Suenaga, Kiyotake
AU - Irie, Kazuhiro
PY - 2012/6/14
Y1 - 2012/6/14
N2 - Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar K i values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.
AB - Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar K i values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.
UR - http://www.scopus.com/inward/record.url?scp=84862275351&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862275351&partnerID=8YFLogxK
U2 - 10.1021/jm300566h
DO - 10.1021/jm300566h
M3 - Article
C2 - 22625994
AN - SCOPUS:84862275351
VL - 55
SP - 5614
EP - 5626
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 11
ER -