期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 15, 页码 4319-4323出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.05.096
关键词
Aplysiatoxin; Debromoaplysiatoxin; Protein kinase C; Tumor promotion; Cancer; Anti-proliferative activity
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [23102011]
- Grants-in-Aid for Scientific Research [23102011] Funding Source: KAKEN
Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities. (C) 2013 Elsevier Ltd. All rights reserved.
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