Structure-activity relationship within a series of okadaic acid derivatives

Okadaic acid (OA) is a potent non-12-O-tetradecanoyl-phorbol-13-acetate (non-TPA) type tumor promoter on mouse skin. OA acts on cells through inhibiting the activity of protein phosphatases and results in the increase of phosphorylation of proteins. Seventeen OA derivatives were evaluated as possibl...

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Bibliographic Details
Published in:Carcinogenesis (New York) 1990-10, Vol.11 (10), p.1837-1841
Main Authors: Nishiwaki, Shinji, Fujiki, Hirota, Suganuma, Masami, Furuya-Suguri, Hiroko, Matsushima, Rie, Iida, Yukari, Ojika, Makoto, Yamada, Kiyoyuki, Uemura, Daisuke, Yasumoto, Takeshi, Schmitz, Francis J., Sugimura, Takashi
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Biological and medical sciences
Brain - enzymology
Carcinogenesis, carcinogens and anticarcinogens
Carcinogens - pharmacology
Chemical agents
Ethers, Cyclic - metabolism
Ethers, Cyclic - pharmacology
Female
Medical sciences
Mice
Okadaic Acid
Ornithine Decarboxylase - biosynthesis
Phosphoprotein Phosphatases - antagonists & inhibitors
Skin - drug effects
Skin - metabolism
Structure-Activity Relationship
Tumors
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Summary:Okadaic acid (OA) is a potent non-12-O-tetradecanoyl-phorbol-13-acetate (non-TPA) type tumor promoter on mouse skin. OA acts on cells through inhibiting the activity of protein phosphatases and results in the increase of phosphorylation of proteins. Seventeen OA derivatives were evaluated as possible tumor promoters by means of three biochemical tests: inhibition of specific [3H]OA binding to a particulate fraction of mouse skin containing protein phosphatases, inhibition of protein phosphatase activity, and induction of ornithine decarboxylase in mouse skin. Potency in each of these biochemical tests correlated well for each of these derivatives. We present results indicating that the carboxyl group as well as the four hydroxyl groups at C-2, C-7, C-24 and C-27 of OA are important for activity. Acanthifolicin, which gave positive responses in these three biochemical tests as strong as those of OA and dinophysistoxin-1, is predicted to be an additional member of the OA class of tumor promoters.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/11.10.1837