Structure-Activity Relationships of Yessotoxins in Cultured Cells

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• 作者：Sara Ferrari ; Patrizia Ciminiello ; Carmen Dell'Aversano ; Martino Forino ; Claudia Malaguti ; Aurelia Tubaro ; Roberto Poletti ; Takeshi Yasumoto ; Ernesto Fattorusso ; and Gian Paolo Rossini
• 刊名：Chemical Research in Toxicology
• 出版年：2004
• 出版时间：September 2004
• 年：2004
• 卷：17
• 期：9
• 页码：1251 - 1257
• 全文大小：109K
• 年卷期：v.17,no.9(September 2004)
• ISSN：1520-5010

文摘

The structure-activity relationship of yessotoxins (YTX) has been probed by measuring thepotency of several YTX analogues to cause the accumulation of a 100 kDa MW fragment ofE-cadherin in MCF-7 breast cancer cells. Under our experimental conditions, the EC₅₀ of YTX,the reference compound, was 0.55 nM. The introduction of a methylene unit adjacent to one ofthe sulfate groups, as is the case with the homoyessotoxin molecule, did not appear to greatlyaffect the potency of the analogue, as the measured EC₅₀ for this compound was 0.62 nM. TheEC₅₀ values we measured for 45-hydroxyhomoyessotoxin and carboxyyessotoxin were about9.4 and 26 nM, respectively, whereas the EC₅₀ of noroxoyessotoxin, lacking most of the C₉chain, was about 50 nM. Thus, significant differences in the potencies of YTX analogues werefound when structural changes involved the C₉ terminal chain of these compounds, leading tothe conclusion that this portion of the molecule is essential for the activity of YTX in MCF-7cells. A comparison of our findings with available information regarding the potency of YTXand its analogues in other experimental systems shows that the EC₅₀'s we measured for thedifferent compounds are up to 200-fold lower and vary in a wider concentration range. Wespeculate that YTX effects could involve two separate receptorial systems.