Correlation of F0F1-ATPase Inhibition and Antiproliferative Activity of Apoptolidin Analogues

Apoptolidin (1) exhibits potent and highly selective apoptosis inducing activity against sensitive cancer cell lines and is hypothesized to act by inhibition of mitochondrial F0F1-ATP synthase. A series of apoptolidin derivatives, including a new intermolecular Diels−Alder adduct, were analyzed for...

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Bibliographic Details
Published in:Organic letters 2006-02, Vol.8 (4), p.589-592
Main Authors: Wender, Paul A, Jankowski, Orion D, Longcore, Kate, Tabet, Elie A, Seto, Haruo, Tomikawa, Taijiro
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Drug Screening Assays, Antitumor
Fibroblasts - drug effects
Macrolides - chemical synthesis
Macrolides - chemistry
Macrolides - pharmacology
Models, Molecular
Molecular Structure
Proton-Translocating ATPases - antagonists & inhibitors
Rats
Tumor Cells, Cultured
Yeasts - enzymology
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Summary:Apoptolidin (1) exhibits potent and highly selective apoptosis inducing activity against sensitive cancer cell lines and is hypothesized to act by inhibition of mitochondrial F0F1-ATP synthase. A series of apoptolidin derivatives, including a new intermolecular Diels−Alder adduct, were analyzed for antiproliferative activity in E1A-transformed rat fibroblasts. Potent F0F1-ATPase inhibition was not a sufficient determinant of antiproliferative activity for several analogues, suggesting the existence of a secondary biological target or more complex mode of action for apoptolidin.
ISSN:1523-7060
1523-7052
DOI:10.1021/ol052800q