Total Synthesis of Fostriecin (CI-920)

The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC50 = 40 μM) and more potent and selective protein...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2001-05, Vol.123 (18), p.4161-4167
Main Authors: Boger, Dale L, Ichikawa, Satoshi, Zhong, Wenge
Format: Article
Language:English
Subjects:
Alkenes - chemical synthesis
Antibiotics, Antineoplastic - chemical synthesis
Polyenes
Pyrones
Streptomyces - chemistry
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Summary:The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC50 = 40 μM) and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC50 = 40−3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations were reached or dose-limiting toxicity established due to problems of drug stability observed during storage of naturally derived material. The synthesis of fostriecin detailed herein is the first stage of efforts that may serve to address these limitations to the clinical examination of this or related promising new antitumor agents.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja010195q