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J Org Chem. 2010 Nov 19;75(22):7505-13. doi: 10.1021/jo1010203. Epub 2010 Jul 29.

Total synthesis and evaluation of phostriecin and key structural analogues.

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  • 1Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.

Abstract

Full details of the total synthesis of phostriecin (2), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (1), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, both inactive and >250-fold), the α,β-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12-C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective).

PMID:
20669916
[PubMed - indexed for MEDLINE]
PMCID:
PMC2978778
Free PMC Article
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