Total synthesis and evaluation of phostriecin and key structural analogues.
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).
Burke
Christopher P
CP
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
Swingle
Mark R
MR
Honkanen
Richard E
RE
Boger
Dale L
DL
D000475:Alkenes / Q000737:chemistry*; D000480:Alkynes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011753:Pyrones; D013237:Stereoisomerism
D000475:Alkenes; D000480:Alkynes; D000970:Antineoplastic Agents; D007783:Lactones; D010755:Organophosphates; D011753:Pyrones; C077328:sultriecin; C000589516:phostriecin; D054648:Protein Phosphatase 2