7 Synthesis of 8-epi-fostriecin and the effect of C8 position's stereochemistry on its biological activity

• Maki Keisuke

  Graduate School of Pharmaceutical Sciences, The University of Tokyo

• Fujii Kunihiko

  Graduate School of Pharmaceutical Sciences, The University of Tokyo

• Kanai Motomu

  Graduate School of Pharmaceutical Sciences, The University of Tokyo

• Shibasaki Masakatsu

  Graduate School of Pharmaceutical Sciences, The University of Tokyo

Bibliographic Information

Other Title

• 7 8-epi-fostriecinの合成と四置換不斉炭素の立体化学の生物活性への影響(口頭発表の部)

Abstract

Fostriecin is a potent antitumor agent, and it is suggested that its activity is attributed to the inhibition of the mitotic entry checkpoint through its highly selective serine/threonine phosphatase 2A (PP2A) inhibition. Because of its unique mechanism of tumor suppression, fostriecin is an ideal lead compound for antitumor drugs. We would like to present here the synthesis of fostriecin and 8-epi-fostriecin, evaluation of their biological activity, and conformational analysis by theoretical calculation to understand the difference of their biological behavior. It is four catalytic asymmetric reactions that feature our synthesis of fostriecin and 8-epi-fostriecin; cyanosilylation of ketone, allylation, direct aldol reaction and Noyori reduction. Especially two reactions developed in our laboratory played important roles. The cyanosilylation constructed the tetrasubstituted chiral center at C8. Both enantiomers could be obtained just by switching the center metals of the catalyst. Direct catalytic asymmetric aldol reaction using acetylene ketone as donor is a versatile reaction which can introduce synthetically useful alkyne moiety. In our synthesis the product alkynone was converted into cis-vinyl iodide, the substrate for the subsequent Stille coupling. By synthesizing 8-epi-fostriecin, we could show here the effectiveness of the strategy, constructing all of the stereocenters by catalytic asymmetric reactions. Just switching the enantioselectivity of catalysts makes it possible to synthesize stereoisomers of a natural product. Biological assay and conformational analysis of fostriecin and 8-epi-fostriecin are now proceeding. The assay is about the inhibitory activity against PP1 and PP2A. Because both of the methyl group and hydroxyl group at C8 are thought to be important for the biological activity, the assay's results of the two compounds might be very much different from each other. And conformational analysis was performed using NMR technique and theoretical calculations. The former revealed the environmental difference around C8 stereocenter and phosphate moiety. Conformation search by MM calculation implicated that coordination of hydroxyl group at C8 to the sodium cation of the phosphate might affect the environmental difference and therefore the biological activity. Now ab initio calculation is being conducted to optimize the geometry of the stable comformers.

Journal

• Symposium on the Chemistry of Natural Products, symposium papers

  Symposium on the Chemistry of Natural Products, symposium papers 47 (0), 37-42, 2005

  Symposium on the Chemistry of Natural Products Steering Committee

Details

• CRID: 1390282681055372800
• NII Article ID: 110006682514
• DOI: 10.24496/tennenyuki.47.0_37
• ISSN: 24331856
• Text Lang: ja
• Data Source:
  • JaLC
  • CiNii Articles
• Abstract License Flag: Disallowed