Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue

J Am Chem Soc. 2007 Mar 7;129(9):2648-59. doi: 10.1021/ja067870m. Epub 2007 Feb 6.

Abstract

FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4' stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by beta-elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkadienes / chemistry
  • Alkenes / chemistry
  • Alkynes / chemistry
  • Allyl Compounds / chemistry
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor / drug effects
  • Cell Proliferation / drug effects*
  • Epoxy Compounds / chemical synthesis
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology*
  • Furans / chemical synthesis
  • Furans / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Oxidation-Reduction
  • Pyrans / chemical synthesis
  • Pyrans / pharmacology*
  • Silver / chemistry
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / pharmacology
  • Stereoisomerism
  • Zirconium / chemistry

Substances

  • Alkadienes
  • Alkenes
  • Alkynes
  • Allyl Compounds
  • Antineoplastic Agents
  • Epoxy Compounds
  • FR 901464
  • Furans
  • Pyrans
  • Spiro Compounds
  • meayamycin
  • Silver
  • Zirconium