Synthesis and biological evaluation of (-)-16-normethyldictyostatin: a potent analogue of (-)-dictyostatin

Org Lett. 2005 Jul 7;7(14):2873-6. doi: 10.1021/ol050808u.

Abstract

[structure: see text] (-)-16-Normethyldictyostatin has been made by total synthesis and is a potent antitumor agent in cells expressing wild-type tubulin and in one mutant cell line that is resistant to paclitaxel, but it is much less active than dictyostatin in another paclitaxel-resistant cell line where Val is substituted for Phe270. This provides strong evidence that the C16 methyl group of the dictyostatins is oriented toward Phe270 in the paclitaxel-binding site on beta-tubulin.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Brain / anatomy & histology
  • Cattle
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Macrolides / chemical synthesis*
  • Macrolides / chemistry
  • Macrolides / pharmacology*
  • Molecular Structure
  • Paclitaxel / pharmacology
  • Phenylalanine / genetics
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tubulin / biosynthesis*
  • Valine / genetics

Substances

  • 16-normethyldictyostatin
  • Antineoplastic Agents
  • Macrolides
  • Tubulin
  • dictyostatin
  • Phenylalanine
  • Valine
  • Paclitaxel