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Dolastatin 11 conformations, analogues and pharmacophore.

Abstract
Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.
AuthorsMd Ahad Ali, Robert B Bates, Zackary D Crane, Christopher W Dicus, Michelle R Gramme, Ernest Hamel, Jacob Marcischak, David S Martinez, Kelly J McClure, Pichaya Nakkiew, George R Pettit, Chad C Stessman, Bilal A Sufi, Gayle V Yarick
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 13 Issue 13 Pg. 4138-52 (Jul 01 2005) ISSN: 0968-0896 [Print] England
PMID15878670 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Actins
  • Depsipeptides
  • dolastatin 11
Topics
  • Actins (metabolism)
  • Animals
  • Cell Survival (drug effects)
  • Depsipeptides (chemical synthesis, chemistry, pharmacology)
  • Drug Screening Assays, Antitumor
  • Humans
  • Leukemia P388 (drug therapy, pathology)
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

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