Dolastatin 11 conformations, analogues and pharmacophore

Md 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 Pettit, Chad C. Stessman, Bilal A. Sufi, Gayle V. Yarick

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4138-4152
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number13
DOIs
StatePublished - Jul 1 2005

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Keywords

  • Anticancer
  • Depsipeptide
  • Dolastatin 11
  • Pharmacophore

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Ali, M. A., Bates, R. B., Crane, Z. D., Dicus, C. W., Gramme, M. R., Hamel, E., Marcischak, J., Martinez, D. S., McClure, K. J., Nakkiew, P., Pettit, G., Stessman, C. C., Sufi, B. A., & Yarick, G. V. (2005). Dolastatin 11 conformations, analogues and pharmacophore. Bioorganic and Medicinal Chemistry, 13(13), 4138-4152. https://doi.org/10.1016/j.bmc.2005.04.040