Novel D-seco paclitaxel analogues: Synthesis, biological evaluation, and model testing

L. Barboni, A. Datta, D. Dutta, G. I. Georg, D. G. Vander Velde, R. H. Himes, M. Wang, J. P. Snyder

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Four new D-secopaclitaxel analogues were synthesized from paclitaxel. The key step of the synthesis involved the opening of the D-ring by Jones oxidation. Two of the compounds had been predicted to be nearly as active as paclitaxel in a minireceptor model of the binding site on tubulin, but all were biologically inactive in an in vitro cytotoxic assay and a tubulin assembly assay. The biological results identify a weakness in our predictive minireceptor model and suggest a corrective remedy in which additional amino acids are needed to accommodate ligand-protein steric effects around the oxetane ring. These changes to the model lead to correct predictions of the bioactivity. Conformational analysis and dynamics simulations of the compounds showed that the 4-acetyl substituent is as important as the oxetane in determining the A ring conformation.

Original languageEnglish (US)
Pages (from-to)3321-3329
Number of pages9
JournalJournal of Organic Chemistry
Issue number10
StatePublished - May 18 2001


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