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Novel D-Seco Paclitaxel Analogues:  Synthesis, Biological Evaluation, and Model Testing

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journal contribution
posted on 18.04.2001, 00:00 by Luciano Barboni, Apurba Datta, Dinah Dutta, Gunda I. Georg, David G. Vander Velde, Richard H. Himes, Minmin Wang, James P. Snyder
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.