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

Four new D-secopaclitaxel analogues were synthesized from paclitaxel. The k ey step of the synthesis involved the opening of the D-ring by Jones oxidat ion. Two of the compounds had been predicted to be nearly as active as pacl itaxel in a minireceptor model of the binding site on tubulin, but all were biologically inactive in an in vitro cytotoxic assay and a tubulin assembl y assay. The biological results identify a weakness in our predictive minir eceptor model and suggest a corrective remedy in which additional amino aci ds are needed to accommodate ligand-protein steric effects around the oxeta ne ring. These changes to-the model lead to correct predictions of the bioa ctivity. Conformational analysis and dynamics simulations of the compounds showed that the 4-acetyl substituent is as important as the oxetane in dete rmining the A ring conformation.