title: Novel d-seco paclitaxel analogues: synthesis, biological evaluation, and model testing.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Drug Discovery Program, Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: L
authors.initials: L
authors.lastname: Barboni
authors.forename: A
authors.initials: A
authors.lastname: Datta
authors.forename: D
authors.initials: D
authors.lastname: Dutta
authors.forename: G I
authors.initials: GI
authors.lastname: Georg
authors.forename: D G
authors.initials: DG
authors.lastname: Vander Velde
authors.forename: R H
authors.initials: RH
authors.lastname: Himes
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: J P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D000077143:Docetaxel; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D043823:Taxoids; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel; D017239:Paclitaxel