Novel d-seco paclitaxel analogues: synthesis, biological evaluation, and model testing.
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.
Barboni
L
L
Department of Medicinal Chemistry and Drug Discovery Program, Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66045, USA.
Datta
A
A
Dutta
D
D
Georg
G I
GI
Vander Velde
D G
DG
Himes
R H
RH
Wang
M
M
Snyder
J P
JP
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
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel; D017239:Paclitaxel