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The impact of cyclopropane configuration on the biological activity of cyclopropyl-epothilones.
Journal article

The impact of cyclopropane configuration on the biological activity of cyclopropyl-epothilones.

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  • 2014-07-22
Published in:
  • ChemMedChem. - 2014
cancer
epothilones
inhibitors
microtubules
stereoselective synthesis
structure-activity relationships
Cell Line
Cyclopropanes
Epothilones
Humans
Molecular Structure
English Two cis-12,13-cyclopropyl-epothilone B variants have been synthesized, differing only in the configuration of the stereocenters at C12 and C13. The syntheses were based on a common allylic alcohol intermediate that was converted into the corresponding diastereomeric hydroxymethyl-cyclopropanes by means of stereoselective Charette cyclopropanations. Macrocyclizations were accomplished through ring-closing metathesis (RCM). Substantial differences between the two compounds were found with regard to microtubule binding affinity, antiproliferative activity and their effects on the cellular microtubule network. While the analogue with the cyclopropane moiety oriented in a corresponding way to the epoxide configuration in natural epothilones was almost equipotent with epothilone A, the other was significantly less active. Based on these findings, natural epothilone-like activity of cis-fused 12,13-cyclopropyl-epothilone analogues is tightly linked to the natural orientation of the cyclopropane moiety.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/217169
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