title: The impact of cyclopropane configuration on the biological activity of cyclopropyl-epothilones.
abstract: 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.
authors.affiliation: ETH Zürich, Department of Chemistry & Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Fabienne Z
authors.initials: FZ
authors.lastname: Gaugaz
authors.forename: Mariano
authors.initials: M
authors.lastname: Redondo-Horcajo
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Amanda
authors.initials: A
authors.lastname: Cobos-Correa
authors.forename: Markus
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
mesh_terms: D002460:Cell Line; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology; D034261:Epothilones / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure
chemical_list: D003521:Cyclopropanes; D034261:Epothilones; C030797:cyclopropane
keywords: cancer; epothilones; inhibitors; microtubules; stereoselective synthesis; structure-activity relationships