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

Gaugaz, FZ, Redondo-Horcajo, M, Barasoain, I, Diaz, JF, Cobos-Correa, A, Kaufmann, M and Altmann, K (2014) The impact of cyclopropane configuration on the biological activity of cyclopropyl-epothilones. ChemMedChem. pp. 2227-2232.


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

Item Type: Article
Additional Information: NIBR author: Cobos-Correa, A institute: NIBR contributor address: (Gaugaz, Altmann) ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Vladimir-Prelog-Weg 4, Zurich 8093, Switzerland (Redondo-Horcajo, Barasoain, Diaz) Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, Madrid 28040, Spain (Cobos-Correa, Kaufmann) Novartis Institute for Biomedical Research, Basel 4056, Switzerland
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11


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