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The Impact of Cyclopropane Configuration on the Biological Activity of Cyclopropyl‐Epothilones
Author(s) -
Gaugaz Fabienne Z.,
RedondoHorcajo Mariano,
Barasoain Isabel,
Díaz J. Fernando,
CobosCorrea Amanda,
Kaufmann Markus,
Altmann KarlHeinz
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402129
Subject(s) - epothilones , cyclopropane , epothilone , stereochemistry , moiety , stereocenter , chemistry , metathesis , diastereomer , stereoselectivity , ring closing metathesis , allylic rearrangement , polyketide , epoxide , ring (chemistry) , enantioselective synthesis , organic chemistry , biosynthesis , polymer , polymerization , enzyme , catalysis
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.