Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of combretastatin A4.
To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (-)-1b, (-)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities.
Institut Curie, Centre de Recherche, 26 rue d'Ulm, Paris F-75248 Cedex 05, France.
Nancy
N
Ty
Renée
R
Pontikis
Guy G
GG
Chabot
Emmanuelle
E
Devillers
Lionel
L
Quentin
Stéphane
S
Bourg
Jean-Claude
JC
Florent
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
D003521:Cyclopropanes; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C021985:cyclopropene; C058728:fosbretabulin; D003078:Colchicine