Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of combretastatin A4

被引:24
作者
Ty, Nancy [1 ,2 ]
Pontikis, Renee [1 ,2 ]
Chabot, Guy G. [3 ,4 ]
Devillers, Emmanuelle [1 ,2 ]
Quentin, Lionel [3 ,4 ]
Bourg, Stephane [5 ,6 ]
Florent, Jean-Claude [1 ,2 ]
机构
[1] Inst Curie, Ctr Rech, F-75248 Paris 05, France
[2] CNRS, UMR 176, F-75248 Paris 05, France
[3] Univ Paris 05, Fac Sci Pharmaceut & Biol, F-75006 Paris, France
[4] INSERM, CNRS, Lab Pharmacol Chim Genet & Imagerie, U 1022,UMR 8151, F-75006 Paris, France
[5] Univ Orleans, ICOA, CNRS, UMR 7311, F-45067 Orleans 2, France
[6] Ctr Biophys Mol, CNRS, UPR 4301, F-45071 Orleans 2, France
关键词
Vascular disrupting agents; Tubulin; Combretastatin; Cyclopropyl compounds; Palladium catalyzed reactions; VASCULAR DISRUPTING AGENTS; IN-VITRO; NATURAL-PRODUCTS; A-4; PHOSPHATE; DERIVATIVES; CIS; COLCHICINE; TUBULIN; BINDING;
D O I
10.1016/j.bmc.2012.11.056
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2013 Published by Elsevier Ltd.
引用
收藏
页码:1357 / 1366
页数:10
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