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European journal of medicinal chemistry v.143, 2018년, pp.473 - 490   SCI SCIE
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A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4: Design, synthesis, molecular modelling, and biological evaluation

Naret, Timothée (BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France ) ; Bignon, Jérôme (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) ; Bernadat, Guillaume (BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France ) ; Benchekroun, Mohamed (BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France ) ; Levaique, Helene (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) ; Lenoir, Christine (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) ; Dubois, Joelle (Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, F-91198, Gif sur Yvette, France ) ; Pruvost, Alain (Service de Pharmacologie et d'Immunoanalyse (SPI), CEA, INRA, University Paris-Saclay, F-91191, Gif sur Yvette, France ) ; Saller, François (INSERM, UMR-S1176, University Paris-Saclay, F-94276, ) ; Borgel, Delphine ; Manoury, Boris ; Leblais, Veronique ; Darrigrand, Romain ; Apcher, Sébastien ; Brion, Jean-Daniel ; Schmitt, Etienne ; Leroux, Frédéric R. ; Alami, Mouad ; Hamze, Abdallah ;
  • 초록  

    Abstract A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of iso combretastatin A-4 was synthesized with the goal of evaluating the effect of these compounds on the proliferative activity. The introduction of fluorine atom was performed on the phenyl ring or at the linker between the two aromatic rings. The modification of iso CA-4 by introduction of difluoromethoxy group at the para-position ( 3i ) and substitution of the two protons of the linker by two fluorine atoms ( 3m ), produced the most active compounds in the series, with IC 50 values of 0.15–2.2 nM ( 3i ) and 0.1–2 nM ( 3m ) respectively, against a panel of six cancer cell lines. Compounds 3i and 3m had greater antiproliferative activity in comparison with references CA-4 or iso CA-4, the presence of fluorine group leads to a significant enhancement of the antiproliferative activity. Molecular docking studies indicated that compounds 3i and 3m occupy the colchicine binding site of tubulin. Evaluation of cytotoxicity in Human noncancer cells indicated that the compounds 3i and 3m were practically ineffective in quiescent peripheral blood lymphocytes, and may have a selective antiproliferative activity against cancer cells. Analyses of cell cycle distribution, and morphological microtubules organization showed that compound 3m induced G 2 /M phase arrest and, dramatically disrupted the microtubule network. Highlights New fluorinated analogs of iso CA-4 were synthesized. Compounds 3i and 3m exhibit cytotoxic activities on nM to sub nM range over six cancer cell lines. Strong tubulin polymerization inhibition were observed for the compound 3i (IC 50 = 0.4 μM). Compounds 3i and 3m have very poor activities over peripheral blood lymphocytes with IC 50 > 10 mM. Docking studies indicate that 3i and 3m interact with the colchicine binding site. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    isoCA-4 .   Fluorinated analogs .   Cytotoxic .   Cancer .   Tubulin inhibitors.  

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