TY - JOUR
T1 - A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4
T2 - Design, synthesis, molecular modelling, and biological evaluation
AU - Naret, Timothée
AU - Bignon, Jérôme
AU - Bernadat, Guillaume
AU - Benchekroun, Mohamed
AU - Levaique, Helene
AU - Lenoir, Christine
AU - Dubois, Joelle
AU - Pruvost, Alain
AU - Saller, François
AU - Borgel, Delphine
AU - Manoury, Boris
AU - Leblais, Veronique
AU - Darrigrand, Romain
AU - Apcher, Sébastien
AU - Brion, Jean Daniel
AU - Schmitt, Etienne
AU - Leroux, Frédéric R.
AU - Alami, Mouad
AU - Hamze, Abdallah
N1 - Publisher Copyright:
© 2017 Elsevier Masson SAS
PY - 2018/1/1
Y1 - 2018/1/1
N2 - A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of isocombretastatin 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 isoCA-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 IC50 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 isoCA-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 G2/M phase arrest and, dramatically disrupted the microtubule network.
AB - A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of isocombretastatin 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 isoCA-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 IC50 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 isoCA-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 G2/M phase arrest and, dramatically disrupted the microtubule network.
KW - Cancer
KW - Cytotoxic
KW - Fluorinated analogs
KW - Tubulin inhibitors
KW - isoCA-4
UR - http://www.scopus.com/inward/record.url?scp=85036495644&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.11.055
DO - 10.1016/j.ejmech.2017.11.055
M3 - Article
C2 - 29202409
AN - SCOPUS:85036495644
SN - 0223-5234
VL - 143
SP - 473
EP - 490
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -