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Iso CombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity
Author(s) -
Soussi Mohamed Ali,
Provot Olivier,
Bernadat Guillaume,
Big Jérome,
Desravines Déborah,
Dubois Joëlle,
Brion JeanDaniel,
Messaoudi Samir,
Alami Mouad
Publication year - 2015
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.201500069
Subject(s) - cytotoxicity , quinazoline , chemistry , cancer cell , stereochemistry , in vitro , cytotoxic t cell , matrigel , tubulin , umbilical vein , microtubule , biochemistry , cancer , biology , microbiology and biotechnology , genetics
A series of novel iso combretaquinazolines ( iso CoQ) 4 were quickly prepared by coupling N ‐toluenesulfonylhydrazones with 4‐chloroquinazolines under palladium catalysis. These compounds, which can be regarded as iso combretastatin A‐4 ( iso CA‐4) analogues that lack the 3,4,5‐trimethoxyphenyl ring, displayed nanomolar‐level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The iso CoQ compounds 2‐methoxy‐5‐(1‐(2‐methylquinazolin‐4‐yl)vinyl)phenol ( 4 b ), 4‐[1‐(3‐fluoro‐4‐methoxyphenyl)vinyl]‐2‐methylquinazoline ( 4 c ), and 2‐methoxy‐5‐(1‐(2‐methylquinazolin‐4‐yl)vinyl)aniline ( 4 d ), which respectively bear the greatest resemblance to iso CA‐4, iso FCA‐4, and iso NH 2 CA‐4, are able to arrest HCT116 cancer cells in the G 2 /M cell‐cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary‐like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5‐trimethoxyphenyl ring of iso CA‐4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.