IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

Mohamed Ali Soussi (1) , Olivier Provot , Guillaume Bernadat (2) , Jérôme Bignon (3) , Déborah Desravines (3) , Joëlle Dubois (3) , Jean-Daniel Brion (1) , Samir Messaoudi (1) , Mouad Alami (1)

1 BioCIS - Biomolécules : Conception, Isolement, Synthèse
2 INSU - CNRS - Institut national des sciences de l'Univers
3 ICSN - Institut de Chimie des Substances Naturelles

A series of novel isocombretaquinazolines (isoCoQ) 4 was quickly prepared using the coupling of N-tosylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which could be regarded as isoCA-4 analogues devoid of the 3,4,5-trimethoxyphenyl ring, displayed a nanomolar level of cytotoxicity against various human cancer cells and inhibited tubulin polymerization effectively. IsoCoQ 4b, 4c and 4d having the greatest ressemblance to isoCA-4, isoFCA-4 and isoNH2CA-4, respectively, led to the arrest of HCT116 cancer cell lines in the G2/M phase of the cell cycle at a very low concentration. Preliminary in vitro antivascular results showed that 4d has disrupted a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All of these results clearly demonstrated that the replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 by a quinazoline nucleus is possible and leads to new highly promising derivatives of potential for further development as antitubulin agents.

Domaines: Chimie thérapeutique; Chimie organique

Mohamed Ali Soussi, Olivier Provot, Guillaume Bernadat, Jérôme Bignon, Déborah Desravines, et al.. IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity. ChemMedChem, 2015, 10 (8), pp.1392-1402. ⟨10.1002/cmdc.201500069⟩. ⟨hal-02394367⟩