N-Phenyl-N'-(2-chloroethyl)urea analogues of combretastatin A-4: Is the N-phenyl-N'-(2-chloroethyl)urea pharmacophore mimicking the trimethoxy phenyl moiety?
A series of novel N-phenyl-N'-(2-chloroethyl)urea derivatives potentially mimicking the structure of combretastatin A-4 were synthesized and tested for their cell growth inhibition and their binding to the colchicine-binding site of beta-tubulin. Compounds 2a, 3a, and 3b were found to inhibit cell growth at the micromolar level on four human tumor cell lines. Flow cytometric analysis indicates that the new compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. Covalent binding of 2a, 3a, and 3b to the colchicine-binding site of beta-tubulin was confirmed also using SDS-PAGE and competition assays.
Fortin
Sébastien
S
Unité des Biotechnologies et de Bioingénierie, Centre de recherche, C.H.U.Q., Hôpital Saint-François d'Assise, Université Laval, Que., Canada G1L 3L5.
Moreau
Emmanuel
E
Lacroix
Jacques
J
Teulade
Jean-Claude
JC
Patenaude
Alexandre
A
C-Gaudreault
René
R
D050256:Antimitotic Agents / Q000494:pharmacology; D001667:Binding, Competitive; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003078:Colchicine / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry; D014508:Urea / Q000737:chemistry
D050256:Antimitotic Agents; D013267:Stilbenes; D014404:Tubulin; D014508:Urea; C058728:fosbretabulin; D003078:Colchicine