title: Styryl-N-phenyl-N'-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model.
abstract: Combretastatin A-4 (CA-4) is a well-studied and attractive molecular template to develop new antimitotics. Several thousand of modifications were performed on the ring B and the ethenyl bridge of CA-4 but only a few involved the trimethoxyphenyl moiety (TMP, ring A) often considered essential to the antiproliferative and antimicrotubule activities. In this study, we described the design, the preparation, the characterization and the biological evaluation of three new series of CA-4 analogs namely styryl-N-phenyl-N'-ethylureas (SEUs), styryl-N-phenyl-N'-(2-chloroethyl)ureas (SCEUs) and styrylphenylimidazolidin-2-ones (SIMZs) bearing a 3-Cl (series a), 3,5-Me (series b) and TMP (series c) substituents, respectively. All SCEU and SIMZ Z-isomers were active in the high and the low nanomolar range, respectively. Conversely to SEUs and their E-isomers that were significantly less active or inactive. Interestingly, the TMP moiety is giving rise to derivatives exhibiting the lowest antiproliferative activity in the SCEU series (10c) and the most active compound in the SIMZ series (12c). Moreover, SIMZ Z-isomers bearing either a 3-Cl (12a) or a 3,5-Me (12b) exhibited antiproliferative activities that are also in the same order of magnitude as 12c. All SCEU and SIMZ Z-isomers also arrested the cell cycle progression in G2/M phase, bound to the colchicine-binding site and disrupted the cytoskeleton of cancer cells. In addition to the promising and innovative microtubule-disrupting properties of SCEUs and SIMZs, these results show that the TMP moiety is not essential for the cytocidal activity of these new CA-4 analogs.
authors.affiliation: Centre de recherche du CHU de Québec, axe oncologie, Hôpital Saint-François d'Assise, Québec, QC G1L 3L5, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gagné-Boulet
authors.affiliation: Centre de recherche du CHU de Québec, axe oncologie, Hôpital Saint-François d'Assise, Québec, QC G1L 3L5, Canada; Faculté de pharmacie, Université Laval, Pavillon Vandry, Québec, QC G1V 0A6, Canada. Electronic address: sebastien.fortin@pha.ulaval.ca.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fortin
authors.affiliation: Centre de recherche du CHU de Québec, axe oncologie, Hôpital Saint-François d'Assise, Québec, QC G1L 3L5, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Lacroix
authors.affiliation: Centre de recherche du CHU de Québec, axe oncologie, Hôpital Saint-François d'Assise, Québec, QC G1L 3L5, Canada.
authors.forename: Carole-Anne
authors.initials: CA
authors.lastname: Lefebvre
authors.affiliation: Centre de recherche du CHU de Québec, axe oncologie, Hôpital Saint-François d'Assise, Québec, QC G1L 3L5, Canada.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Côté
authors.affiliation: Centre de recherche du CHU de Québec, axe oncologie, Hôpital Saint-François d'Assise, Québec, QC G1L 3L5, Canada; Faculté de médecine, Département de médecine moléculaire, Université Laval, Pavillon Vandry, Québec, QC G1V 0A6, Canada. Electronic address: rene.c-gaudreault@crchudequebec.ulaval.ca.
authors.forename: René
authors.initials: R
authors.lastname: C-Gaudreault
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects*; D015394:Molecular Structure; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D048289:Imidazolidines; D013267:Stilbenes; C000607117:styryl-N-phenyl-N'-(2-chloroethyl)urea; C000607118:styrylphenylimidazolidin-2-one; D014508:Urea; C058728:fosbretabulin
keywords: Antimitotics; Colchicine-binding site inhibitors; Combretastatin A-4; Styryl-N-phenyl-N′-(2-chloroethyl)ureas; Styryl-N-phenyl-N′-ethylureas; Styrylphenylimidazolidin-2-ones