Styryl-N-phenyl-N′-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model

• Published in: European journal of medicinal chemistry 2015-07, Vol.100, p.34-43
• Main Authors: Gagné-Boulet, Mathieu, Fortin, Sébastien, Lacroix, Jacques, Lefebvre, Carole-Anne, Côté, Marie-France, C.-Gaudreault, René
• Format: Article
• Language: English
• Subjects: Antimitotics; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Colchicine-binding site inhibitors; Combretastatin A-4; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Imidazolidines - chemical synthesis; Imidazolidines - chemistry; Imidazolidines - pharmacology; MCF-7 Cells; Microtubules - drug effects; Molecular Structure; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Styryl-N-phenyl-N′-(2-chloroethyl)ureas; Styryl-N-phenyl-N′-ethylureas; Styrylphenylimidazolidin-2-ones; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.05.034

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. [Display omitted] •SCEUs and SIMZs are new and innovative CA-4 analogs.•They are active in the high and the low nanomolar range, respectively.•They block the cell cycle progression in the G2/M phase.•They bind to the C-BS and disrupt the microtubules of cancer cells.•The trimethoxyphenyl moiety is not essential for the activity of SIMZs and SCEUs.