Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

• Published in: Journal of medicinal chemistry 2011-07, Vol.54 (13), p.4559-4580
• Main Authors: Fortin, Sébastien, Wei, Lianhu, Moreau, Emmanuel, Lacroix, Jacques, Côté, Marie-France, Petitclerc, Éric, Kotra, Lakshmi P, C.-Gaudreault, René
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Arylsulfonates - chemical synthesis; Arylsulfonates - chemistry; Arylsulfonates - pharmacology; Benzene Derivatives - chemical synthesis; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Binding Sites; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Sciences; Chick Embryo; Chorioallantoic Membrane - blood supply; Chorioallantoic Membrane - drug effects; Colchicine - metabolism; Coordination chemistry; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Imidazolidines - chemical synthesis; Imidazolidines - chemistry; Imidazolidines - pharmacology; Medicinal Chemistry; Models, Molecular; Molecular Mimicry; Neovascularization, Physiologic - drug effects; Organic chemistry; Quantitative Structure-Activity Relationship; Radiochemistry; Stilbenes - chemistry; Stilbenes - pharmacology; Transplantation, Heterologous; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200488a

Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G2/M phase and bind to the colchicine-binding site on β-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure–activity relationships.