title: Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships.
abstract: The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G(2)/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.
authors.affiliation: Unité des Biotechnologies et de Bioingénierie, Centre de Recherche, CHUQ, Hôpital Saint-François d'Assise, Québec, QC, Canada. sebastien.fortin.1@ulaval.ca
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fortin
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moreau
authors.forename: Jacques
authors.initials: J
authors.lastname: Lacroix
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Côté
authors.forename: Eric
authors.initials: E
authors.lastname: Petitclerc
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
authors.forename: René C
authors.initials: RC
authors.lastname: Gaudreault
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D050256:Antimitotic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000473:pathology; D003078:Colchicine / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D020533:Angiogenesis Inhibitors; D050256:Antimitotic Agents; D003078:Colchicine; D013449:Sulfonamides; D000096926:Benzenesulfonamides