Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships

• Published in: European journal of medicinal chemistry 2011-11, Vol.46 (11), p.5327-5342
• Main Authors: Fortin, Sébastien, Wei, Lianhu, Moreau, Emmanuel, Lacroix, Jacques, Côté, Marie-France, Petitclerc, Éric, Kotra, Lakshmi P., Gaudreault, René C.
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - pharmacology; Animals; Anticancer drugs; Antimicrotubule agents; Antimitotic agents; Antimitotic Agents - chemistry; Antimitotic Agents - metabolism; Antimitotic Agents - pharmacology; Antineoplastic agents; Benzenesulfonamides; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Chick Embryo; Chorioallantoic Membrane - drug effects; Chorioallantoic Membrane - pathology; Colchicine - metabolism; General aspects; Humans; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides; PIB-SA; Quantitative Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - metabolism; Sulfonamides - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.08.034

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 G2/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. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs are a new class of potent antimicrotubule agents binding to the C-BS. [Display omitted] ▸ PIB-SA is new class of antimitotics exhibiting a new molecular scaffold. ▸ PIB-SAs arrest the cell cycle progression in G2/M phase. ▸ PIB-SAs are potent antimicrotubule agents binding to the C-BS. ▸ PIB-SAs were not or only slightly affected by chemoresistance. ▸ PIB-SAs exhibit potent antitumoral and antiangiogenic activity in the CAM assay.