Synthesis, biological evaluation, and structure-activity relationships of novel substituted N-phenyl ureidobenzenesulfonate derivatives blocking cell cycle progression in S-phase and inducing DNA double-strand breaks.
Twenty-eight new substituted N-phenyl ureidobenzenesulfonate (PUB-SO) and 18 N-phenylureidobenzenesulfonamide (PUB-SA) derivatives were prepared. Several PUB-SOs exhibited antiproliferative activity at the micromolar level against the HT-29, M21, and MCF-7 cell lines and blocked cell cycle progression in S-phase similarly to cisplatin. In addition, PUB-SOs induced histone H2AX (γH2AX) phosphorylation, indicating that these molecules induce DNA double-strand breaks. In contrast, PUB-SAs were less active than PUB-SOs and did not block cell cycle progression in S-phase. Finally, PUB-SOs 4 and 46 exhibited potent antitumor activity in HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membranes, which was similar to cisplatin and combretastatin A-4 and without significant toxicity toward chick embryos. These new compounds are members of a promising new class of anticancer agents.
Unité des Biotechnologies et de Bioingénierie, Centre de Recherche, C.H.U.Q., Hôpital Saint-François d'Assise, Québec, QC, G1L 3L5, Canada.
Vanessa
V
Turcotte
Sébastien
S
Fortin
Florence
F
Vevey
Yan
Y
Coulombe
Jacques
J
Lacroix
Marie-France
MF
Côté
Jean-Yves
JY
Masson
René
R
C-Gaudreault
D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019169:Jurkat Cells; D009369:Neoplasms / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation; D016196:S Phase / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology; D013329:Structure-Activity Relationship
C575267:2-ethylphenyl 4-(3-ethylureido)benzenesulfonate; C575266:2-tolyl 4-(3-(2-chloroethyl)ureido)benzenesulfonate; D016588:Anticarcinogenic Agents; D001557:Benzenesulfonates; C468783:H2AX protein, human; D006657:Histones; D048289:Imidazolidines; D010671:Phenylurea Compounds; D013267:Stilbenes; C058728:fosbretabulin; D002945:Cisplatin