title: N-Phenyl-N'-(2-chloroethyl)ureas (CEU) as potential antineoplastic agents. Part 2: role of omega-hydroxyl group in the covalent binding to beta-tubulin.
abstract: Tubulin is the target of many anticancer drugs, including N-phenyl-N'-(2-chloroethyl)urea (CEU). Unlike most anti-beta-tubulin agents, CEUs are protein monoalkylating agents binding through their N'-(2-chloroethyl)urea moiety to an amino acid nearby the colchicine-binding site on beta-tubulin isoform-2. Following the previously synthesized and attractive N-(3-omega-hydroxyalkylphenyl)-N'-(2-chloroethyl)urea that exhibited growth inhibitory activity at the nanomolar level, we investigated the importance of lower alkyl and alkoxy groups to evaluate the effect of hydroxylated group and chain length on both cell growth inhibition and the mechanism of action of CEU. Here, we describe the preparation of two new series of CEU and show that the most potent CEU derivatives beside the omega-hydroxylated 1f were 2f and 3e, respectively. We have confirmed that the pentyl substituted CEUs 1f, 2f, and 3e are still covalently binding to beta-tubulin and still arrest cell division in G(2)/M phase.
authors.affiliation: Unité des Biotechnologies et de Bioingénierie, Centre de Recherche, C.H.U.Q., Hôpital Saint-François d'Assise, Université Laval, Québec, QC, Canada G01L 3L5.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fortin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moreau
authors.forename: Alexandre
authors.initials: A
authors.lastname: Patenaude
authors.forename: Michel
authors.initials: M
authors.lastname: Desjardins
authors.forename: Jacques
authors.initials: J
authors.lastname: Lacroix
authors.forename: Jean L C
authors.initials: JL
authors.lastname: Rousseau
authors.forename: René
authors.initials: R
authors.lastname: C-Gaudreault
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D009369:Neoplasms / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D014404:Tubulin