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.
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.
Fortin
Sébastien
S
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.
Moreau
Emmanuel
E
Patenaude
Alexandre
A
Desjardins
Michel
M
Lacroix
Jacques
J
Rousseau
Jean L C
JL
C-Gaudreault
René
R
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
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D014404:Tubulin