N-Phenyl-N'-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. Part 3: role of carbonyl groups in the covalent binding to the colchicine-binding site.
In the course of the development of N-phenyl-N'-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents, we investigated the effect of carbonylated substituting chains of the aromatic ring of CEU on their covalent binding to the colchicine-binding site (C-BS). In this study, we found that CEU, 5e, 5f, 8e, and 8f substituted by either a methyl ester or a methyl ketyl group at the omega-position exhibited a significant antiproliferative activity on HT-29, M21, and MCF-7 tumor cells. SDS-PAGE assays and cell cycle analysis confirmed that 5e, 5f, 8e, and 8f covalently bind to the C-BS and arrest the cell division in G(2)/M phase. Surprisingly, the presence of omega-carboxyl, omega-ethyl esters or omega-amides decreased significantly both the antiproliferative activity and the specificity toward beta-tubulin.
Moreau
Emmanuel
E
Univ Clermont1, UFR Pharmacie, Laboratoire de Chimie Organique, Clermont-Ferrand F-63001, France. Emmanuel.Moreau@u-clermont1.fr
Fortin
Sébastien
S
Lacroix
Jacques
J
Patenaude
Alexandre
A
Rousseau
Jean L C
JL
C-Gaudreault
René
R
D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D002255:Carbonic Acid / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017606:Chlorine Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003078:Colchicine / Q000737:chemistry*; D004247:DNA / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D017606:Chlorine Compounds; D014404:Tubulin; D002255:Carbonic Acid; D014508:Urea; D004247:DNA; D003078:Colchicine