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

Abstract

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 ω-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 ω-carboxyl, ω-ethyl esters or ω-amides decreased significantly both the antiproliferative activity and the specificity toward β-tubulin.