Antimitotic antitumor agents: Synthesis, structure-activity relationships,and biological characterization of N-aryl-N '-(2-chloroethyl)ureas as new selective alkylating agents

A series of N-aryl-N'-(2-chloroethyl)ureas (CEUs) and derivatives were synt hesized and evaluated for antiproliferative activity against a wide panel o f tumor cell lines. Systematic structure-activity relationship (SAR) studie s indicated that: (i) a branched alkyl chain or a halogen at the 4-position of the phenyl ring or a fluorenyl/indanyl group, (ii) an exocyclic urea fu nction, and (iii) a N'-2-chloroethyl moiety were required to ensure signifi cant cytotoxicity. Biological experiments, such as immunofluorescence micro scopy, confirmed that these promising compounds alter the cytoskeleton by i nducing microtubule depolymerization via selective alkylation of P-tubulin. Subsequent evaluations demonstrated that potent CEUs were weak alkylators, were non-DNA-damaging agents, and did not interact with the thiol function of either glutathione or glutathione reductase. Therefore, CEUs are part o f a new class of antimitotic agents. Finally, among the series of CEUs eval uated, compounds 12, 15, 16, and 27 were selected for further in vivo trial s.