A new generation of N-aryl-N'-(1-alkyl-2-chloroethyl)ureas as microtubule disrupters: synthesis, antiproliferative activity, and beta-tubulin alkylation kinetics

Abstract

New N-aryl-N'-2-chloroethylureas (CEUs) with enhanced cytotoxicity were developed as antimitotic agents potentially useful in cancer chemotherapy. Highly potent CEUs were obtained by introduction of a branched alkylating chain, the N'-(1-methyl-2-chloro)ethyl group. Their cytotoxic activity was enantio-dependent and induced through specific alkylation of beta-tubulin, leading to microtubule disruption and mitotic arrest. Overall, the structural modifications of the CEUs described here significantly improved their kinetics of beta-tubulin alkylation. In this new series, CEUs 16a and 18a displayed particularly enhanced antiproliferative activity related to a faster reaction with beta-tubulin and merit further investigation as potential antitumor agents.