A new generation of N-aryl-N'-(1-alkyl-2-chloroethyl)ureas as microtubule disrupters: synthesis, antiproliferative activity, and beta-tubulin alkylation kinetics.
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.
Mounetou
Emmanuelle
E
Centre de recherche, CHUQ, Hôpital Saint-François d'Assise, 10, rue de l'Espinay, Québec G1L3L5, Canada. Mounetou@inserm484.u-clermont1.fr
Legault
Jean
J
Lacroix
Jacques
J
C -Gaudreault
René
R
D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; C479689:N-(4-isopropyl)phenyl-N'-(1-methyl-2-chloro)ethylurea; D010671:Phenylurea Compounds; D014404:Tubulin; D014508:Urea