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 synthesized and evaluated for antiproliferative activity against a wide panel of tumor cell lines. Systematic structure--activity relationship (SAR) studies 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 function, and (iii) a N'-2-chloroethyl moiety were required to ensure significant cytotoxicity. Biological experiments, such as immunofluorescence microscopy, confirmed that these promising compounds alter the cytoskeleton by inducing microtubule depolymerization via selective alkylation of beta-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 of a new class of antimitotic agents. Finally, among the series of CEUs evaluated, compounds 12, 15, 16, and 27 were selected for further in vivo trials.
Centre de Recherche, CHUQ, Hôpital Saint-François d'Assise, 10, rue de l'Espinay, Québec G1L3L5, Canada. Mounetou@inserm484.u-clermont.fr
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Mounetou
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Legault
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Lacroix
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C-Gaudreault
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D019084:Fluorescent Antibody Technique, Indirect; D005978:Glutathione / Q000737:chemistry; D005980:Glutathione Reductase / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D014404:Tubulin; D014508:Urea; D005980:Glutathione Reductase; D005978:Glutathione