BIOMAT Database Logo BIOMAT Database Logo

Antimitotic antitumor agents: synthesis, structure-activity relationships, and biological characterization of N-aryl-N'-(2-chloroethyl)ureas as new selective alkylating agents. 2001

E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Centre de Recherche, CHUQ, Hôpital Saint-François d'Assise, 10, rue de l'Espinay, Québec G1L3L5, Canada. Mounetou@inserm484.u-clermont.fr

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.

UI MeSH Term Description Entries
D008870 Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein TUBULIN and are influenced by TUBULIN MODULATORS. Microtubule
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D005978 Glutathione A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides. Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D005980 Glutathione Reductase Catalyzes the oxidation of GLUTATHIONE to GLUTATHIONE DISULFIDE in the presence of NADP+. Deficiency in the enzyme is associated with HEMOLYTIC ANEMIA. Formerly listed as EC 1.6.4.2. Glutathione-Disulfide Reductase,Reductase, Glutathione,Reductase, Glutathione-Disulfide
D006224 Cricetinae A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS. Cricetus,Hamsters,Hamster
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014404 Tubulin A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from SPERM FLAGELLUM; CILIA; and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to COLCHICINE; VINCRISTINE; and VINBLASTINE. alpha-Tubulin,beta-Tubulin,delta-Tubulin,epsilon-Tubulin,gamma-Tubulin,alpha Tubulin,beta Tubulin,delta Tubulin,epsilon Tubulin,gamma Tubulin

Related Publications

E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Synthesis and structure-activity relationships of N-aryl(indol-3-yl)glyoxamides as antitumor agents.
September 2009, Bioorganic & medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Optimized N-phenyl-N'-(2-chloroethyl)ureas as potential antineoplastic agents: synthesis and growth inhibition activity.
December 2005, Bioorganic & medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
1-Aryl-3-(2-chloroethyl) ureas: synthesis and in vitro assay as potential anticancer agents.
February 1988, Journal of pharmaceutical sciences,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Synthesis and structure-activity relationships of 3-aminobenzophenones as antimitotic agents.
May 2004, Journal of medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Synthesis, antiproliferative activity evaluation and structure-activity relationships of novel aromatic urea and amide analogues of N-phenyl-N'-(2-chloroethyl)ureas.
July 2010, European journal of medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Hypoxia-selective antitumor agents. 9. Structure-activity relationships for hypoxia-selective cytotoxicity among analogues of 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide.
July 1994, Journal of medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
HEXAHYDROPYRIMIDINES. IV. SYNTHESIS OF 2-(4-(N,N-BIS(2-CHLOROETHYL)AMINO)ARYL)-1,3-BIS(ARALKYL)HEXAHYDROPYRIMIDINES AS ANTITUMOR AGENTS.
January 1964, Journal of medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Synthesis and structure-activity relationships of N-benzyl-N-(X-2-hydroxybenzyl)-N'-phenylureas and thioureas as antitumor agents.
January 2010, Bioorganic & medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Synthesis and structure-activity relationships of N-methyl-5,6,7-trimethoxylindoles as novel antimitotic and vascular disrupting agents.
February 2013, Journal of medicinal chemistry,
E Mounetou, and J Legault, and J Lacroix, and R C-Gaudreault
Hypoxia-selective antitumor agents. 3. Relationships between structure and cytotoxicity against cultured tumor cells for substituted N,N-bis(2-chloroethyl)anilines.
January 1990, Journal of medicinal chemistry,
Copied contents to your clipboard!