title: Synthesis, DNA binding, topoisomerase inhibition and cytotoxic properties of 2-chloroethylnitrosourea derivatives of hoechst 33258.
abstract: A number of novel 2-chloroethylnitrosourea derivatives of Hoechst 33258 were synthesized and examined for cytotoxicity in breast cancer cell cultures and for inhibition of topoisomerases I and II. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [3H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that these compounds were more active than Hoechst 33258. The DNA-binding ability of these compounds was evaluated by an ultrafiltration method using calf thymus DNA, poly(dA-dT)2 and poly(dG-dC)2, indicated that these compounds as well as Hoechst 33258 well interact with AT base pair compared with GC pair. Binding studies indicate that these compounds bind more tightly to double-stranded DNA than the parent compound Hoechst 33258. The degree to which these compounds inhibited cell growth breast cancer cells was generally consistent with their relative DNA binding affinity. Mechanistic studies revealed that these compounds act as topoisomerase I (topo I) or topoisomerase II (topo II) inhibitors in plasmid relaxation assays.
authors.affiliation: Department of Medicinal Chemistry and Drug Technology, Medical University of Białystok, Poland. kbiel@amb.edu.pl
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bielawski
authors.forename: Anna
authors.initials: A
authors.lastname: Bielawska
authors.forename: Tomasz
authors.initials: T
authors.lastname: Anchim
authors.forename: Sławomir
authors.initials: S
authors.lastname: Wołczyński
mesh_terms: D000818:Animals; D006690:Bisbenzimidazole / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity*; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D026942:DNA Topoisomerases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000633:toxicity; D006801:Humans; D009607:Nitrosourea Compounds / Q000138:chemical synthesis / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D059003:Topoisomerase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D009607:Nitrosourea Compounds; D059003:Topoisomerase Inhibitors; D004247:DNA; D026942:DNA Topoisomerases; D006690:Bisbenzimidazole