title: Structure-activity studies of novel amidine analogues of chlorambucil: correlation of cytotoxic activity with DNA-binding affinity and topoisomerase II inhibition.
abstract: A series of amidine analogues of chlorambucil (9-12), where 5-[4-(N-alkylamidino)phenyl]-2-furancarboxamide and the chlorambucil moiety are linked by a NH(CH(2))(2)NH chain, was synthesized and their cytotoxicity has been tested against the growth of human breast cancer MCF-7 cells. Evaluation of the cytotoxicity of compounds 9-12 employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA demonstrated that these conjugates were more active than chlorambucil. Data from the ethidium displacement assay indicated that these compounds bind in the minor groove of DNA and show moderate specificity for AT base pairs. Compounds 9-12 were potent topoisomerase II inhibitors, with 50% inhibitory concentrations (IC(50))ranging from 10 to 40 microM. The cytotoxicity of the compounds 9-12 correlates with their DNA-binding affinities and their relative potency as topoisomerase II inhibitors. Altogether, these data suggest (i) that the cytotoxic activity of compounds 9-12 may be due to the combined effects of alkylation, DNA-minor groove binding, and (ii) that N-(2-aminoethyl)-5-(4-N-alkylamidinophenyl)-2-furancarboxamides (5-8) ligands are suitable linkers that favors DNA targeting by chlorambucil derivatives.
authors.affiliation: Department of Medicinal Chemistry and Drug Technology, Medical Academy of Białystok, Białystok, Poland. kbiel@amb.edu.pl
authors.forename: Anna
authors.initials: A
authors.lastname: Bielawska
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bielawski
authors.forename: Sławomir
authors.initials: S
authors.lastname: Wołczyński
authors.forename: Tomasz
authors.initials: T
authors.lastname: Anchim
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D002699:Chlorambucil; D004247:DNA