title: Synthesis and cytotoxic activity of novel amidine analogues of bis(2-chloroethyl)amine.
abstract: Novel nitrogen mustard agents 7-12 involving 4-(N,N-bis(2-chloroethyl)aminophenyl)propylamine linked to a 5-(4-N-alkylamidinophenyl)-2-furancarboxylic acid moiety by the formation of an amide bond have been synthesized, characterized, and evaluated for their in-vitro cytotoxic activity against MDA-MB-231 and MCF-7 human breast cancer cells. Evaluation of the cytotoxicity of 7-12 employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA demonstrated that these compounds exhibit remarkable cytotoxic effects in comparison with 4-[bis(2-chloroethyl)amino]benzenebutanoic acid. Compounds 7 and 9, which possess a cationic amidine and 4,5-dihydro-1H-imidazol function moiety are approximately ten times more potent than 4-[bis(2-chloroethyl)amino]benzenebutanoic acid. The new compounds were evaluated as DNA topoisomerase II inhibitors. The cytotoxicity of the compounds 7-12 correlates with their DNA-binding affinities and their relative potency as topoisomerase II inhibitors.
authors: Department of Medicinal Chemistry and Drug Technology, Medical University of Bialystok, Bialystok, Poland. kbiel@umwb.edu.pl
authors: Krzysztof
authors: K
authors: Bielawski
authors: Anna
authors: A
authors: Bielawska
authors: Bozena
authors: B
authors: Poplawska
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008466:Mechlorethamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D008466:Mechlorethamine; D004247:DNA; D013936:Thymidine