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.