Amidine analogues of melphalan: Synthesis, cytotoxic activity, and DNA binding properties

Design, synthesis, and cytotoxic activity of amidine derivatives of melphalan are described and structure-activity relationships are discussed. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [H-3]thymidine incorporation into DNA in both MD-AMB-231 and MCF-7 human breast cancer cells demonstrated that these compounds were more active than melphalan. Data from the ethidium displacement assay showed that these compounds were able to bind in the minor groove-binding mode in AT sequences of DNA. The cytotoxic properties of the amidine analogues of melphalan towards cultured human breast cancer cells correlate with topoisomerase II inhibitory properties but not with DNA-binding properties.