The strategy of using small
peptides for effective targeting of
tumor cells in
chemotherapy has proven beneficial. Recently we showed that J1 (
L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating
nitrogen mustard-containing
dipeptide, exhibited strong cytotoxic activity in fresh human
tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human
tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17
nitrogen mustard-containing
dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single
amino acid mustard derivative
melphalan and its ethyl and isopropyl
esters. Also P2 (
L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human
tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like
amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the
dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active
biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.