Design, synthesis and biological activity of 5-fluorouracil-distamycin hybrids

The design, synthesis, and the evaluation of the cytotoxic activity of a novel group of hybrids, namely a mol. combination of the natural antibiotic agent distamycin A and the antimetabolite 5-fluorouracil is reported and structure-activity relationships are discussed. This homologous series [I; n = 1-6] consisted of the oligopeptides distamycin A joined to 5-fluorouracil by aliph. carboxylic acid moieties contg. a polymethylene chain [(CH2)n, where n = 1 up to 6]. In vitro antitumor activity of this new class of derivs. was appreciable for compds. with at least two methylenes I (n = 2-6). For these compds. the in vitro antitumor activity was not influenced by the length of the -[CH2]n linker, being comparable to that of the parent compd. distamycin A. Arrested polymerase-chain expts. demonstrated selective binding of the 5-fluorouracil-distamycin hybrids to A+T rich DNA sequences.