Relationship between DNA-binding and biological activity of anilinoacridine derivatives containing the nucleic acid-binding unit SPKK.

The synthesis of two peptidic derivatives, including an anilinoacridine chromophore (related to the antileukemic drug amsacrine) and either the tetrapeptide SPKK (a nucleic acid-binding unit) (1) or the octapeptide SPKKSPKK (2), has been carried out. The interaction of both drugs with DNA has been studied. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the tetrapeptidic or octapeptidic portion is located in the DNA minor groove. Compound 1 fully intercalates into DNA. In contrast, minor groove binding of the octapeptide SPKKSPKK seems to partially modify the intercalative properties of the acridine moiety of 2. In vitro cytostatic and cytotoxic activities against a murine leukemia cell line (L1210), as well as inhibition of [3H]thymidine incorporation, are reported. Compound 1, which is a better inhibitor of DNA synthesis than 2, is also 2.8-fold more potent in terms of growth inhibition. Both drugs are efficient cytostatic agents, but are weakly cytotoxic. The DNA-binding abilities of the two molecules are well correlated to their biological properties. Thus, DNA can be considered as the primary target for these new ligands.