DNA-binding and DNA-cleaving properties of a synthetic model AGAGLU related to the antitumour drugs AMSA and bleomycin (original) (raw)

1988, Biochemical and Biophysical Research Communications

We have previously described two synthetic models gathering a simplified model of the complexing part of Bleomycin (Blm) and the intercalating moiety of m-AMSA. These molecules, namely AGGA and AGAMGA, do not seem able to cleave DNA as Blm does. The present work is devoted to the study of a new derivative, AGAGLU, which includes in its structure a judiciously chosen connector between the two parts of the molecule. This compound, the chelating and DNA-binding properties of which are described here, has been shown to induce single-strand breakage of duplex DNA in a high level. ~ 1988 Acad .... P ..... zn= m-AMSA, 4'-(9-acridinylamino)-methanesulfon-m-anisidide is active against a wide spectrum of transplantable tumors (1-3) including L1210 and P388 leukemia, B16 melanoma, Lewis lung carcinoma, C3H mammary adenocarcinoma and mammary tumor in CD8F I mice and is currently in clinical use. The antineoplastic activity of the drug is believed to be due to DNA strand scissions involving an oxidative process (4,5) and/or a modification of DNA topoisomerases II function (6,7). It has been demonstrated that the primary step of the mode of action is a recognition of the DNA target by intercalation of the acridine ring (8). A lot of chemical modifications of this key structure have been reported by different laboratories in order to improve the affinity of the molecule to the binding sites. In particular, we have introduced at the 4-position of the phenyl ring a dipeptide Lys-Gly and the obtained compound ALGA was found to bind DNA with a high affinity, to show a high cytotoxic activity and a cell cycle effect (9,10). Another important modification consisted in replacing the dipeptide chain by a more sophisticated peptide including the simplified complexing part of Bleomycin (Blm), an antitumor drug used in the treatment of squamous cell carcinomas and malignant lymphomas (!1,12). The DNA-binding, the metal-chelating and cytotoxic properties of this interesting molecule AGGA were