SYNTHESIS AND ANTITUMOR PROPERTIES OF AN ANTHRAQUINONE BISUBSTITUTED BY THE COPPER CHELATING PEPTIDE GLY-GLY-L-HIS

A new molecule 4 [(GGH-DAE)2DHQ] associating the 1,4,5,8-tetrahydroxya nthraquinone ring (DHQ) of the antitumor drug mitoxantrone (2), two di aminoethylene chains (DAE), and the metal-chelating peptide Gly-Gly-Hi s (GGH) has been synthesized. Such a molecule presents characteristics able to induce antitumor activity: compound 4 intercalates into DNA a s measured by DELTAT(m), fluorescence quenching, and viscometry; ESR s tudies demonstrate that several types of Cu complexes are formed depen ding on PH; and the production of free radicals, as evidenced by spin- trapping, is enhanced by 4. In vitro, in leukemia cells L1210 and mamm ary cells MCF7, 4 is slightly less cytostatic than mitoxantrone, but s ubstantially less toxic. In vivo, in leukemia P388 on mice, a T/C valu e of 230 is obtained at 25 mg/kg, higher than the one of mitoxantrone, which is toxic at the same dose.