Morier-Teissier E, Boitte N, Helbecque N, Bernier J L, Pommery N, Duvalet J L, Fournier C, Hecquet B, Catteau J P, Hénichart J P
Inserm U 16, Lille, France.
J Med Chem. 1993 Jul 23;36(15):2084-90. doi: 10.1021/jm00067a005.
A new molecule 4 [(GGH-DAE)2DHQ] associating the 1,4,5,8-tetrahydroxyanthraquinone ring (DHQ) of the antitumor drug mitoxantrone (2), two diaminoethylene chains (DAE), and the metal-chelating peptide Gly-Gly-His (GGH) has been synthesized. Such a molecule presents characteristics able to induce antitumor activity: compound 4 intercalates into DNA as measured by delta Tm, fluorescence quenching, and viscometry; ESR studies demonstrate that several types of Cu complexes are formed depending on pH; and the production of free radicals, as evidenced by spin-trapping, is enhanced by 4. In vitro, in leukemia cells L1210 and mammary cells MCF7, 4 is slightly less cytostatic than mitoxantrone, but substantially less toxic. In vivo, in leukemia P388 on mice, a T/C value of 230 is obtained at 25 mg/kg, higher than the one of mitoxantrone, which is toxic at the same dose.
