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-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.
Morier-Teissier
E
E
Inserm U 16, Lille, France.
Boitte
N
N
Helbecque
N
N
Bernier
J L
JL
Pommery
N
N
Duvalet
J L
JL
Fournier
C
C
Hecquet
B
B
Catteau
J P
JP
Hénichart
J P
JP
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002614:Chelating Agents / Q000138:chemical synthesis; D005609:Free Radicals; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D000970:Antineoplastic Agents; D002614:Chelating Agents; D005609:Free Radicals; D009842:Oligopeptides; C037026:diglycyl-histidine