Metal Cu(II) and Zn(II) bipyridyls as inhibitors of lactate dehydrogenase

Abstract

Metal complex-protein interaction is an evolving concept for determining cellular targets of metallodrugs. Lacatate dehydrogenase (LDH) is critically implicated in tumor growth and therefore, considered to be an important target protein for anti-tumor metal complexes. Due to efficient biocompatibility of copper (Cu(2+)) and zinc (Zn(2+)), we synthesized CubpyAc(2) . H(2)O (Cu-bpy) and ZnbpyAc(2) . H(2)O (Zn-bpy; where bpy = 2,2' bipyridine, Ac = CH(3)COO(-)) complexes and evaluated their interaction with and modulation of LDH in mouse tissues. The increasing concentration of both the complexes showed a significant shift in UV-Vis spectra of LDH. The binding constant data (Kc = 1 x 10(3) M(-1) for Cu-bpy and 7 x 10(6) M(-1) for Zn-bpy) suggested that Zn-bpy-LDH interaction is stronger than that of Cu-bpy-LDH. LDH modulating potential of the complexes were monitored by perfusing the mice tissues with non-toxic doses of Cu-bpy and Zn-bpy followed by activity measurement and analysis of LDH isozymes on non-denaturing polyacrylamide gel electrophoresis (PAGE). As compared to the control sets, Cu-bpy caused a significant decline (P < 0.05-0.001) in the activity of LDH in all the tissues studied. However, Zn-bpy showed inhibition of LDH only in liver (P < 0.01), kidney (P < 0.001) and heart (P < 0.01), but with no effect in spleen, brain and skeletal muscle tissues. PAGE analysis suggested that all the five LDH isozymes are equally sensitive to both the complexes in the respective tissues. The results suggest that Cu- and Zn-bpy are able to interact with and inhibit LDH, a tumor growth supportive target protein at tissue level.