Concerning the role of zinc in the antitumor activity of 3-ethoxy-2-oxobutyraldehyde bis(thiosemicarbazonato) zinc(II) and related chelates

Abstract

The pH-dependent stability constants for several bis(thiosemicarbazonato) zinc(II) and copper(II) complexes have been measured. The zinc chelates are very much less stable than the copper complexes. This is reflected in their stabilities in plasma and ascites tumor fluid. While the copper complexes are undissociated, 3-ethoxy-2-oxobutyraldehyde bis(thiosemicarbazonato) zinc(II) (ZnKTS) and its N 4-methylthiosemicarbazone derivative are nearly completely dissociated in plasma and only somewhat less in ascites fluid. However, 3-ethoxy-2-oxobutyraldehyde bis( N 4-dimethylthiosemicarbazonato) zinc(II) is stable in each medium in accord with its larger stability constant. The free ligands approach a similar final state of zinc chelation as their corresponding zinc chelates. In neither medium is copper unequivocally bound by the ligands. These results are used to assess the importance of ZnKTS in the mechanism of cytotoxicity in vivo and to rationalize the large variation in cytotoxicity observed in vitro with these zinc complexes.