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Molecular Pharmacology, Vol 13, 89-98, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Studies of the Reaction of 2-Formylpyridine Thiosemicarbazone and Its Iron and Copper Complexes with Biological Systems

WILLIAM ANTHOLINE 1, JUDITH KNIGHT 1, HARRY WHELAN 1, and DAVID H. PETERING 1

1 Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201

The interactions of 2-formylpyridine thiosemicarbazone with various biochemical systems have been studied to understand the potential behavior of this antitumor agent in vivo. This ligand removes iron from ferritin to form the iron(III) complex. The complex is rapidly reduced by hemoglobin and is only slowly reoxidized by oxygen in aqueous solution or plasma. Both the iron(III) and iron(II) chelates are stable in plasma. These results suggest that the iron(II) complex exists in vivo. However, the thermodynamic stability of the copper complex is also consistent with its formation in biological systems. Electron paramagnetic resonance spectra show that in plasma two adduct species of the copper complex form. One of these may involve histidine. Reaction of the ligand or its iron, copper, or zinc complex with the assay mixture used for ribonucleoside diphosphate reductase produces in each case the iron(II) complex of the ligand. These results are used to interpret a number of observations on the physiological effects of agr-N-formyl heterocyclic thiosemicarbazones as well as some features of the inhibition of ribonucleoside diphosphate reductase by these compounds.

Submitted on March 10, 1976
Accepted on August 16, 1976




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Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics