Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure-Activity Relationships of the Novel PPP4pT Series.

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe(III), Cu(II), and Zn(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC 50 : 0.009-0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe(III) complexes to the heme plane and its oxidation. The 1:1 Cu(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation.