二-2-吡啶酮缩氨基硫脲表现出显着的抗癌功效，促使 DpC 进入临床试验。然而，DpC 会诱导有害的氧合肌红蛋白氧化，从而抑制发育。为了解决这个问题，制备了新型取代苯基缩氨基硫脲 (PPP4pT) 类似物及其 Fe(III)、Cu(II) 和 Zn(II) 配合物。 PPP4pT 类似物表现出有效的抗增殖活性（IC50：0.009-0.066 μM），其中 1:1 Cu:L 复合物显示出最大功效。导致 PPP4pT:Cu(II) 复合物氧化还原电位降低的取代与较高的抗增殖活性相关，而电位的增加与氧化还原活性的增加相关。令人惊讶的是，氧化还原活性和抗增殖功效之间没有相关性。 PPP4pT:Fe(III) 复合物比临床试验的缩氨基硫脲、Triapine、COTI-2 和 DpC 或早期的缩氨基硫脲系列更能显着减弱氧肌红蛋白氧化。苯基和苯乙烯基取代基的掺入导致空间封锁，防止 PPP4pT:Fe(III) 配合物接近血红素平面及其氧化。 1:1 Cu(II):PPP4pT 复合物对金属转移呈惰性，不会诱导氧-肌红蛋白氧化。

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 (IC50: 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.