Isosteric Replacement of Sulfur to Selenium in a Thiosemicarbazone: Promotion of Zn(II) Complex Dissociation and Transmetalation to Augment Anticancer Efficacy

Abstract

We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) to create a selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl and styryl moieties to sterically inhibit the approach of their Fe­(III) complexes to the oxy-myoglobin heme plane. Importantly, in contrast to the Fe­(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe­(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. Furthermore, PPTP4c4mSe demonstrated more potent antiproliferative activity than the homologous thiosemicarbazone, PPTP4c4mT, with their selectivity being superior or similar, respectively, to the clinically trialed thiosemicarbazone, COTI-2. An advantageous property of the selenosemicarbazone Zn­(II) complexes relative to their thiosemicarbazone analogues was their greater transmetalation to Cu­(II) complexes in lysosomes. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.