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

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.