Advantages of Novel Anti-cancer Selenosemicarbazones: Preferential Reactivity of Their Fe(III), Cu(II), and Zn(II) Complexes with Key Physiological Reductants/Ligands Versus Isosteric Thiosemicarbazones

Fe(III) complexes of clinically trialed thiosemicarbazones demonstrate deleterious oxy-myoglobin and oxy-hemoglobin oxidation. Therefore, the PPP4pSe selenosemicarbazone analogues were designed with several PPP4pSe Fe(III) complexes completely preventing deleterious oxy-myoglobin oxidation. This was ascribed to the decreased potentials of their Fe(III) complexes and steric hindrance effects. The Fe(III), Cu(II), and Zn(II) complexes of PPP4pSe demonstrated greater reactivity with physiological reductants/ligands (glutathione, l-cysteine, or l-ascorbate), than respective complexes of the isosteric thiosemicarbazone, PPP4pT. Considering this: (1) [Fe(PPP4pSe)₂]⁺ demonstrated increased reduction relative to [Fe(PPP4pT)₂]⁺ with glutathione and l-cysteine, while l-ascorbate led to comparable reduction; (2) glutathione led to complete dissociation of [Zn(PPP4pSe)₂], while incomplete dissociation of [Zn(PPP4pT)₂] occurred; and (3) [Cu(PPP4pSe)Cl] demonstrated complete coordinate sphere substitution with glutathione, l-cysteine, and l-ascorbate, whereas [Cu(PPP4pT)Cl] demonstrated partial substitution. The role of glutathione in all three latter reactions is significant, given the greater reactivity of the selenosemicarbazone, and glutathione's key role in selenosemicarbazone and thiosemicarbazone anticancer activity.