Designing Tailored Thiosemicarbazones with Bespoke Properties: The Styrene Moiety Imparts Potent Activity, Inhibits Heme Center Oxidation, and Results in a Novel Stealth Zinc(II) Complex?

A novel, potent, and selective antitumor agent, 3-thiosemicarbazone (PPP44mT), and its analogues were synthesized and characterized and displayed strikingly distinctive properties. This activity was mediated by the inclusion of a styrene moiety, which through steric and electrochemical mechanisms prevented deleterious oxy-myoglobin or oxy-hemoglobin oxidation relative to other potent thiosemicarbazones, i.e., di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thio semicarbaz one (DpC) or di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). Structure-activity relationship analysis demonstrated specific tuning of PPP44mT electrochemistry further inhibited oxy-myoglobin or oxy-hemoglobin oxidation. Both PPP44mT and its Cu(II) complexes showed conspicuous almost immediate cytotoxicity against SK-N-MC tumor cells (within 3 h). In contrast, [Zn(PPP44mT)2] demonstrated a pronounced delay in activity, taking 48 h before marked antiproliferative efficacy was apparent. As such, [Zn(PPP44mT)2] was designated as a stealth Zn(II) complex that overcomes the near immediate cytotoxicity of PPP44mT or its copper complexes. Upon examination of the suppression of oncogenic signaling, [Zn(PPP44mT)2] was superior at inhibiting cyclin D1 expression compared to DpC or Dp44mT.

Automated summary

A novel and selective antitumor agent, 3-thiosemicarbazone (PPP44mT), and its analogues with distinctive properties were synthesized and characterized. The inclusion of a styrene moiety prevented the oxidation of oxy-myoglobin or oxy-hemoglobin, which is different from other potent thiosemicarbazones such as DpC or Dp44mT. PPP44mT and its Cu(II) complexes exhibited immediate cytotoxicity against SK-N-MC tumor cells, while [Zn(PPP44mT)2] showed delayed antiproliferative efficacy and superior inhibition of cyclin D1 expression compared to DpC or Dp44mT.