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”
Mahendiran Dharmasivam, Büşra Kaya, Tharushi P. Wijesinghe, Mahan Gholam Azad, Miguel A. Gonzálvez, Mohammad Hussaini, Jason Chekmarev, Paul V. Bernhardt, Des R. Richardson
Abstract
A novel, potent, and selective antitumor agent, namely ( E )-3-phenyl-1-(2-pyridinyl)-2-propen-1-one 4,4-dimethyl-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-thiosemicarbazone (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.