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, 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.

本研究合成并表征了一种新型、强效且选择性优异的抗肿瘤剂——(E)-3-苯基-1-(2-吡啶基)-2-丙烯-1-酮4,4-二甲基-3-硫代半卡巴腙（PPP44mT）及其类似物，二者均展现出极为独特的生物学特性。该抗肿瘤活性源于苯乙烯基团的引入：相较于其他强效硫代半卡巴腙类化合物（即二(2-吡啶基)甲酮-4-环己基-4-甲基-3-硫代半卡巴腙（DpC）与二(2-吡啶基)甲酮-4,4-二甲基-3-硫代半卡巴腙（Dp44mT）），该基团可通过空间位阻与电化学机制，避免氧合肌红蛋白与氧合血红蛋白发生有害氧化。构效关系分析显示，对PPP44mT的电化学特性进行特异性调控，可进一步抑制上述两种蛋白的氧化过程。PPP44mT及其铜(II)配合物对SK-N-MC肿瘤细胞均展现出显著的快速细胞毒性，可在3小时内发挥杀伤作用。与之相反，二(PPP44mT)合锌(II)配合物（[Zn(PPP44mT)₂]）的活性则表现出显著延迟性，需历经48小时方可显现出明显的抗增殖效能。基于此，该锌(II)配合物被定义为"隐形锌(II)配合物"，可规避PPP44mT及其铜配合物所具备的快速细胞毒性。在对致癌信号通路抑制作用的考察中，二(PPP44mT)合锌(II)配合物在抑制细胞周期蛋白D1表达方面，效果优于DpC与Dp44mT。