Dipartimento di Scienze Biomediche, Università di Padova , via Ugo Bassi 58/b, 35131 Padova, Italy.
J Med Chem. 2014 Nov 13;57(21):8849-59. doi: 10.1021/jm5013165. Epub 2014 Oct 28.
Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (1, FcOH; 2, FcOHTAM) and of their corresponding quinone methides (QMs), 1-QM, and 2-QM, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC50 ≈ 2.5 μM) than the hydroxyferrocifens (IC50 ≈ 15 μM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both 2 and 2-QM inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while 1 and 1-QM were scarcely effective. This difference of behavior was ascribed to the competitive conversion of 1-QM to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of 1 and 2 in cancer cells.
许多抗癌化合物是硫氧还蛋白还原酶（TrxR）的强抑制剂，TrxR 是参与细胞氧化还原调节的硒酶。本研究考察了两种羟基二茂铁（1，FcOH；2，FcOHTAM）及其相应的醌甲基化物（QMs）1-QM 和 2-QM 对这些酶的影响。在体外，两种 QMs 都是比羟基二茂铁（IC50≈15 μM）更强的 TrxR 抑制剂（IC50≈2.5 μM）。这种抑制是由于 TrxR 的倒数第二个硒代半胱氨酸残基与 QMs 发生迈克尔加成反应所致。在 Jurkat 癌细胞中，2 和 2-QM 以相同的比例抑制 TrxR，导致硫氧还蛋白的氧化形式积累，而 1 和 1-QM 则几乎没有效果。这种行为差异归因于 1-QM 在质子介质中竞争性转化为无活性的茚。这组实验首次证实了二茂铁醌甲基化物在几个生物靶标上的作用，并为这些效应提供了分子基础。它还突出了 1 和 2 在癌细胞中的作用机制的差异。
