期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 21, 页码 8849-8859出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5013165
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资金
- COST Actions [CM1105, CM1106]
- Minister dell'Istruzione, Universita e Ricerca (MIUR) Italy [PRIN 20107Z8XBW]
- University of Padova (Italy) [CPDA130272]
- Agence Nationale de la Recherche [ANR-10-BLAN-706]
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 mu M) than the hydroxyferrocifens (IC50 15 mu M). 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.
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