Bioorganic & Medicinal Chemistry 2011-01-01

Hypericins and thioredoxin reductase: Biochemical and docking studies disclose the molecular basis for effective inhibition by naphthodianthrones.

Francesca Sorrentino, Anastasia Karioti, Paola Gratteri, Maria Pia Rigobello, Guido Scutari, Luigi Messori, Alberto Bindoli, Matteo Chioccioli, Chiara Gabbiani, Maria Camilla Bergonzi, Anna Rita Bilia

Index: Bioorg. Med. Chem. 19 , 631-41, (2011)

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Abstract

Cytosolic (TrxR1) and mitochondrial (TrxR2) thioredoxin reductases experience pronounced concentration- and time-dependent inhibition when incubated with the two naphthodianthrones hypericin and pseudohypericin. Pseudohypericin turned out to be a quite strong inhibitor of TrxR1 (IC(50)=4.40μM) being far more effective than hypericin (IC(50)=157.08μM). In turn, the IC(50) values measured toward TrxR2 were 7.45μM for pseudohypericin and 43.12μM for hypericin. When compared to pseudohypericin, the inhibition caused by hypericin usually required significantly longer times, in particular on TrxR1. These important differences in the inhibitory potencies and profiles were analysed through a molecular modeling approach. Notably, both compounds were found to accommodate in the NADPH-binding pocket of the enzyme. The binding of the two naphthodianthrones to thioredoxin reductase seems to be particularly strong as the inhibitory effects were fully retained after gel filtration. Also, we found that TrxR inhibition by hypericin and pseudohypericin does not involve the active site selenol/thiol motif as confirmed by biochemical and modeling studies. The resulting inhibition pattern is very similar to that produced by the two naphthodianthrones on glutathione reductase. As the thioredoxin system is highly overexpressed in cancer cells, its inhibition by hypericin and pseudohypericin, natural compounds showing appreciable anticancer properties, might offer new clues on their mechanism of action and open interesting perspectives for future tumor therapies.Copyright © 2010 Elsevier Ltd. All rights reserved.