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Synthesis and biological evaluation of new inhibitors of thioredoxin - thioredoxin reductase.

Szymon Kłossowski 1Izabela Ziuzia 1Angelika Szokalska 2Marta Swiech 2Jakub Golab 2Ryszard Ostaszewski 1

1. Institute of Organic chemistry of the Polish Academy of Sciences (ICHOPAS), Kasprzaka 44/52, Warsaw 01-224, Poland
2. Medical University of Warsaw, Banacha 1, Warsaw 02-097, Poland


     Thioredoxin system (TR) is responsible for regulating redox state in cell. The system is based on two enzymes: thioredoxin and thioredoxin reductase. Thioredoxin helps tumor to manage oxidative stress, the side effect of very quick proliferation.1  Inhibition of the thioredoxin system will damage this defense system what may sensitize cells to other chemotherapeutics. Some TR inhibitor, such as PX-12, are currently clinically tested in solid tumor therapies.2

    In active site of both enzymes there are two cysteine residues which are oxidized or reduced in the disulfide bond formation manner.3 Those cysteines can be covalently alkylated by alkylating agents i.ex. compound 1.Alkylated residues are no longer able to create disulfide bond and enzyme activity is blocked. Although 1 inhibits TR in very low concentration, it cannot act as a drug, because of high reactivity and low selectivity.  
In our work, to increase the selectivity we have incorporated an electrophilic fragment of compound 1 into peptidemimetic scaffold, using Ugi reaction as a key step. The result of this studies and their biological evaluation of those new inhibitors will be presented.

1.  Tonissen K. F., Trapani D.G., Mol. Nutr. Food. Res., 2009, 53, 87 -103
2.  Kirkpatrick, D. L., Kuperus, M., Dowdeswell, M., Potier, N., Biochem.Pharmacol. 1998,     55, p. 987 –994.
3. Gromer S., Urig S., Becker K.Med. Res. Rev., 2004 24, 1, p. 40-89


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Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Szymon Kłossowski
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Submitted: 2010-03-15 10:13
Revised:   2010-03-15 10:13