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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2. Studies toward Novel Peptidomimetc Inhibitors of Thioredoxin-Thiredoxin Reductase System
3. Synthesis of marker compounds for detailed explanation the mechanism of anticancer activity of peptidomimetics with β-acyloxymethacrylic fragment
4. Chemoenzymatic approach to the synthesis of bioactive tripeptide mimetics for treatment of cancer
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7. Synthesis of novel, peptidic kinase inhibitors with cytotoxic activity
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