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


Legal notice
  • Legal notice:

    Copyright (c) Pielaszek Research, all rights reserved.
    The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
    In every case, proper references including Author(s) name(s) and URL of this webpage: must be provided.


Related papers
  1. Studies towards stereoselective bionanocatalysis on gold nanoparticles
  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
  5. Synthesis of novel, thioredoxin - thioredoxin reductase inhibitors
  6. Selective monoacylation of alkane-α,ω-diols using crude acetone powders of animal tissues
  7. Synthesis of novel, peptidic kinase inhibitors with cytotoxic activity
  8. First attempts at the enzyme-promoted hydrolysis of N-acyl phosphonoamides

Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Szymon Kłossowski
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-15 10:13
Revised:   2010-03-15 10:13